Transcatheter Aortic Valve Replacement With the Medtronic Transcatheter Aortic Valve Replacement System In Patients at Low Risk for Surgical Aortic Valve Replacement
Phase: NA
Conditions: Aortic Valve Stenosis
Sponsor: Medtronic Cardiovascular

 
                    Coronary and Structural Heart Clinical 
 
CIP: Medtronic TAVR in Low Risk Patients                                 Medtronic Confidential 
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Transcatheter Aortic Valve Replacement 
With the Medtronic Transcatheter Aortic Valve Replacement System 
In Patients at Low Risk for Surgical Aortic Valve Replacement 
 
Clinical Investigational Plan 
Document Number: 10234430DOC 
Revision: 1J  
16-JUL-2018 
Global Sponsor:  
 
 
 
 
Medtronic 
Coronary and Structural Heart Clinical 
 
 
 
 
 
 
 
 
 
8200 Coral Sea St NE, MVS 66 
 
 
 
 
 
 
 
 
 
Mounds View, MN 55112 
 
 
 
 
 
 
 
 
 
United States 
 
 
 
 
 
 
 
 
 
 
Regional Sponsor: Europe  
 
 
Medtronic Bakken Research Centre BV 
Coronary and Structural Heart Department 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Regional Sponsor: Australia 
 
 
Medtronic Australasia Pty Ltd 
                          New Zealand 
 
 
2 Alma Road, Macquarie Park 
NSW 2113 
Australia 
 
Medtronic New Zealand Ltd 
Level 3, Building 5, 666 Great South Road 
Penrose, Auckland 1051 
New Zealand 
 
Regional Sponsor: Canada  
 
 
Medtronic of Canada Ltd. 
99 Hereford St., Brampton 
ON, L6Y 0R3, 
Canada 
800-217-1617 
 
Regional Sponsor: Japan  
 
 
Medtronic Japan Co., Ltd. 
1-2-70 Konan , Minato-ku  
Tokyo 108-0075  
Japan 
 
CONFIDENTIAL and PROPRIETARY 
This document contains confidential information and is solely the property of Medtronic. Acceptance of this document constitutes an agreement 
by the recipient that no unpublished information contained herein will be published or disclosed without the prior written approval of Medtronic. 
This document may be disclosed to the appropriate Institutional Review Board (IRB) or Ethics Committee (EC) with the stipulation that the IRB/EC 
treats the information contained herein as the confidential property of Medtronic. 
 

 
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Version History 
 
Version 
Summary of Changes 
Author(s)/Title 
1A 
Not Applicable, New Document 
Charles Boldt/Sr Clinical 
Research Manager 
Sharla Chenoweth, Sr 
Principal Statisician 
Hongyan Qiao, Principal 
Statisician 
Michael Boulware, 
Clinical Research 
Manager 
1B 
Revised to incorporate feedback from FDA on 12 February 2016. 
1. Clarfied sample size is up to 1256 subjects 
2. Added statement to informed consent template regarding long term 
durability of TAVR 
Charles Boldt/Sr Clinical 
Research Manager 
Sharla Chenoweth, Sr 
Principal Statisician 
1C 
1. Added EuroQol (EQ-5D) instrument to assess health-related quality of 
life at one year 
2. Extended follow-up duration from 5 years to 10 years 
3. Added exclusion criterion for “significant aortopathy requiring ascending 
aortic replacement” 
4. Revised AS severity criteria to clarify that AVA, mean gradient, and max 
aortic velocity should be by TTE 
5. Added inclusion criteria for asymptomatic patients with severe AS and 
LVEF < 50% 
6. Reduced interval from PCI with BMS to randomization to 30 days 
7. Added clause to clarify subjects with BAV after qualifying echo must 
meet AS severity criteria at time of submission to screening committee 
8. Revised analysis section to indicate rates of prosthetic valve 
endocarditis, prosthetic valve thrombosis, all stroke, life-threatening 
bleed, and valve-related dysfunction requiring repeat procedure will be 
provided at 30 days, 6 months, 12 months, and annually thereafter 
through 10 years 
9. Corrected typographical errors in Table 16 (Parameters for grading of 
aortic regurgitation) 
10. Deleted role of legal representative (as vulnerable subjects are not 
allowed) 
11. Added name of investigational device manufacturer, number of 
investigational devices, description of comparator device, and 
description of expectation for maintanence of equipment 
12. Revised definition of adverse event relationships to be consistent with 
MEDDEV 2.7/3, revision 3 (May 2015) 
13. Renamed “LVOT/Aortic Valve velocity ratio to “Doppler Velocity Index” 
14. Revised AE reporting requirements to require reporting of only SAE and 
deviced-related AE after subject has completed his/her 2 year follow-up 
15. Clarified that index PCI should be performed at study center, and PCI 
operators to be considered sub-investigators. 
16. Modified the data analysis section to add analysis sets for “as treated” 
and “per protocol” 
17. Sample size was changed to 1200 (previous is 1256 for mITT) for the AT 
sets for consistency. 
18. Added Evolut 34R TAV size to the description of investigational devices 
Charles Boldt/Sr Clinical 
Research Manager 
Hongyan Qiao, Principal 
Statistician 
Jessica Halverson, 
Clinical Research 
Manager 
 

 
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19. Revised Intended Use statement (Section 2.3) to indicate trial data 
intended to support expanded indication to low risk patients. 
1D 
1. Incorporated Medtronic TAVR 2.0 Devices 
2. Increased investigational sites to up to 100 
3. Clarified that the <3% predicted risk of mortality at 30 days is per 
multidisciplinary local heart team assessment and not the STS score 
4. Clarified that revascularization decision during screening for 
stratification is determined by need for revascularization during SAVR 
5. Removed the collection of cardiac enzymes 
6. Added Health Economic Data Collection Language 
7. Incorporated the Clinical Investigation Plan Addendum, Version 1A 
(10577419DOC Rev 1A) 
8. Incorporated the Clinical Investigation Plan Addendum; Australia/New 
Zealand, Version 1A (10581435DOC Rev 1A) 
9. Added Qualify of Life Questionairre Appendix 
10. Removed Report of Prior Investigations 
11. Corrected a typo in section 3.3.3.2.2 “…the additional outcome 
measures of NYHA and quality of life will use the AT set” 
12. Clarified that surgical bioprostheses in the control arm must be 
commercially available in both the United States and the geography in 
which the study center is located. 
13. Updated grammatical and formatting issues throughout the document 
Lisa Slusser/Sr. Clinical 
Research Specialist 
1E 
1. Increased LTI sites to up to 50 worldwide 
Lisa Slusser/Sr. Clinical 
Research Specialist 
1F 
1. Added Japan regional sponsor address 
2. Clarified echocardiography inclusion criteria must be at rest 
3. Added Japan for investigation sites and regions 
4. Section 2.0 Background was updated with recent information 
5. Added TAVR Implant Team definition 
6. Added and enrolled to Screening Population once a patient provides 
informed consent 
7. Added Intervention/repair of the mitral and/or tricuspid valve is only 
allowed during the SAVR procedure, but there must be no intent to 
perform the intervention/repair prior to the implant 
8. Separated baseline assessments to clarify which are required prior to 
screening submission and which are required prior to the index 
procedure 
9. Clarified the discharge window 
10. Clarified that MRS assessment should be performed with any suspected 
or confirmed stroke event 
11. Clarified that in countries where required, specifically the United States 
and Japan, the local heart team’s interventional cardiologist(s) and 
cardiac surgeon(s) must jointly participate in the intra-operative 
technical aspects of the TAVR procedure 
Lisa Slusser/Sr. Clinical 
Research Specialist 
Morgan Lillehei/Clinical 
Research Specialist 

 
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12. Added Name of secondary operator to TAVR Implant Procedure data 
collection 
13. Added Name of primary surgeon to SAVR Implant Procedure data 
collection 
14. Added commercial use for Evolut 34 mm devices if investigational 
devices are unavailable 
15. Removed CEC and DSMB from Appendix VII (Leaflet 
Thickening/Immobility Sub-Study Protocol), section 4.10 
16. Removed CoreValve 31 mm System 
17. Removed the three year signature requirement for CVs 
18. Updated Table 11 as requested by competent authority in Switzerland 
19. Added the French Addendum reference in Section 3.3.5 
20. Added applicable regulations for Japan 
21. Added Japan monitoring requirements 
22. Added to section 3.3.29.4 - “Copies of source documents will be 
requested to support event adjudication by the Clinical Events 
Committee. In Japan, availability of source documentation may be 
limited due to hospital policies. If a specific source document is not 
available, necessary information may be transcribed onto the relevant 
CRF page.”   
23. Clarified subclavian access diameter requirements for eligibility criteria 
#30 
24. Sample size language was changed from “up to” to “at least” 1200 
subjects and “at least 300 evaluable subjects (150 TAVR and 150 SAVR)” 
in the LTI Sub-Study, allowing randomization up to 1400 subjects to 
complete the LTI Sub-Study and Japan enrollment requirements. 
25. Increased LTI sites to “up to 100 globally” 
26. In APPENDIX VII section 4.11 statistical analysis, “the frequencies and 
95% confidence intervals of” was deleted based on FDA’s suggestion. 
27. Updated 3-year to 10-year annual visit windows to a +/- 60-day window 
28. Added unscheduled visit criteria 
29. Incorporated the EnVeo PRO delivery catheter system and EnVeo PRO 
loading system for the Evolut R and TAVR 2.0 systems and Incorporated 
the EnVeo R delivery system for the TAVR 2.0 system 
30. Removal of anticoagulation as an exclusion for the LTI Sub-Study 
31. Removal of The Australian Clinical Study Handbook reference 
 
 
1G 
1. The allowance of randomized subjects was increased to up to 1540 
subjects 
Morgan Lillehei/Clinical 
Research Specialist 
1H 
1. Updated TAVR 2.0 to Evolut PRO to align with IFU 
2. Added an additional interim analysis at the time when 850 subjects have 
had the chance to be followed for 12 months 
3. Removed clinical assessments and echocardiographic exams for 6, 8, and 
9 year visits 
Morgan Lillehei / 
Clinical Research 
Specialist 

 
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4. Changed the 6-month visit follow-up window to 183 to 213 days after 
the subject’s index procedure 
5. Corrected the Enveo PRO product number (Table 15) for the 23 mm 
Evolut PRO valve 
1J 
1. Removed the language of stopping subject accrual associated with 
the  timing of the first interim analysis. 
2. Added Section 3.3.3.7 Multiplicity Considerations and clarified the 
primary endpoint superiority testing order. 
3. Made formatting changes to Sections 3.3.3.5 and 3.3.3.6 to 
remove numbering of each endpoint. Additionally, removed 
Section 3.3.3.7 title “Additional Outcome Measures” to clarify all 
secondary effectiveness endpoints. 
Hongyan Qiao, PhD / 
Sr. Principal Statistician 
Medtronic approvals are maintained in an electronic document control system. 
 

 
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Contents 
1.0 SYNOPSIS.................................................................................................................................... 12 
2.0 PURPOSE ..................................................................................................................................... 15 
2.1 
Background and Rationale ...................................................................................................... 15 
2.2 
Medtronic Transcatheter Aortic Valve Replacement System ..................................................... 17 
2.2.1 
Evolut R system .......................................................................................................... 17 
2.2.2 
Medtronic  Evolut PRO System.................................................................................... 17 
2.3 
Intended Use .......................................................................................................................... 18 
2.4 
Trial Objectives...................................................................................................................... 19 
2.4.1 
Primary Objective ....................................................................................................... 19 
2.4.2 
Exploratory Objective.................................................................................................. 19 
2.5 
Trial Endpoints ...................................................................................................................... 19 
2.5.1 
Primary Safety and Effectiveness Endpoint ................................................................... 19 
2.5.2 
Secondary Safety Endpoints ......................................................................................... 19 
2.5.3 
Secondary Effectiveness Endpoints .............................................................................. 19 
2.7 
Rationale for Selection of Trial Endpoints................................................................................ 20 
3.0 TRIAL PROTOCOL ...................................................................................................................... 21 
3.1 
Ethics and Regulatory Compliance .......................................................................................... 21 
3.1.1 
Applicable Regulations ................................................................................................ 21 
3.1.2 
Institutional Review Board and Ethics Committee ......................................................... 21 
3.1.3 
Regulatory Submissions............................................................................................... 22 
3.1.4 
Ethical Conduct of the Trial ......................................................................................... 22 
3.2 
Trial Organization .................................................................................................................. 23 
3.2.1 
Investigational Sites..................................................................................................... 23 
3.2.2 
Trial Site Investigative Team Members......................................................................... 23 
3.2.2.1 
Site Co-Principal Investigators ..................................................................................... 23 
3.2.2.2 
Heart Team ................................................................................................................. 23 
3.2.2.3 
TAVR Implant Team ................................................................................................... 24 
3.2.2.4 
Echocardiographer ...................................................................................................... 24 
3.2.2.5 
Trial Coordinator......................................................................................................... 24 
3.2.2.6 
Cardiovascular Imaging Specialist ................................................................................ 24 
3.2.3 
Screening Committee .................................................................................................. 24 
3.2.4 
Publication Committee ................................................................................................ 24 
3.2.5 
Clinical Investigational Agreement and Financial Disclosure ......................................... 25 
3.2.6 
Curriculum Vitae......................................................................................................... 25 

 
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3.2.7 
Trial Training.............................................................................................................. 25 
3.3 
Methodology.......................................................................................................................... 25 
3.3.1 
Patient Population ....................................................................................................... 25 
3.3.2 
Trial Design ................................................................................................................ 25 
3.3.3 
Statistical Aspects ....................................................................................................... 26 
3.3.3.1 
Historical Data ............................................................................................................ 26 
3.3.3.2 
Analysis Sets............................................................................................................... 27 
3.3.3.3 
Description of Baseline Variables ................................................................................. 27 
3.3.3.4 
Primary Objective ....................................................................................................... 27 
3.3.3.4.1 
Hypothesis of Non-inferiority....................................................................................... 28 
3.3.3.4.2 
Randomization ............................................................................................................ 28 
3.3.3.4.3 
Sample Size and Analysis ............................................................................................ 28 
3.3.3.5. 
Secondary Safety Endpoints ......................................................................................... 29 
3.3.3.6 
Secondary Effectiveness Endpoints .............................................................................. 29 
3.3.3.7 Multiplicity Considerations ................................................................................................. 30 
3.3.3.7.1 Ordered List of Secondary Objectives to be Tested to Support Labeling Claims ................... 31 
3.3.3.8 
Missing Data............................................................................................................... 32 
3.3.3.9 
LTI Analysis ............................................................................................................... 33 
3.3.4 
Number of Subjects and Investigational Devices, Trial Duration .................................... 33 
3.3.5 
Subject Selection Criteria............................................................................................. 33 
3.3.5.1 
Inclusion Criteria......................................................................................................... 33 
3.3.5.2 
Exclusion Criteria........................................................................................................ 34 
3.3.6 
Informed Consent ........................................................................................................ 35 
3.3.7 
Revisions in Patient Information and Informed Consent Form ........................................ 35 
3.3.8 
Screening, Enrollment, and Randomization ................................................................... 36 
3.3.9 
Required Evaluations................................................................................................... 39 
3.3.10 
Post-Implant Anti-thrombotic Therapy.......................................................................... 42 
3.3.11 
Subject Disposition...................................................................................................... 42 
3.3.12 
Implant Procedure (TAVR) .......................................................................................... 43 
3.3.13 
Implant Procedure (SAVR) .......................................................................................... 44 
3.3.14 
Clinical Assessment..................................................................................................... 44 
3.3.15 
Echocardiography ....................................................................................................... 44 
3.3.16 
Missed Follow-up Visits .............................................................................................. 45 
3.3.17 
Unscheduled Follow-up Visits...................................................................................... 45 
3.3.18 
Protocol Deviations ..................................................................................................... 46 

 
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3.3.19 
Trial Materials and Trial Specific Equipment ................................................................ 47 
3.3.20 
Device Accountability ................................................................................................. 47 
3.3.21 
Device Malfunction or Explant..................................................................................... 48 
3.3.22 
Subject Withdrawal or Discontinuation ......................................................................... 48 
3.3.23 
Early Suspension or Termination of the Trial ................................................................ 49 
3.3.24 
Early Suspension or Termination of a Trial Site............................................................. 49 
3.3.25 
Revisions or Amendments to the Clinical Investigational Plan........................................ 49 
3.3.26 
Adverse Events, Adverse Device Effects, and Device Deficiencies ................................. 50 
3.3.26.1 
Definitions .................................................................................................................. 50 
3.3.26.2 
Evaluation and Documentation of Adverse Events and Device Deficiencies .................... 51 
3.3.26.3 
Anticipated Adverse Events ......................................................................................... 53 
3.3.26.4 
Adverse Event Reporting Requirements for Clinical Sites .............................................. 54 
3.3.26.5 
Documentation and Reporting of Device Deficiencies ................................................... 54 
3.3.26.6 
Emergency Contact Details for Reporting SAE, SADE, UADE, and Device Deficiencies 55 
3.3.27 
Clinical Events Committee........................................................................................... 55 
3.3.28 
Data Safety Monitoring Board...................................................................................... 55 
3.3.29 
Role of Sponsor Representatives .................................................................................. 56 
3.3.30 
Data and Quality Management Procedures .................................................................... 56 
3.3.30.1 
Data Collection ........................................................................................................... 56 
3.3.30.2 
Time Windows for Completion and Submission of eCRFs ............................................. 57 
3.3.30.3 
Data Review and Processing ........................................................................................ 57 
3.3.30.4 
Source Documents....................................................................................................... 57 
3.3.30.5 
Subject Confidentiality ................................................................................................ 58 
3.3.31 
Records and Reports .................................................................................................... 58 
3.3.31.1 
Responsibilities of the Investigator ............................................................................... 58 
3.3.31.2 
Responsibilities of the Sponsor..................................................................................... 63 
3.3.31.3 
Record Retention......................................................................................................... 72 
3.3.31.4 Additional Contact Information ......................................................................................... 72 
4.0 RISK/BENEFIT ANALYSIS ......................................................................................................... 73 
4.1 
Description of Risk Analysis ................................................................................................... 73 
4.2 
Risks ..................................................................................................................................... 73 
4.3 
Measures to Mitigate Risks to Trial Subjects ............................................................................ 75 
4.4 
Benefits ................................................................................................................................. 75 
4.5 
Alternatives ........................................................................................................................... 75 

 
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4.6 
Results from the Risk Analysis and Justification for the Trial .................................................... 75 
5.0 DESCRIPTION OF INVESTIGATIONAL DEVICES ..................................................................... 77 
5.1 
Evolut R System..................................................................................................................... 77 
5.1.1 
Evolut R TAV ............................................................................................................. 78 
5.1.2 
EnVeo R Catheter Delivery System with EnVeo InLine Sheath ...................................... 79 
5.1.3 
EnVeo PRO Catheter Delivery System ......................................................................... 79 
5.1.4 
EnVeo R Loading System ............................................................................................ 82 
5.1.5 EnVeo PRO Loading System ................................................................................................. 83 
5.2 Medtronic Evolut PRO System ..................................................................................................... 86 
5.2.1 Medtronic Evolut PRO Transcatheter Aortic Valve ................................................................. 88 
5.2.2 Medtronic Evolut PRO Delivery Catheter System.................................................................... 88 
5.2.3 
EnVeo R Catheter Delivery System with EnVeo InLine Sheath ...................................... 88 
5.2.4 EnVeo PRO Delivery Catheter System ................................................................................... 89 
5.2.5 Medtronic Evolut PRO Loading System ................................................................................. 89 
5.2.6 EnVeo PRO Loading System ................................................................................................. 90 
5.3 
Manufacturer of the Investigational Devices............................................................................. 90 
5.4 
Comparator Devices ............................................................................................................... 90 
6.0  MONITORING AND AUDITING................................................................................................. 91 
6.1 
Monitoring............................................................................................................................. 91 
6.2 
Auditing ................................................................................................................................ 91 
6.3 
Trial Closure .......................................................................................................................... 91 
7.0 LABELING................................................................................................................................... 92 
8.0 CONSENT MATERIALS .............................................................................................................. 92 
9.0 INVESTIGATOR BROCHURE AND REPORT OF PRIOR INVESTIGATIONS............................. 92 
10.0 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE INFORMATION ............................. 92 
11.0 OTHER INSTITUTIONS AND PROFESSIONAL SERVICES........................................................ 92 
12.0 PUBLICATION POLICY .............................................................................................................. 92 
13.0 SPONSOR TRIAL PERSONNEL................................................................................................... 93 
14.0 INSURANCE/SUBJECT INDEMNIFICATION ............................................................................. 93 
APPENDIX I: ECHOCARDIOGRAPHY PROCEDURES ...................................................................... 94 
1.0 Required Exams............................................................................................................................. 94 
2.0 General Imaging and Recording Procedures .................................................................................... 94 
2.1 
List of Recommended Images ................................................................................................. 95 
3.0 Data Requirements......................................................................................................................... 97 
4.0 Acquisition of Key Variables .......................................................................................................... 98 
4.1 
LVOT Diameter ..................................................................................................................... 98 

 
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4.2 
LVOT Velocity ...................................................................................................................... 99 
4.3 
Aortic Valve Velocities..........................................................................................................100 
4.4 
Assessment of Prosthetic Aortic Regurgitation ........................................................................100 
4.5 
Assessment of Mitral Regurgitation ........................................................................................102 
4.6 
Assessment of Tricuspid Regurgitation ...................................................................................102 
4.7 
Assessment of Left Ventricular Function and Left Atrial Size...................................................103 
4.8 
Assessment of Left Ventricular Diastolic Function ..................................................................103 
5.0 Core Lab Analysis ........................................................................................................................104 
APPENDIX II: MDCT ACQUISTION GUIDELINES: PRE-TAVR PLANNING ...................................107 
1.0 Introduction..................................................................................................................................107 
2.0 General Requirements ...................................................................................................................107 
3.0 ECG-gated Contrast Enhanced Scan of Aortic Root ........................................................................107 
3.1 
Post-processing .....................................................................................................................107 
3.2 
Required Aortic Root Measurements ......................................................................................108 
3.2.1 
Reformatting of Images ..............................................................................................109 
3.2.2 
Aortic Annulus Measurements ....................................................................................110 
3.2.3 
Sinus of Valsalva Measurements .................................................................................111 
4.0 
Evolut R and Evolut PRO TAV Sizing Matrix.........................................................................112 
APPENDIX III: DEFINITIONS OF STS FACTORS AND OTHER CO-MORBIDITIES ........................113 
1.0 STS Factors ..................................................................................................................................113 
2.0 Other Factors Not Captured by Traditional Risk Score49 ..................................................................119 
APPENDIX IV: RESHEATH AND RECAPTURE DEFINITIONS ........................................................120 
APPENDIX V: DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS .............................121 
1.0 Safety Endpoint Definitions...........................................................................................................121 
2.0 Other Related Complications .........................................................................................................126 
4.0 Event Code List ............................................................................................................................129 
5.0 Classification of Causal Relationships ............................................................................................131 
APPENDIX VI: SAMPLE INFORMED CONSENT FORM: MAIN TRIAL ...........................................134 
APPENDIX VII: LEAFLET THICKENING/IMMOBILITY SUB-STUDY PROTOCOL ........................135 
1.0 Synopsis.......................................................................................................................................135 
2.0 Background ..................................................................................................................................135 
3.0 Sub-Study Objective .....................................................................................................................136 
4.0 Methodology ................................................................................................................................136 
4.1 
Sub-Study Design..................................................................................................................136 
4.2 
Investigational Sites...............................................................................................................136 
4.3 
Number of Subjects ...............................................................................................................136 

 
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4.4 
Subject Selection Criteria.......................................................................................................136 
4.4.1 
Inclusion Criteria........................................................................................................136 
4.4.2 
Exclusion Criteria.......................................................................................................136 
4.5 
Informed Consent ..................................................................................................................137 
4.6 
Screening and Enrollment ......................................................................................................137 
4.7 
Post Procedure Anti-thrombotic Therapy ................................................................................137 
4.8 
Required Evaluations.............................................................................................................137 
4.9 
Unblinding of MDCT Core Laboratory Findings .....................................................................137 
4.10 
Adverse Events, Clinical Events Committee, Data Safety Monitoring Board .............................138 
4.11 
Statistical Analysis ................................................................................................................138 
5.0 MDCT Image Acquisition .............................................................................................................138 
5.1 
General requirements.............................................................................................................138 
5.1.1 
General requirements for CT hardware ........................................................................138 
5.1.2 
General requirements for CT data acquisition ...............................................................138 
5.1.3 
General requirements for CT data reconstruction ..........................................................138 
5.2 
Specific recommendations .....................................................................................................138 
5.2.1 
Heart rate control........................................................................................................138 
5.2.2 
Acquisition technique .................................................................................................139 
5.2.3 
Acquisition settings ....................................................................................................140 
5.2.4 
Contrast administration ...............................................................................................140 
5.2.5 
Image reconstruction ..................................................................................................140 
6.0 MDCT Core Laboratory Data Analysis ..........................................................................................141 
6.1 
Assessment and documentation of image quality based on pre-defined standards.......................141 
6.2 
Leaflet thickening and immobility (LTI) assessments ..............................................................141 
6.2.1 
Leaflet thickening.......................................................................................................141 
6.2.2 
Leaflet immobility ......................................................................................................141 
6.2.3 
Prosthesis position and expansion ................................................................................141 
7.0 Sample Informed Consent Addendum for LTI Sub-Study ................................................................142 
APPENDIX VIII: Quality of Life Questionairres....................................................................................143 
REFERENCES ....................................................................................................................................144 
 
 
 

 
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1.0 SYNOPSIS 
Title 
Transcatheter Aortic Valve Replacement (TAVR) in Patients with the Medtronic 
Transcatheter Aortic Valve Replacement System (TAVR) in Patients at Low Risk for Surgical 
Aortic Valve Replacement (SAVR) 
Purpose 
Evaluate the safety and effectiveness of the Medtronic TAVR System in patients with severe 
aortic stenosis at low risk for SAVR 
Design 
Multi-center, international, prospective, randomized, interventional, pre-market. Subjects 
will be randomized on 1:1 basis to either TAVR with the Medtronic TAVR system or to SAVR 
Devices 
Investigational Devices 
• 
Evolut R 23, 26, 29, and 34 mm Transcatheter Aortic Valve (TAV) 
• 
Enveo R Delivery Catheter System with EnVeo Inline Sheath and EnVeo R Loading 
System 
• 
Medtronic Evolut PRO TAV 23, 26, and 29 mm 
• 
Medtronic Evolut PRO Delivery Catheter System with InLine Sheath 
• 
Medtronic Evolut PRO Loading System 
• 
EnVeo PRO Delivery Catheter System and EnVeo PRO Loading System (US Onlyi) 
Control Devices 
Any commercially available bioprosthesis (stented or stentless) in both the United States 
and the geography in which the study center is located. 
Primary Objective 
Demonstrate that the safety and effectiveness of the Medtronic TAVR system as measured 
by rates of all-cause mortality or disabling stroke at two years is non-inferior to SAVR in the 
treatment of severe aortic stenosis in subjects who have a low predicted risk of operative 
mortality for SAVR 
Exploratory 
Objective 
Evaluate the incidence of Leaflet Thickening or Immobility (LTI) detected by Multi-Detector 
Computed Tomography (MDCT) following TAVR or SAVR (through sub-study) 
Primary Endpoint 
All-cause mortality or disabling stroke at 2 years 
Secondary 
Endpoints 
Safety 
• 
Composite of death, disabling stroke, life-threatening bleed, major vascular 
complication, or AKI (II or III) at 30 days 
• 
New permanent pacemaker implantation at 30 days 
• 
Prosthetic valve endocarditis at one year 
• 
Prosthetic valve thrombosis at one year 
• 
All stroke (disabling and non-disabling) at one year 
• 
Life-threatening bleed at one year 
• 
Valve-related dysfunction requiring repeat procedure at one year 
Effectiveness 
• 
Valve-related dysfunction (moderate or severe stenosis or regurgitation) at one year 
• 
Quality of Life as assessed by Kansas City Cardiomyopathy (KCCQ) at 30 days and one 
year 
• 
Repeat hospitalization for aortic valve disease at one year 
• 
Device Success (VARC II) 
                                                                 
i The   Delivery Catheter System and EnVeo PRO Loading System are limited for use at investigational sites located in the United States. 

 
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• 
Hemodynamic performance metrics by Doppler echocardiography at one year  
• 
New York Heart Association (NYHA) functional classification at one year 
• 
Health-related quality of life at one year as assessed by EQ-5D survey instrument 
 
1.0 SYNOPSIS (continued) 
Investigation Sites 
Up to 100 sites in the United States, Europe, Canada, Australia, New Zealand, and Japan 
Number of Subjects 
At least 1200 subjects, inclusive of at least 300 evaluable subjects (150 Medtronic TAVR and 
150 SAVR) in LTI Sub-Study 
Patient Population 
Subjects with severe aortic stenosis with an indication for SAVR with a bioprosthesis whose 
predicted risk of mortality at 30 days is <3% per multidisciplinary local heart team 
assessment 
Key Inclusion 
Criteria 
• 
Patient is considered low risk for SAVR, where low risk is defined as predicted risk of 
mortality for SAVR <3% at 30 days per multidisciplinary local heart team assessment  
• 
Severe aortic stenosis, defined as: 
 
Symptomatic aortic stenosis 
Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), OR mean gradient 
≥40 mmHg, OR maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography 
at rest 
 
Asymptomatic aortic stenosis: 
- 
Very severe aortic stenosis with an aortic valve area of ≤1.0 cm2 (or aortic 
valve area index of ≤0.6 cm2/m2), AND maximal aortic velocity ≥5.0 m/sec, 
or mean gradient ≥60 mmHg by transthoracic echocardiography at rest, OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), 
AND a mean gradient ≥40 mmHg, or maximal aortic valve velocity ≥4.0 
m/sec by transthoracic echocardiography at rest, AND an exercise tolerance 
test that demonstrates a limited exercise capacity, abnormal BP response, 
or arrhythmia OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), 
AND mean gradient ≥40 mmHg, or maximal aortic valve velocity ≥4.0 m/sec 
by transthoracic echocardiography at rest, AND a left ventricular ejection 
fraction <50%. 
• 
Indicated for SAVR with a bioprosthesis 
Key Exclusion 
Criteria 
• 
Bicuspid aortic valve identified by echocardiography, MDCT, or Magnetic Resonance 
Imaging 
• 
Significant ascending aortopathy 
Subject Evaluation 
(Main trial) 
• 
Clinical assessment at pre and post-procedure, discharge, 30 days, 6 months, 1 year, 18 
months, 2 years, 3 years, 4 years, 5 years, 7 years and 10 years 
• 
Transthoracic echo at pre and post-procedure, 30 days, 6 months, 1 year, 2 years, 3 
years, 4 years, 5 years, 7 years and 10 years 
• 
Multi-Detector Computed Tomography at pre-procedure 
• 
Blood samples at pre- and post-procedure, discharge, and 30 days 
• 
12-lead ECG at pre- and post-procedure, discharge, and 30 days 

 
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• 
Adverse event review will be conducted at all visits and via telephone for the 6, 8, and 
9 year follow-up visits 
Subject Evaluation 
(LTI Sub-study) 
• 
MDCT at 30 days and one year post-implantation 
1.0 SYNOPSIS (continued) 
Co-Principal 
Investigators 
Jeffrey Popma, MD, Interventional Cardiologist. 
Beth Israel Deaconess Medical Center, Boston MA 
Michael Reardon, MD, Cardiothoracic Surgeon 
Houston Methodist Hospital, Houston TX 
Professional 
Services 
• 
Independent Echocardiography Core Laboratory 
• 
Independent Clinical Events Committee 
• 
Independent Data Safety Monitoring Committee 
• 
Independent MDCT Core Laboratory (for LTI Sub-Study) 
• 
Independent Explant Pathology Core Laboratory 
Duration 
Total study duration is estimated to be 12 years (time from first subject implanted to ten 
year follow-up on last subject implanted) 
 
 

 
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2.0 PURPOSE 
2.1 Background and Rationale 
Over the past ten years, transcatheter aortic valve replacement (TAVR) has emerged as a transformative 
technology for the management of severe aortic stenosis. TAVR has become the standard of care for 
patients with aortic stenosis who are inoperable or at extreme risk for surgical aortic valve replacement, 1, 2 
and is the preferred alternative for patients with severe aortic stenosis who are at high risk for surgical 
aortic valve replacement. 3, 4 Following Cribier’s first implantation in 2002,5 TAVR has evolved to become a 
standard procedure at specialized heart centers worldwide, and is now performed with only moderate 
sedation rather than general anesthesia in many patients. 
TAVR was initially performed in patients at the highest risk for surgical aortic valve replacement, but data 
indicate that patients at intermediate risk are increasingly being treated with TAVR. A recent report from 
the United States national TVT Registry showed a median Society of Thoracic Surgeons Predicated Risk of 
Mortality (STS-PROM) at 30 days of approximately 7% in patients treated with TAVR from November 2011 
through March 2013.6 Several reports from European centers demonstrate a shift to intermediate risk 
patients, and have shown low mortality and stroke rates in these patients.7-9 Large randomized trials are 
ongoing with the potential to confirm these early results in intermediate risk patients.10 The PARTNER IIA 
trial involving the balloon-expandable Sapien valve (Edwards Lifesciences, Irvine CA, USA) has enrolled 2000 
intermediate-risk patients with an STS-PROM between 4% and 8%. The SURTAVI trial, with an estimated 
enrollment of up to 2000 patients, includes patients with a predicted risk of mortality of ≥3% and <15% (by 
local heart team assessment) undergoing TAVR with the self-expanding Medtronic CoreValve system 
(Medtronic, Minneapolis, MN, USA). Both trials have a primary composite endpoint of all-cause mortality 
and disabling stroke at two years post-TAVR, randomized against surgical aortic valve replacement (SAVR).  
Data from the SURTAVI trial were submitted to the FDA and on July 10, 2017 the Medtronic CoreValve 
system was approved in the United States for patients at intermediate risk for SAVR. 
Nonetheless, conventional surgical aortic valve replacement (SAVR) with general anesthesia, sternotomy, 
and cardiopulmonary bypass remains the gold standard for patients at low or intermediate operative risk.11-
13 Conventional SAVR is associated with low perioperative risk, and provides excellent functional outcomes 
with satisfactory long-term survival, even in elderly patients.14-20 Therefore, evidence from rigorous clinical 
trials are needed to evaluate the application of TAVR in low-risk patients before it is assimilated into the 
overall management of patients with aortic stenosis who are good candidates for SAVR. 
The Medtronic CoreValve TAVR system received the CE Mark in 2007, and FDA approvals for Extreme Risk 
and High Risk patient populations in 2014. To date, over 65,000 patients have been implanted with the 
Medtronic CoreValve in over 70 countries, with approximately 11,000 of these patients enrolled in post-
approval registries or clinical trials that further confirm the safety and performance of the CoreValve 
product. There is now extensive published experience demonstrating the CoreValve system is fulfilling its 
intended role with a favorable risk/benefit ratio,21-24and rigorous clinical trials have established its safety 
and effectiveness, with improved mortality and quality of life compared with medical therapy in extreme 
risk patients,2 and even superiority to SAVR among high operative risk patients.4, 25 
While there have been significant improvements in TAVR outcomes due to better patient selection, 
increasing operator experience, and iterations in device technology, important issues remain. Clinical 

 
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challenges where further advances would be desirable include the occurrence of major procedural 
complications,26-28stroke,29-31paravalvular aortic regurgitation,32, 33vascular complications,34, 35 and need for 
new permanent pacemaker implantation.36-39 
To this end, Medtronic has developed modifications to the CoreValve frame and delivery catheter system 
to enable resheathing or full recapture of the device before it is released from the delivery system. These 
modifications are incorporated in the CoreValve Evolut R system (hereafter “Evolut R”). The ability to 
resheath or recapture the device allows the operator to reposition or remove the bioprosthesis if the initial 
implant positioning is sub-optimal (too high or too low). This feature is desirable in that it facilitates 
accurate final positioning which may mitigate risks associated with sub-optimal positioning such as 
paravalvular leak,40, 41 acute migration,28 and AV-conduction disturbance related to implant depth.36 In 
addition, the EnVeo R Delivery Catheter System with EnVeo InLine Sheath provides physicians the option to 
use a lower profile introducer sheath (outer diameter), which may reduce the risk for major vascular 
complications.42 
A comprehensive protocol of bench and animal testing of the Evolut R system has demonstrated its 
functionality, and has confirmed that changes to enable recapture have not impacted the structural 
integrity, hydrodynamic performance, or durability of the CoreValve bioprosthesis. Beginning in October 
2013, clinical studies of the Evolut 23R, 26R, and 29R mm valve sizes involving 301 patients have been 
conducted in Australia, New Zealand, Europe, and the United States. These clinical studies confirm that 
TAVR with the Evolut R system can be performed with an acceptable incidence of procedural and device-
related complications, that short term safety and clinical efficacy of the Evolut R system are similar to the 
predicate CoreValve system, and there is no new safety risks associated with the use of the 
resheath/recapture feature. Results from these studies were used to gain the CE Mark in February 2015 for 
the Evolut R 26 and 29 mm valve sizes, and FDA approval in June of 2015 for the Evolut R 23, 26 and 29 mm 
sizes.43, 44 
In June 2016, enrollment began in the United States in a 60 subject study of the Evolut R 34 mm TAVR 
system. The Evolut R 34 mm IDE study is an addendum to the original Evolut R United States IDE study, and 
followed the same protocol. The purpose of this study was to assess the safety and efficacy of the Evolut R 
34mm TAVR system, which is an extension of the Evolut R family, intended to extend the range of treatable 
annular diameters with the Evolut R TAVR system. Data from the initial 15 subjects with 30 day follow-up 
were submitted to FDA as PMA supplement, and on 26 October 2016, the Evolut R 34 mm was approved 
for use in the United States for subjects at high or extreme risk for SAVR. On July 10, 2017 the Evolut R 23, 
26, 29 and 34 mm was approved in the United States for patients at intermediate risk for SAVR. 
In order to continue striving for improvement with our TAVR systems, Medtronic has developed additional 
modifications to the Medtronic Evolut R system. An outer wrap covering the external frame on the first 1.5 
cells of the inflow of the valve was added. The purpose of the wrap is to improve paravalvular leak (PVL) 
performance by enhancing sealing around the perimeter of the device inflow. It does this by reducing the 
open space and providing larger surface area contact between the device and native annulus over the 1.5 
cells that it covers. This iteration of Evolut R is called the Medtronic Evolut PRO system. 
Medtronic has completed a comprehensive protocol of bench testing that collectively has demonstrated 
the functionality of Evolut PRO, and that the changes associated with the modification to the valve have not 

 
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impacted the structural integrity, hydrodynamic performance, or durability of the Evolut PRO bioprosthesis. 
In May 2016, enrollment began in the United States to study the  Evolut PRO system. Data from this trial 
were submitted to FDA and on March 20, 2017 the  Evolut PRO system was approved for use in the United 
States for subjects at high or extreme risk for SAVR. On July 10, 2017 the  Evolut PRO system was approved 
in the United States for patients at intermediate risk for SAVR. 
Medtronic has also developed additional modifications to the Medtronic EnVeo delivery system and loading 
system components. The EnVeo PRO Delivery Catheter System (DCS) and the EnVeo PRO Loading System 
(LS) represent a modification to the EnVeo R DCS and EnVeo R LS components.  There is no change to the 
Evolut R TAVs and  Evolut PRO TAVs, or their intended use with the use of these additional modifications. 
The EnVeo PRO DCS and LS were submitted to the FDA and approved for high, extreme, and intermediate 
risk use in the United States on January 17, 2018.This trial will evaluate the safety and effectiveness of the 
Medtronic Transcatheter Aortic Valve Replacement system (CoreValve, Evolut R and  Evolut PRO systems) 
in patients with aortic stenosis who are at low predicted risk for mortality at 30 days with SAVR. Data from 
this trial will be used to support regulatory submissions to seek an expansion of the approved indication to 
include patients who are indicated for aortic valve replacement with a low predicated risk of mortality with 
SAVR. 
2.2 Medtronic Transcatheter Aortic Valve Replacement System 
The Medtronic Transcatheter Aortic Valve Replacement (TAVR) system in this trial includes the following 
TAVR systems: 
2.2.1 
Evolut R system 
The Evolut R System is a recapturable transcatheter aortic valve replacement system comprised of the 
following three components:  
1. 
Evolut R Transcatheter Aortic Valve (TAV) 
2. 
EnVeo R Delivery Catheter System (DCS) with EnVeo InLine Sheath or EnVeo PRO Delivery Catheter 
System (DCS) 
3. 
EnVeo R Loading System (LS) or EnVeo PRO Loading System (LS) 
2.2.2 
Medtronic  Evolut PRO System 
The Medtronic  Evolut PRO System is a transcatheter aortic valve replacement system comprised of the 
following three components: 
1. Medtronic  Evolut PRO Transcatheter Aortic Valve (TAV) 
2. Medtronic  Evolut PRO Delivery Catheter System (DCS) with InLine Sheath or EnVeo R Delivery 
Catheter System (DCS) with EnVeo InLine Sheath or EnVeo PRO Delivery Catheter System (DCS)  
3. Medtronic  Evolut PRO Loading System (LS) or EnVeo PRO Loading System (LS) 
The Evolut R and  Evolut PRO TAV treat aortic stenosis by displacing and functionally replacing the 
dysfunctional native valve with a bioprosthetic valve delivered on a catheter while the heart is still beating, 
thus avoiding the risks of cardiopulmonary bypass.45-48 Their intended performance is to relieve aortic valve 
stenosis without inducing significant regurgitation, thereby restoring effective aortic valve function. 

 
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A detailed description of the Evolut R and  Evolut PRO systems are provided in Section 5.0 Description of 
Investigational Devices. 
2.3 Intended Use 
Data from this trial will be used to support an expansion of the currently approved indication to include 
patients with aortic stenosis who are indicated for aortic valve replacement and are deemed at low 
predicted risk for mortality for SAVR, where low risk is defined as predicted risk of mortality for SAVR <3% 
at 30 days per multidisciplinary local heart team assessment. 
 

 
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2.4 
Trial Objectives 
2.4.1 Primary Objective 
The primary objective of this trial is to demonstrate that the safety and effectiveness of the Medtronic 
TAVR systems, as measured by the rate of all-cause mortality or disabling stroke at 2 years, is non-inferior 
to SAVR in the treatment of severe aortic stenosis in subjects who have a low predicted risk of mortality at 
30 days for SAVR. 
2.4.2 
Exploratory Objective 
An exploratory objective is to evaluate the incidence of findings of prosthetic valve leaflet thickening or 
leaflet immobility (LTI) by Multi Detector Computed Tomography following TAVR with the Medtronic TAVR 
system or SAVR with commercially available surgical bioprotheses. 
2.5 
Trial Endpoints 
The following endpoints will be used to evaluate the primary trial objectives: 
2.5.1 Primary Safety and Effectiveness Endpoint 
• 
The rate of all-cause mortality or disabling stroke at 2 years 
2.5.2 Secondary Safety Endpoints 
• 
The rate of the composite of death, disabling stroke, life-threatening bleed, major vascular 
complication, or AKI (II or III) at 30 days 
• 
The rate of new permanent pacemaker implantation at 30 days 
• 
The rate of prosthetic valve endocarditis at one year 
• 
The rate of prosthetic valve thrombosis at one year 
• 
The rate of all stroke (disabling and non-disabling) at one year 
• 
The rate of life-threatening bleeding at one year 
• 
The rate of valve-related dysfunction requiring repeat procedure at one year 
2.5.3 Secondary Effectiveness Endpoints 
• 
The rate of valve-related dysfunction, defined as moderate or severe prosthetic valve stenosis, or 
moderate or severe prosthetic regurgitation at one year (per VARC II) 
• 
Quality of Life as assessed by Kansas City Cardiomyopathy (KCCQ) at 30 days and one year 
• 
The rate of repeat hospitalization for aortic valve disease at one year 
• 
Device Success (VARC II), defined as 
o Absence of procedural mortality, AND 
o Correct positioning of a single prosthetic heart valve into the proper anatomical location, AND 
o Intended performance of the prosthetic heart valve, defined as the absence of patient-prosthesis-
mismatch and mean aortic valve gradient less than 20 mmHg (or peak velocity <3 m/sec), AND 
absence of moderate or severe prosthetic valve regurgitation. 
• 
Hemodynamic performance metrics by Doppler echocardiography 

 
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o Mean aortic gradient at one year  
o Effective orifice area at one year 
o Degree of total, peri, and transvalvular prosthetic regurgitation at one year  
• 
New York Heart Association (NYHA) functional classification at one year  
• 
Health-related quality of life at one year as assessed by EQ-5D survey instrument 
2.7 
Rationale for Selection of Trial Endpoints 
The basis for the selection of these endpoints includes the following considerations: 
• 
They are clinically relevant and address important safety and effectiveness aspects of the Medtronic 
TAVR System compared to SAVR. 
• 
They are objectively defined and measurable in the majority of subjects. 
• 
They are consistent with current recommendations for endpoints in TAVR clinical studies.  
 
 

 
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3.0 TRIAL PROTOCOL 
3.1 Ethics and Regulatory Compliance 
3.1.1 
Applicable Regulations 
This trial was designed to reflect the Good Clinical Practice (GCP) principles outlined in ISO 14155:2011. 
These include the protection of the rights, safety and well-being of human subjects, controls to ensure the 
scientific conduct and credibility of the clinical investigation and the definition of responsibilities of the 
sponsor and investigators. 
The trial will be conducted according to federal, national and local laws, regulations, standards, and 
requirements of the countries/geographies where the trial is being conducted. The trial will also be 
conducted in accordance with the Declaration of Helsinki. The principles of the Declaration of Helsinki are 
implemented in this trial by means of the Patient Informed Consent (IC) process, Ethics Board approval, trial 
training, clinical trial registration, pre-clinical testing, risk benefit assessment, and publication policy. 
In the United States, the trial will be conducted under an FDA Investigational Device Exemption (IDE) in 
compliance with 21 CFR Parts 11, 50, 54, 56 and 812, and ISO 14155:2011. In addition, the trial will be 
conducted in compliance with 21 CFR Part 11 and 54 in all participating geographies. In Europe and Canada, 
the trial will be conducted in compliance with ISO 14155:2011. In Canada, SOR/98-282, Section 79-88 will 
also be followed. In Europe, MDD 93/42/EEC and MEDDEV 2.7/3 will also be followed. In Australia and New 
Zealand the trial will be conducted in compliance with local regulations and ISO 14155:2011. In Japan, the 
trial will be conducted in accordance with the ethical principles of the Japan GCP Ordinance, the 
Pharmaceutical and Medical Device Act as well as ISO 14155:2011. 
Regulatory authority notification/approval to conduct the trial is required in all participating geographies. 
Investigational sites will be not be activated, nor begin enrolling subjects until the required 
approval/favorable opinion from the respective regulatory agency has been obtained (as appropriate). 
Additionally, any requirements imposed by a local regulatory agency or Ethics Board shall be followed, as 
appropriate. 
This trial will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110-85, 
Section 810(a)). 
3.1.2 
Institutional Review Board and Ethics Committee 
The trial will be conducted in accordance with the requirements of local Institutional Review Boards and 
Ethics Committees. The responsible Institutional Review Board (IRB) or Ethics Committee (EC) at each 
investigational site must approve the trial protocol and informed consent form. Trial activities will not 
commence prior to receipt of documentation of IRB/EC approval by the site and Medtronic. The 
Investigator and trial staff must comply with the requirements of their IRB/EC, including any additional 
requirements imposed by the IRB/EC after initial approval. 
Prior to enrolling subjects, each investigation site’s IRB/EC will be required to approve the current CIP, the 
Informed Consent form, and any other written information to be provided to the subjects. Trial sites in the 

 
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United States must also utilize IRB approved Health Insurance Portability and Accountability Act (HIPAA) 
Authorization. 
IRB/EC approval of the clinical trial must be received in the form of a letter and provided to Medtronic 
before commencement of the trial at an investigation site. The approval letter must contain enough 
information to identify the version or date of the documents approved. In addition the approval letter 
needs to be accompanied by an IRB/EC roster or letter of compliance, to allow verification that the 
investigator, other center trial staff, and/or Medtronic personnel are not members of the IRB/EC. If they are 
members of the IRB/EC, written documentation is required stating that he/she did not participate in the 
approval process. Investigators must inform Medtronic of any change in status of IRB/EC approval once the 
investigation site has started enrollment. If any action is taken by an IRB/EC with respect to the 
investigation, that information will be forwarded to Medtronic by the respective investigator.  
3.1.3 Regulatory Submissions 
Each site must fulfill all local regulatory requirements prior to enrolling subjects. Each study site must have 
written documentation of site/investigator readiness, including but not limited to IRB/EC approval of the 
current version of the CIP, Informed Consent form, a signed Investigator’s Agreement, current investigator 
curriculum vitae, and documentation of training. The principal investigators and their institutions shall 
agree to this CIP and any amendments and indicate their approval by signing and dating the Clinical Trial 
Agreement. 
Each center is required to have documented approval from their local Regulatory Authority prior to their 
first subject enrollment. Medtronic will obtain a copy of the approval letter from the Regulatory 
Authorities. 
Other documents referred to in this CIP are listed as follows and will be made available upon request: 
• 
Monitoring Plan 
• 
Data Management Plan 
• 
Statistical Analysis Plan 
• 
Safety Plan 
• 
Electronic Case Report Forms (eCRFs) 
If a regulatory authority imposes any additional requirements (eg, safety reports, progress reports), 
Medtronic will prepare the required documents and send them to the respective authority. 
Any revisions or amendments to the CIP, Investigator Brochure, or Informed Consent documents will be 
submitted to all affected Regulatory Authorities. A final report will be submitted to all Regulatory 
Authorities upon trial closure. 
3.1.4 Ethical Conduct of the Trial 
The trial will be conducted in accordance with the design and specific provisions of this protocol, in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are 
consistent with Good Clinical Practice (GCP) and the applicable regulatory requirements. 
The principles of the Declaration of Helsinki have all been implemented by means of the patient informed 
consent process, IRB/EC approval, trial training, clinical trial registration, preclinical testing, risk benefit 

 
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assessment, and publication policy. Pediatric, legally incompetent, or otherwise vulnerable patients are not 
eligible for the trial. Further, the Medtronic TAVR system will not be used as an emergency treatment. 
3.2 
Trial Organization 
3.2.1 Investigational Sites 
This trial may be conducted at up to 100 sites in the United States, Canada, Europe, Australia, New Zealand, 
and Japan. Investigative sites will meet the following criteria: 
1. The site will have extensive experience with TAVR and SAVR, including the following: 
• 
cardiothoracic surgeon with either ≥100 career AVRs, or ≥25 AVRs in a calendar year 
• 
an interventional cardiologist with ≥20 TAVR procedures in the prior year, or ≥40 TAVR procedures 
in the prior two years. 
2. The site will have the presence or capacity of establishing an investigative team consisting of the 
following: 
• 
interventional cardiologist with expertise in transcatheter aortic valve replacement 
• 
cardiothoracic surgeon with expertise in aortic valve replacement 
• 
echocardiographer 
• 
trial coordinator 
3. Sites that participate in the LTI Sub-Study will have capability of performing high quality retrospective 
ECG gated MDCT scans, and validated CT equipment that meets minimum requirements for temporal 
resolution. 
Information on the investigational sites (eg, name, address, PI) will be maintained in a separate document. 
3.2.2 
Trial Site Investigative Team Members 
The following is a description of the key personnel who will form the investigative team at each trial site. 
3.2.2.1 Site Co-Principal Investigators 
Each site will have two Co-Principal Investigators (PI), one who is an interventional cardiologist, and one 
who is a cardiothoracic surgeon. The Co-PIs have overall responsibility for the conduct of the trial at the 
site, including protecting the rights, safety, and welfare of the study subjects at their site, the integrity of 
the trial data generated by their site, and for ensuring the trial is conducted in compliance with the Clinical 
Investigation Plan, 21 CFR 812, and IRB/EC requirements. 
3.2.2.2 Heart Team 
Each site will utilize a local heart team to assess eligibility of the prospective subject for the trial. 
At a minimum, the local Heart Team should include the following members: 
1. A cardiothoracic surgeon 
2. An interventional cardiologist 
3. An echocardiographer 
The site Co-PIs may also serve as a member of the Heart Team. 

 
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3.2.2.3 TAVR Implant Team 
Each site will have a TAVR implant team with extensive experience with TAVR procedures. Operator 1 and 
Operator 2 must meet the minimum TAVR qualification as described in Section 3.2.1 (1). 
3.2.2.4 Echocardiographer 
Each site will have a designated cardiologist whose primary responsibilities are to ensure the required 
echocardiograms are performed in accordance with the CIP, and for reviewing and approving the site 
echocardiography eCRFs, if authorized by the PI. The designated echocardiographer may also serve as a 
member of the local Heart Team. 
3.2.2.5 Trial Coordinator 
Each site will have a designated trial coordinator whose responsibilities include coordination of trial 
activities, follow-up evaluations, and maintaining the records defined in the CIP. 
3.2.2.6 Cardiovascular Imaging Specialist 
Sites that participate in the LTI Sub-Study will have a designated cardiovascular imaging specialist, whose 
primary responsibilities are to ensure the required MDCT images are acquired in accordance with the LTI 
Sub-Study protocol and for review of the acquired images. The Cardiovascular Imaging Specialist is either a 
radiologist or cardiologist with expertise in MDCT. 
3.2.3 
Screening Committee 
A Screening Committee will be used to ensure patient selection is appropriate and consistent among trial 
sites. The role of the Screening Committee will include the following:  
• 
Confirmation that subjects are at low predicted risk of mortality at 30 days for SAVR 
• 
Confirmation that subjects are anatomical suitable for implantation for both TAVR and SAVR 
The Screening Committee will include interventional cardiologists and cardiac surgeons. Prior to the onset 
of the trial, the Screening Committee will establish a charter that describes its roles, responsibilities, and 
processes. 
3.2.4 
Publication Committee 
A Publication Committee will provide direction and support in the development of clinical publications. The 
Publication Committee will consist of trial investigators and Medtronic representatives. The Publication 
Committee will be responsible to: 
• 
Define the publication plan 
• 
Review, approve, and prioritize publication proposals 
• 
Provide input on the scientific merit and clinical relevance of ancillary publications 
• 
Identify the manuscript/abstract first author(s)/writer(s)/presenter(s) 
• 
Review publications prior to submission 

 
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3.2.5 
Clinical Investigational Agreement and Financial Disclosure 
A Clinical Investigation Agreement shall be signed by the participating investigation site and/or the principal 
investigator at each investigation center per the local legal requirements, and returned to Medtronic prior 
to trial center activation. The investigator is required to indicate their approval of the CIP (and any 
subsequent amendments), by signing and dating the agreement. All investigators will be asked to complete 
financial disclosure statements provided by Medtronic prior to their participation in the trial. 
3.2.6 
Curriculum Vitae 
Signed and dated curriculum vitae shall be obtained for all investigators, including their current position at 
the investigation site in compliance with applicable local regulations.  
3.2.7 
Trial Training 
Prior to investigational center activation or subsequent involvement in trial activities, Medtronic will 
provide training to the investigative team on the trial methods, procedures, and requirements. Training 
may be conducted via site initiation visits, investigator meetings, and/or other media sessions. Medtronic 
will maintain documentation of these training sessions. For new trial team members that join the trial after 
site activation, the PI may provide training on the trial with permission from Medtronic. Additionally, 
Medtronic representative(s) may be present at each site’s implant procedures as part of the ongoing 
training process. 
3.3 Methodology 
3.3.1 
Patient Population 
The population includes males and females with severe aortic stenosis with a clinical indication for surgical 
aortic valve replacement with a bioprosthesis who are at low predicted risk of mortality at 30 days for 
surgical aortic valve replacement. 
3.3.2 
Trial Design 
This is a multi-center, international, prospective, randomized, interventional trial. The primary trial 
objective will be accomplished by 1:1 randomization to TAVR and SAVR and assessing the clinical endpoints 
and outcome measures described in Section 2.5. The exploratory objective will be accomplished through 
evaluation of the data as described in the LTI Sub-Study, APPENDIX VII: LEAFLET THICKENING/IMMOBILITY 
SUB-STUDY PROTOCOL. 
The trial methods include the following measures to minimize potential sources of bias: 
• 
An external, independent Screening Committee will confirm subject eligibility and anatomical 
suitability. 
• 
An external, independent Clinical Events Committee (CEC) will review and adjudicate, at minimum, all 
deaths and endpoint related adverse events. Safety endpoint results will be based on CEC 
adjudications. 
• 
All sites will follow a standardized protocol for acquisition of echocardiographic endpoint data. 
• 
An Echo Core Lab will evaluate all echocardiograms. Echocardiographic trial endpoint results will be 
based on Core Lab assessments. 

 
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• 
Trial sites should follow their institutional procedures for maintenance of echocardiography and 
laboratory equipment used for assessing the trial variables. 
3.3.3 
Statistical Aspects 
3.3.3.1 Historical Data 
Although the experience with surgical aortic valves in low surgical risk aortic valve replacement populations 
is extensive, it was not considered possible to leverage much of the data from these studies directly as 
surgical aortic valve replacement series typically enroll patient populations which include a proportion 
subjects with a bicuspid or unicuspid valve which may be as high as approximately 50%50 and also include 
subjects with purely or primarily regurgitant lesions (also excluded from this trial) whose outcomes may 
differ from patients with aortic stenosis. As a result, series for which individual patient data were available 
or which were known to attempt exclusion of patients with bicuspid or unicuspid valves comprise the 
primary basis for the event rate estimate and additional series were considered only confirmatory in 
nature. Table 1 presents the rates of all-cause mortality at 24 months from studies which were considered 
in developing the event rate estimate. The simple weighted average from the studies was 11.4% which was 
adjusted up to 12% to account for the possibility that surgical candidates at extremely low risk (i.e. the 
healthiest and youngest potential subjects) may forego randomization into a TAVR trial until longer term 
data and data from lower surgical risk patients are available for TAVR. 
 
Table 1. Surgical series supporting all-cause mortality event rate estimate 
Surgical Series 
Number in cohort 
24-Month all-cause mortality K-M 
Rate 
NOTION SAVR cohort1 
134 
9.8% 
3f Pivotal cohort1 
405 
12.7% 
Mosaic sub-analysis2 
646 
9.9% 
Freestyle sub-analysis3 
323 
13.5% 
Simple Weighted Average 
1508 
11.4% 
1Entire cohort leveraged (data on file) 
2Sub-group analysis excluding subjects <65 years of age, with congenital bicuspid valves or with a purely regurgitant lesion 
3Sub-group analysis excluding subjects <65 years of age, with congenital bicuspid valves, with a purely regurgitant lesion or with 
the Freestyle valve implanted as a full-root replacement 
The 24-month event rate estimate for non-fatal disabling stroke of 3% was generated primarily from the 
CoreValve US Pivotal High Risk Trial SAVR (3.9%) and TAVR (2.0%) cohorts which used event definitions 
consistent with this trial.25 Additional sources of data considered include the NOTION SAVR cohort (4.6%) 
and the Mosaic and Freestyle cohort sub-analyses (which had rates of 2.0% and 2.3% respectively) all of 
which collected clinical stroke/cerebrovascular accidents. 
The expected sample size for this trial was determined based on the primary endpoint of all-cause mortality 
or disabling stroke at 24 months. The assumed values πT = πC = 0.15 are based on an assumed rate of all-
cause mortality of 12% at 24 months and a non-fatal disabling stroke rate of 3% at 24 months. 

 
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3.3.3.2 Analysis Sets 
3.3.3.2.1 
Screening Population 
All subjects with severe aortic stenosis who provide an informed consent will be considered screened and 
enrolled and all available data will be entered into the Electronic Data Capture (EDC) system. 
3.3.3.2.2 
Randomized Population 
If the subject signs informed consent, meets all inclusion and none of the exclusion criteria, and the Heart 
Team determines the subject is suitable for randomization in the trial, then the subject is reviewed by the 
Screening Committee. If the subject is approved by the Screening Committee and the subject is randomized 
to either TAVR or SAVR, the subject is added to the randomized population. Within the randomized 
population the following analysis sets are distinguished: 
• 
The intention to treat (ITT) set: Subjects are reported according to the randomized assignment, SAVR 
or TAVR, regardless of what, if any, therapy was actually received. 
• 
The as treated (AT) set: The AT set consists of all ITT subjects with an attempted implant procedure, 
defined as when the subject is brought into the procedure room and any of the following have 
occurred: anesthesia administered, vascular line placed, TEE placed or any monitoring line placed. 
Subjects will be analyzed according to their first attempted procedure (TAVR or SAVR). 
• 
The implanted set: The Implanted set consists of all the AT subjects who are actually implanted with 
either the TAV or SAV. 
• 
The per protocol (PP) set: The PP set will be defined based on the ICH E9 Statistical Principles, and will 
be specified in the statistical analysis plan (SAP). 
The primary analysis for the primary objective, secondary safety objectives, secondary effectiveness 
objectives (except for valve dysfunction, hemodynamic performance metrics, and device success) will use 
the AT set. Valve dysfunction, hemodynamic performance metrics, and device success will use the 
implanted set. 
3.3.3.3 Description of Baseline Variables 
Baseline demographic and clinical variables will be summarized for each of the treatment groups for the 
ITT, AT, and implanted sets. Continuous variables will be summarized as means, medians, standard 
deviations, interquartile ranges, minima and maxima and compared between treatment groups using a 
Bayesian analog of a two-sample t-test or the non-parametric Wilcoxon rank-sum test. Categorical variables 
will be summarized as frequencies and percentages and compared between treatment groups using a 
Bayesian version of a comparison of proportions. 
3.3.3.4 Primary Objective 
The primary endpoint of all-cause mortality or disabling stroke at 24 months post procedure will be 
evaluated using the absolute difference of the TAVR rate and the SAVR rate for all-cause mortality or 
disabling stroke during a fixed follow-up of 24 months time. The hypothesis test is designed to show non-
inferiority of TAVR to SAVR for the primary endpoint. 

 
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3.3.3.4.1 
Hypothesis of Non-inferiority 
The primary objective is to establish that TAVR is non-inferior to SAVR for the primary endpoint. The 
hypothesis of interest is: 
H: πT < πC + δ 
where πT and πC denote binary rates of all-cause mortality or disabling stroke during a fixed follow-up of 24 
months for the treatment (TAVR) and control (SAVR) groups, and δ = 0.06. This trial is designed using 
Bayesian statistical techniques. TAVR will be declared to be non-inferior to SAVR if it can be established that 
the posterior probability Pr(Hδ=0.06 | data) > Ψ, where Ψ is a pre-specified threshold value. In addition, the 
primary endpoint (superiority) will be tested according to the testing order specified in Section 3.3.3.7 
Multiplicity Considerations. 
3.3.3.4.2 
Randomization 
Randomization will follow a 1:1 (treatment:control) allocation ratio and be stratified by site and need for 
revascularization, using a blocked randomization scheme with blocks of randomly varying sizes. The sample 
size for the AT population is 1200 subjects. The first interim analysis (timed to occur when 850 subjects are 
followed for 12 months) will be conducted for the purpose of possibly passing the primary objective. If the 
criterion for passing the primary objective is not met at this time, the second interim analysis (timed to 
occur when 1200 subjects are followed for 12 months) will again be conducted for the purpose of possibly 
passing the primary objective. If non-inferiority is not concluded at either of the interim analyses, follow-up 
will continue until all subjects have reached 24 months (24 months after the last LTI subject’s procedure 
date), and a final analysis will occur. 
3.3.3.4.3 
Sample Size and Analysis 
The sample size is guided by a standard frequentist non-inferiority power analysis. Under the assumptions 
of πT = πC = 0.15, non-inferiority margin δ=0.06, 1:1 randomization, α= 0.05, and power = 85%, the method 
of Farrington and Manning51 as implemented in PASS 201352 indicates that the required sample size for a 
single-look analysis is 1032. To allow for around 6% dropout, 1100 subjects must be accrued. Furthermore, 
to compensate for power lost in a three-look group sequential analysis plan with alpha spending, the 
sample size would have to be increased to 120053. Two interim analyses for possible "early win" are 
planned when 850 subjects have reached 12 months, and when 1200 subjects have reached 12 months. 
This trial is designed using Bayesian statistical techniques. The first interim analysis will be timed to occur 
12 months after the 850th procedure date for the purpose of declaring an early win will occur. At this 
analysis, if P(Hδ=0.06 | data) > Ψ, non-inferiority will be declared at this time, and a regulatory submission will 
follow. Otherwise, follow-up will continue until the second interim analysis (timed to occur 12 months after 
the 1200th procedure date), where again if the posterior probability of non-inferiority P(Hδ=0.06 | data) > Ψ, 
non-inferiority will be concluded and a regulatory submission will follow.  If non-inferiority is not concluded 
at either of the interim analyses, all subjects will be followed to 24 months (24 months after the last LTI 
subject’s procedure date), when a final analysis will occur. At the final analysis, the standard for trial 
success will again be P(Hδ=0.06 | data) > Ψ. These three analyses are termed "Win Looks." 

 
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If non-inferiority is established at either interim analysis, a test of superiority may be performed (See 
Section 3.3.3.7 Multiplicity Considerations for additional requirements and testing sequence).  If P(Hδ=0 | 
data) > ΨSUP, superiority will be established at this time.  However, if P(Hδ=0 | data) ≤ ΨSUP, subjects will 
continue to be followed until the full cohort has had the chance to be followed for 24 months (24 months 
after the last LTI subject’s procedure date), at which time a delayed determination of superiority may be 
made if P(Hδ=0 | data) > ΨSUP.  
The statistical approach for these analyses is Bayesian, and simulations for the trial design will be provided 
in a separate document. The prior distributions for πT and πC in these calculations are Beta (1,1). The 
threshold Ψ and ΨSUP will be specified in a separate document; this value is selected by trial-and-error to 
achieve a type I error (under simulation) of at most 0.05 for non-inferiority testing and at most 0.025 for 
superiority testing. 
3.3.3.5. Secondary Safety Endpoints 
• 
The rate of the composite of death, disabling stroke, life-threatening bleed, major vascular 
complications, or AKI (II or III) at 30 days 
• 
The rate of new permanent pacemaker implantation at 30 days 
• 
The rate of prosthetic valve endocarditis at one year 
• 
The rate of prosthetic valve thrombosis at one year 
• 
The rate of all stroke (disabling and non-disabling) at one year 
• 
The rate of life-threatening bleeding at one year 
• 
The rate of valve-related dysfunction requiring repeat procedure at one year 
The incidence estimates for each endpoint above will be provided for the two treatment groups at the 
specified time point. The statistical method will be the Bayesian version of a comparison of proportions 
(with predictions). In addition, Kaplan-Meier estimates will be provided at the following time points: 30 
days, 6 months, 12 months, and annually thereafter through 10 years. 
3.3.3.6 Secondary Effectiveness Endpoints 
• 
The rate of valve-related dysfunction, defined as moderate or severe prosthetic valve stenosis, or 
moderate or severe prosthetic regurgitation at one year (per VARC II) 
The incidence estimate will be provided for the two treatment groups at the specified time point. The 
statistical method will be the Bayesian version of a comparison of proportions (with predictions). The 
incidence estimates will also be reported at the following time points: 30 days, 6 months, one year, 2 
years, 3 years, 4 years, 5 years, 7 years and 10 years.  
• 
Quality of Life as assessed by Kansas City Cardiomyopathy (KCCQ) change from baseline at 30 days and 
one year 
The endpoint will be evaluated using a Bayesian analog of a two-sample t-test or the non-parametric 
Wilcoxon rank-sum test. The descriptive statistics for KCCQ change from baseline will also be reported 
at 30 days, 6 months, one year, and annually thereafter through 5 years. 
• 
The rate of repeat hospitalization for aortic valve disease at one year. 

 
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The incidence estimate will be provided for the two treatment groups at the specified time point. The 
statistical method will be the Bayesian version of a comparison of proportions (with predictions). In 
addition, the Kaplan-Meier estimates will be provided at the following time points: 30 days, 6 months, 
12 months, and annually thereafter through 10 years. 
• 
Device Success (VARC II), defined as 
o Absence of procedural mortality, AND 
o Correct positioning of a single prosthetic heart valve into the proper anatomical location, AND 
o Intended performance of the prosthetic heart valve, defined as the absence of patient-prosthesis-
mismatch and mean aortic valve gradient less than 20 mmHg (or peak velocity <3 m/sec), AND 
absence of moderate or severe prosthetic valve regurgitation. 
The incidence estimate will be provided for the TAVR group. 
• 
Hemodynamic performance metrics by Doppler echocardiography 
o Mean aortic gradient at one year 
o Effective orifice area at one year 
o Degree of total, peri, and transvalvular prosthetic regurgitation at one year 
For mean gradient and effective orifice area, the descriptive statistics will be reported at each of the 
assessed time point (30 days, 6 months, one year, 2 years, 3 years, 4 years, 5 years, 7 years and 10 
years). Prosthetic regurgitation severity will be reported as proportions at each of the assessed time 
point (30 days, 6 months, one year, 2 years, 3 years, 4 years, 5 years, 7 years and 10 years). 
• 
New York Heart Association (NYHA) functional classification at one year.  
NYHA function classification will be reported as proportions at each of the assessed time point (30 days, 
6 months, one year, 2 years, 3 years, 4 years, 5 years, 7 years and 10 years). 
• 
Health-related quality of life at one year as assessed by EQ-5D survey instrument. 
3.3.3.7 Multiplicity Considerations 
It is recognized that with a multiplicity of tests comes an inflation in the chance of a false finding of 
superiority or non-inferiority. Therefore, for the purpose of seeking approved labeling claims on designated 
secondary objectives, the following standard will be used:  if the primary objective demonstrates non-
inferiority, claims will be sought for selected secondary non-inferiority and superiority objectives and for 
superiority on the primary objective metric. These will be tested via a hierarchical (sequential) testing order 
that preserves the overall study-wise type I error rate at the level of 0.05.  The testing order is specified 
below. The following secondary objectives are tested in order, and testing continues if and only if all 
previous objectives have met their designated success criterion.      
1. Transvalvular mean gradient at 1 year (non-inferiority) 
2. Effective orifice area at 1 year (non-inferiority) 
3. Change in NYHA classification from baseline to 1 year (non-inferiority) 
4. Change in KCCQ score from baseline to 1 year (non-inferiority)  

 
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5. Transvalvular mean gradient at 1 year (superiority) 
6. Effective orifice area at 1 year (superiority) 
7. Change in KCCQ score from baseline to 30 days (superiority)  
All of the above non-inferiority will be tested with a type I error standard of 0.05 and superiority tests will 
be tested with a type I error standard of 0.025.  If all of the above tests meet their success criterion, the 
primary endpoint (superiority) will be tested using a type I error rate of 0.025. 
For the purposes of seeking claims, these objectives will only be evaluated once, at the same time as non-
inferiority of the primary objective is established.  The only exception to this is the primary endpoint 
superiority test, which carries the possibility of a delayed determination of superiority and may thus meet 
its success criterion at a different time (see Section 3.3.3.4.3 Sample Size and Analysis). 
The remaining secondary endpoints (see Section 3.3.3.5. Secondary Safety Endpoints and Section 3.3.3.6 
Secondary Effectiveness Endpoints) may be of interest for scientific reasons but will not be the basis for 
supporting labeling claims; they are thus outside of the hierarchical testing procedure. Similarly, for those 
objectives that test non-inferiority, if non-inferiority is established, a test of superiority may also be 
conducted, but unless specifically itemized in the list, such superiority testing is not part of the hierarchical 
testing procedure; these superiority tests may be of interest for scientific reasons but will not be the basis 
for supporting labeling claims. 
3.3.3.7.1 Ordered List of Secondary Objectives to be Tested to Support Labeling Claims 
1. Transvalvular mean gradient at 1 year (non-inferiority). The hypothesis of interest is  
H: µTAVR < µSAVR +5 
where µTAVR and µSAVR denote the average mean gradient at 1 year, measured in mmHg.  This objective 
will be evaluated using a Bayesian version of a two-sample t-test. The posterior probability P(H | data) 
will be calculated and compared to a threshold of 0.95.  
Rationale for Delta:  A difference less than 5 mmHg for mean gradient is not considered clinically 
relevant for the TAVR Low Risk Executive Committee. 
2. Effective orifice area at 1 year (non-inferiority). The hypothesis of interest is  
H: µTAVR > µSAVR – 0.1 
where µTAVR and µSAVR denote the mean effective orifice area at 1 year, measured in cm2.  This objective 
will be evaluated using a Bayesian version of a two-sample t-test. The posterior probability P(H | data) 
will be calculated and compared to a threshold of 0.95.   
Rationale for Delta:  A difference less than 0.1 cm2 for effective orifice area is not considered clinically 
relevant for the TAVR Low Risk Executive Committee. 
3. Change in NYHA classification from baseline to 1 year (non-inferiority). The hypothesis of interest is  
H: µTAVR > µSAVR – 0.375 
where µTAVR and µSAVR denote the mean number of classification improvements in NYHA from baseline 
to 1 year.  For subjects with NYHA categories at both baseline and 1-year visit, the NYHA classification 
improvements will be calculated as NYHAbaseline – NYHA12month. The objective will be evaluated using a 

 
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Bayesian version of a two-sample t-test. The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.95.    
Rationale for Delta:  A difference less than 0.375 for NYHA classification is not considered clinically 
relevant for the TAVR Low Risk Executive Committee. 
4. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 1 year (non-
inferiority). The hypothesis of interest is  
H: µTAVR > µSAVR -5 
where µTAVR and µSAVR denote the mean changes in the KCCQ score from baseline to 1 year.  For subjects 
with KCCQ score at both baseline and 1 year, the change in KCCQ will be calculated as KCCQ1year – 
KCCQbaseline. The objective will be evaluated using a Bayesian version of a two-sample t-test. The 
posterior probability P(H | data) will be calculated and compared to a threshold of 0.95.   
Rationale for Delta:  A 5-point improvement or decrease in KCCQ is the minimum difference that is 
clinically relevant. 54  
5. Transvalvular mean gradient at 1 year (superiority). The hypothesis of interest is  
H: µTAVR < µSAVR  
where µTAVR and µSAVR denote the average mean gradient at 1 year, measured in mmHg.  This objective 
will be evaluated using a Bayesian version of a two-sample t-test. The posterior probability P(H | data) 
will be calculated and compared to a threshold of 0.975.  
6.  Effective orifice area at 1 year (superiority). The hypothesis of interest is  
H: µTAVR > µSAVR   
where µTAVR and µSAVR denote the mean effective orifice area at 1 year, measured in cm2.  This objective 
will be evaluated using a Bayesian version of a two-sample t-test. The posterior probability P(H | data) 
will be calculated and compared to a threshold of 0.975.   
7. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 days 
(superiority).  The hypothesis of interest is  
H: µTAVR > µSAVR  
where µTAVR and µSAVR denote the mean changes in the KCCQ score from baseline to 30 days.  For 
subjects with KCCQ score at both baseline and 30 days, the change in KCCQ will be calculated as 
KCCQ30day – KCCQbaseline. The objective will be evaluated using a Bayesian version of a two-sample t-
test. The posterior probability P(H | data) will be calculated and compared to a threshold of 0.975. 
3.3.3.8 Missing Data 
Every effort will be undertaken to minimize missing data. However, some missing data is inevitable, and the 
trial is designed with the expectation that there may be up to 6% of primary data missing at 24 months. The 
reasons for missing data will be described and evaluated for assessment of possible bias. The distribution of 
prognostic factors between subjects with data and those without data will be examined to evaluate any 
potential sources of bias. 

 
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3.3.3.9 LTI Analysis 
The incidence of LTI will be assessed when at least 150 TAVR and at least 150 SAVR evaluable subjects have 
completed the 30 day MDCT scans and the 1 year MDCT scans. This analysis will not impact the Type I error 
rate of this trial as no decisions to alter the main trial are allowed based on this analysis. 
3.3.4 
Number of Subjects and Investigational Devices, Trial Duration 
This trial will involve at least 1200 subjects in the AT population among all active sites. No site will implant 
more than 100 subjects without prior authorization from Medtronic. Subjects who exit from the trial after 
implantation will not be replaced. 
Subjects will be consented for follow-up through 10 years. The enrollment period is estimated to be 
between 18 to 24 months; therefore the estimated total duration of the trial (first subject enrolled to last 
subject completing his/her last follow-up exam) is estimated to be 12 years. The number of investigational 
TAVR systems used in the trial is estimated to between 600 and 700 (based on sample size and 1:1 
randomization).  
Randomization will continue until the required number of subjects in the LTI Sub-Study and the Japan 
addendum are met, up to 1540 randomized subjects. 
3.3.5 
Subject Selection Criteria 
3.3.5.1 Inclusion Criteria 
Prospective subjects must meet all of following inclusion criteria to be eligible for implantation: 
1. Severe aortic stenosis, defined as follows: 
a) For symptomatic patients: 
Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), OR mean gradient ≥40 
mmHg, OR Maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest 
b) For asymptomatic patients: 
- 
Very severe aortic stenosis with an aortic valve area of ≤1.0 cm2 (or aortic valve area index of 
≤0.6 cm2/m2), AND maximal aortic velocity ≥5.0 m/sec , or mean gradient ≥60 mmHg by 
transthoracic echocardiography at rest, OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND a mean gradient 
≥40 mmHg or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at 
rest, AND an exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP 
response, or arrhythmia OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND mean gradient 
≥40 mmHg, or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at 
rest, AND a left ventricular ejection fraction <50%. 
2. Patient is considered low risk for SAVR, where low risk is defined as predicted risk of mortality for SAVR 
<3% at 30 days per multidisciplinary local heart team assessment. 
3. The subject and the treating physician agree that the subject will return for all required post-procedure 
follow-up visits. 

 
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3.3.5.2 Exclusion Criteria 
If any of the following exclusion criteria are present, the prospective subject is not eligible for implantation: 
1. Any condition considered a contraindication for placement of a bioprosthetic valve (eg, subject is 
indicated for mechanical prosthetic valve). 
2. A known hypersensitivity or contraindication to any of the following that cannot be adequately pre-
medicated: 
a. aspirin or heparin (HIT/HITTS) and bivalirudin 
b. ticlopidine and clopidogrel 
c. Nitinol (titanium or nickel) 
d. contrast media 
3. Blood dyscrasias as defined: leukopenia (WBC <1000 mm3), thrombocytopenia (platelet count <50,000 
cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states. 
4. Ongoing sepsis, including active endocarditis. 
5. Any percutaneous coronary or peripheral interventional procedure with a bare metal stent within 30 
days prior to randomization, or drug eluting stent performed within 180 days prior to randomization. 
6. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left main coronary 
artery. 
7. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 10 
weeks of Heart Team assessment. 
8. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support. 
9. Recent (within 2 months of Heart Team assessment) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA). 
10. Gastrointestinal (GI) bleeding that would preclude anticoagulation. 
11. Subject refuses a blood transfusion. 
12. Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, 
prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate 
rehabilitation from the procedure or compliance with follow-up visits). 
13. Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid conditions. 
14. Other medical, social, or psychological conditions that in the opinion of the investigator precludes the 
subject from appropriate consent or adherence to the protocol required follow-up exams. 
15. Currently participating in an investigational drug or another device trial (excluding registries). 
16. Evidence of an acute myocardial infarction ≤30 days before the trial procedure due to unstable 
coronary artery disease (WHO criteria). 
17. Need for emergency surgery for any reason. 
18. Subject is pregnant or breast feeding. 
19. Subject is less than legal age of consent, legally incompetent, or otherwise vulnerable 
Anatomical exclusion criteria: 
20. Pre-existing prosthetic heart valve in any position. 
21. Severe mitral regurgitation amenable to surgical replacement or repair. 

 
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22. Severe tricuspid regurgitation amenable to surgical replacement or repair. 
23. Moderate or severe mitral stenosis amenable to surgical replacement or repair. 
24. Hypertrophic obstructive cardiomyopathy with left ventricular outflow gradient. 
25. Bicuspid aortic valve verified by echocardiography, MDCT, or MRI. 
26. Prohibitive left ventricular outflow tract calcification. 
27. Sinus of Valsalva diameter unsuitable for placement of the self-expanding bioprosthesis. 
28. Aortic annulus diameter of <18 or >30 mm. 
29. Significant aortopathy requiring ascending aortic replacement. 
For transfemoral or transaxillary (subclavian) access: 
30. Access vessel mean diameter <5.0 mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean 
diameter <5.5 mm for Evolut 34R mm or  Evolut PRO TAV. However, for transaxillary (subclavian) access 
in patients with a patent LIMA, access vessel mean diameter <5.5mm for Evolut 23R, 26R, or 29R mm 
TAV, or access vessel mean diameter <6.0 mm for the Evolut 34R or  Evolut PRO TAV ii. 
 
France 
Inclusion and exclusion criteria required in France are included in the Clinical Investigation Plan Addendum: 
France – Addendum for France to Clinical Investigational Plan Document Number 10234430DOC. 
3.3.6 
Informed Consent 
Prior to enrolling in the trial, patients should be fully informed of the details of trial participation as 
required by applicable regulations, the site’s IRB and by Medtronic. Informed consent must be obtained 
from each patient prior to conducting any protocol-induced activities beyond standard of care, by using the 
informed consent form (ICF) approved by that site’s IRB and by Medtronic. The ICF must be signed and 
dated by the patient and by the person obtaining the consent. Any additional persons required by the site’s 
IRB to sign the informed consent form must also comply. 
Prior to the patient signing the ICF, the investigator or authorized designee will fully explain to the patient 
the nature of the research, trial procedures, anticipated benefits, and potential risks of participation in the 
trial. The investigator or delegate will allow adequate time for the patient to read and review the consent 
form and to ask questions. Signing the ICF serves to document the written and verbal information that the 
investigator or authorized delegate provides to the patient, the patient’s understanding of the information, 
and his/her agreement to participate. The investigator or authorized delegate must document in the 
patient’s medical records that the patient was consented and the date on which the consent was obtained. 
The original signed consent form will be retained in the patient’s trial records and a copy of the informed 
consent will be provided to the patient. 
3.3.7 
Revisions in Patient Information and Informed Consent Form 
Medtronic will inform the investigators whenever information becomes available that may be relevant to 
the subject’s continued participation in the trial. The revised information will be sent to the investigator for 
                                                                 
iiFor subjects with a patent LIMA undergoing tranaxillary (subclavian) access, the minimal access vessel mean diameter is 5.5 mm for the Evolut 23R, 
26R, and 29R TAV, and 6.0 mm for the Evolut 34R and Evolut PRO TAV. 

 
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approval by the IRB/EC. After approval by the IRB/EC, a copy of this information must be provided to the 
participating subjects, and the informed consent process as described above needs to be repeated. The 
investigator or his/her designee should inform the subject in a timely manner. 
3.3.8 
Screening, Enrollment, and Randomization 
The process of patient screening, subject enrollment, and randomization is as follows (Figure 1): 
1. Patients identified by or presented to the trial site with aortic stenosis will be screened by the 
investigative team for the criteria described in 3.3.5, Subject Selection Criteria, using available medical 
records, including relevant imaging studies previously performed for diagnostic purposes. 
2. If the patient is deemed a potential candidate for the trial, the investigational status of the Medtronic 
TAVR System and all aspects of the trial will be explained to the patient. The patient will then be invited 
to participate in the Low Risk Trial. Sites participating in the LTI Sub-study will also invite patients to 
consent for the LTI Sub-Study. 
3. If the patient agrees to participate, written informed consent will be obtained. This will be considered 
the point of enrollment, and the subject will be assigned a Subject ID number. 
4. The subject will undergo transthoracic echocardiography (TTE) to assess his/her degree of aortic 
stenosis. 
5. Subjects who meet the criteria for aortic stenosisiii will undergo:  
a. 
Multi-Detector Computed Tomography (MDCT) of their peripheral vasculature and aortic annulus 
to assess anatomic suitability for the Medtronic TAVR , and 
b. 
Local Heart Team assessment to determine his/her operative risk profile for SAVR. 
6. If the local Heart Team considers the subject anatomically suitable for implantation and at low risk for 
SAVR, the subject‘s clinical information will be submitted to the Screening Committee. The Heart Team 
assessment must be documented. The following information should be submitted to the Screening 
Committee: 
• 
Clinical assessments including STS-PROM, medical history and co-morbidities 
• 
TTE data on degree of aortic stenosis 
• 
MDCT data on anatomical suitabilityiv 
7. The Screening Committee will review the clinical information to confirm the eligibility of the subject for 
implantation. 
8. Subjects confirmed eligible for implantation by the Screening Committee will be randomized in a 1:1 
fashion to either TAVR or SAVR, stratified by site and the need for coronary revascularization during 
SAVR. Coronary artery bypass graft (CABG) should be conducted during the index procedure. 
Concomitant percutaneous coronary intervention (PCI)v and TAVR is encouraged; however staging is 
left to the discretion of the operator. Intervention/repair of the mitral and/or tricuspid valve is only 
                                                                 
iiiIf a subject has balloon aortic valvuloplasty after their qualifying TTE, they must have repeat TTE to confirm he/she meets criteria for severe aortic 
stenosis as described in Section 3.3.5.1 prior to submission to the screening committee. 
iv Anatomical suitability will be confirmed by Medtronic Screening Lab. Information on MDCT procedures and sizing recommendations is provided in 
Appendix II, Section 4.0. 
v Index PCI should be performed at the TAVR implanting center; index PCI operators will be considered investigators. 

 
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allowed if deemed necessary during the SAVR procedure, but there must be no intent to do this type of 
intervention/repair prior to implant. 
9. Trial randomization will not be blinded. Once randomization is complete and a treatment arm is 
assigned, crossover from SAVR to TAVR treatment is not permitted. The sponsor will strictly monitor 
device dispensation to ensure that only those subjects randomized to the Medtronic TAVR treatment 
arm receive the Medtronic TAV. Distribution of the subjects within the trial groups will be controlled at 
the implanting sites by means of central randomization using interactive voice/web randomization 
service (IXRS). The randomization scheme will be securely stored at the IXRS provider. 
10. Implantation should occur within 90 days of Screening Committee approval. 
11. Subjects who consent to participate in the LTI study will also follow the LTI sub-study protocol as 
described in APPENDIX VII: LEAFLET THICKENING/IMMOBILITY SUB-STUDY PROTOCOL 
Patients should give written consent before undergoing any protocol-required testing. However, if any of 
protocol-required baseline/screening evaluations (eg, echocardiography, MDCT, coronary arteriography, lab 
work) have been performed for clinical diagnostic purposes prior to consenting, they can be used as the 
protocol-required exams, provided they were obtained within the protocol-required time windows and contain 
the necessary information. 
 

 
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Figure 1. Flow diagram of trial entry process. 
 

 
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3.3.9 
Required Evaluations 
Follow-up protocol required evaluations should be performed at the trial site. The protocol required 
evaluations for each trial interval are listed as follows, and summarized in Table 2 and Table 3. 
Baseline/Pre-implant Required prior to Screening Committee Submission (within 12 weeks prior to 
submission to the Screening Committee; except for MDCT and coronary arteriography) vi 
• 
Clinical assessment and history (eg, clinical history, STS-PROM, co-morbidities, NYHA) v 
• 
Coronary arteriography 
• 
TTE 
• 
Heart Team assessment 
• 
MDCT (peripheral vasculature and aortic annulus) 
• 
Adverse Events 
Baseline/Pre-implant Required prior to Index Procedure 
• 
12-lead ECG 
• 
Complete blood count, creatinine,  
• 
Modified Rankin Score 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
Euro-Qol (EQ-5D) Quality of Life survey 
• 
Anti-thrombotic medications 
• 
Adverse Events 
Implant Procedure (TAVR subjects) 
• 
Post-deployment hemodynamics and aortography (final result) 
• 
Adverse Events 
12 to 24 Hours Post Procedure 
• 
12 lead ECG 
• 
Adverse Events 
18 hours to 7 days Post Procedure (Device Success) 
• 
TTE (for device success) 
• 
Creatinine 
• 
Adverse Events 
Discharge (7 days post procedure or discharge, whichever comes first) 
• 
Clinical assessment (NYHA not assessed at discharge) 
• 
12 lead ECG 
• 
Modified Rankin Score 
• 
Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 
 
                                                                 
v i Pre-implant MDCT and Coronary arteriography should be performed within 365 days of submission to the screening committee date 
v  Definitions of STS risk factors and other co-morbidities are provided in Appendix III 

 
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30 days (between 30 to 45 days post implant) 
• 
Clinical assessment 
• 
TTE 
• 
12 lead ECG 
• 
Creatinine 
• 
Modified Rankin Score 
• 
KCCQ 
• 
EQ-5D 
• 
Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 
Six Months (between 183 to 213 days post implant) 
• 
Clinical assessment 
• 
TTE 
• 
Modified Rankin Score 
• 
KCCQ 
• 
EQ-5D 
• 
Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 
One Year (between 365 and 395 days post implant) 
• 
Clinical assessment 
• 
TTE 
• 
Modified Rankin Score 
• 
KCCQ 
• 
EQ-5D 
• 
Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 
18 Months (between 545 and 575 days post-implant) 
• 
Clinical assessment 
• 
Modified Rankin Score 
• 
Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 
Two Year (between 730 and 760 days post-implant) 
• 
Clinical assessment 
• 
TTE 
• 
Modified Rankin Score 
• 
KCCQ 
• 
Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 

 
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Annually from 3 years through 5 years (between implant anniversary date and +/-60 days after) 
• 
Clinical assessment 
• 
TTE 
• 
Modified Rankin Score 
• 
KCCQ 
• 
 Anti-thrombotic medications 
• 
I.N.R. (for subjects on VKA) 
• 
Adverse Events 
6 years, 8 years and 9 years (between implant anniversary date and +/-60 days after) 
• 
Adverse Event review conducted via telephone 
7 years and 10 years (between implant anniversary date and +/-60 days after) 
• 
Clinical assessment 
• 
TTE 
• 
Adverse Events 
 
Other Evaluations 
• 
Creatinine clearance will be derived by the trial database system using the Cockcroft-Gault equation. 
• 
A Modified Rankin Score assessment should be conducted at 1 and 3 months following any suspected 
or confirmed stroke event. 
Table 2. Summary of visit schedule and required evaluations through 5 years 
 
Baseline 
(Pre-
Implant) 
Implant 
12 to 24 
Hrs 
18 Hrs to 
7 Days 
(Device 
Success) 
Discharge  
30 
Days 
6 
Months 
1 
Year 
18 
Months 
Annual 
(through 
5 Years) 
Clinical 
Assessment 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coronary 
Arteriography 
X 
 
 
 
 
 
 
 
 
 
MDCT 
X 
 
 
 
 
 
 
 
 
 
TTE 
X 
 
 
X 
 
X 
X 
X 
 
X 
12-lead ECG 
X 
 
X 
 
X 
X 
 
 
 
 
Modified 
Rankin Score 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Hemodynamics 
 
X 
 
 
 
 
 
 
 
 
Aortography 
 
X 
 
 
 
 
 
 
 
 
Complete 
Blood Count 
X 
 
 
 
 
 
 
 
 
 
Creatinine 
X 
 
 
X 
 
X 
 
 
 
 
I.N.R. 
 
 
 
 
X 
X 
X 
X 
X 
X 
Anti-
thrombotic 
medications 
X 
 
 
 
X 
X 
X 
X 
X 
X 
KCCQ 
X 
 
 
 
 
X 
X 
X 
 
X 
EQ-5D 
X 
 
 
 
 
X 
X 
X 
 
 

 
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Table 3. Summary of visit schedule and required evaluations from 6 through 10 years 
 
Years 6, 8, and 9 
Years 7 and 10 
Clinical 
Assessment 
 
X 
Adverse Events 
X 
X 
TTE 
 
X 
Visit Windows 
Baseline 
Within 12 weeks prior to submitting to the screening committee (except for MDCT and coronary arteriography) as 
noted in Section 3.3.9) 
Discharge 
Discharge from index procedure or 7 days post implant, whichever comes first 
30 Days  
Between 30 and 45 days post implant 
6 Months 
Between 183 and 213 days post implant 
1 Year 
 
Between 365 and 395 days post implant 
18 Months 
Between 545 and 575 days post-implant 
2 Year 
 
Between 730 and 760 days post-implant 
3 – 10 years Between implant anniversary date and +/-60 days after 
Notes 
1. 
NYHA assessment not required at discharge 
2. 
TTE for device success should be performed within 18 hours to 7 days post-procedure 
3. 
Adverse events should be assessed at each visit 
4. 
Hemodynamics and aortography for TAVR subjects only 
5. 
I.N.R. only required for subjects on VKA 
6. 
TTE can be collected at 8 year follow-up visit if missed during 7 year visit 
 
Throughout this trial, UB-04 summary bills and itemized hospital bills for TAVR and SAVR subjects will be collected by 
the Baim Institute at select clinical sites in the US. Prior to the collection of billing information, patients will be asked 
to provide the information and permission to obtain such billing records for the length of their follow-up period. All 
related data will be kept in a secure and confidential database. 
 
3.3.10 Post-Implant Anti-thrombotic Therapy 
Management of subject’s anti-thrombotic regimen will be per the discretion of the investigator, in 
accordance with the 2014 AHA/ACC Guideline for the Management of Patients With Valvular 
Heart Disease.13 
The recommended post implant anti-thrombotic regimen for TAVR subjects will be 30 days or more of Dual 
Anti-Platelet Therapy (DAPT) followed by aspirin through 12 months. 
The recommended post implant regimen for SAVR subjects will be a Vitamin K Antagonist (VKA) or aspirin 
in accordance with current guidelines. 
3.3.11 Subject Disposition 
Sites will maintain a log of subjects consented, his/her assigned treatment group, date attempted and 
implanted, as well as the Subject ID numbers assigned to each patient. Subjects who are consented but are 
not taken to the procedure room for implantation will be exited from the trial, and will not be followed 
beyond the date of trial exit. 

 
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Subjects who are taken to the procedure room for implantation but do not receive a TAV or surgical valve 
for any reason will be followed for the trial duration. Subjects that have their TAV or SAVR bioprosthesis 
explanted will be followed for the trial duration. 
3.3.12 Implant Procedure (TAVR) 
The implantation procedure is performed according to the standard procedures of the implanting 
physicians. In countries where required, specifically the United States and Japan, the local heart team’s 
interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical 
aspects of the TAVR procedure. Procedural aspects specific to the Medtronic TAVR system should be 
performed according to the Instructions for Use, with the exception of the use of pre-deployment balloon 
aortic valvuloplastyvii. The following variables will be collected regarding the TAVR implantation procedure: 
• 
Name of the primary and secondary operator 
• 
Anesthesia type (general or local) 
• 
Delivery catheter access site and vessel diameter of access site 
• 
Use of EnVeo InLine Sheath alone, OR use of separate introducer sheath size and type 
• 
Pre-deployment BAV (yes/no) 
• 
Use of rapid pacing during BAV and deployment (yes/no) 
• 
Size of TAV implanted 
• 
Post-implant dilation (yes/no) 
• 
Post-implant pressures at final result (LV systolic and end-diastolic, aortic systolic and diastolic) 
• 
Implantation of TAV within the desired location (yes/no) 
• 
Post-implant degree of prosthetic regurgitation by angiography (Sellers criteria)55 
• 
Post-implant degree of prosthetic paravalvular regurgitation by TEE, if performed 
• 
Post-implant degree of prosthetic transvalvular regurgitation by TEE, if performed 
• 
More than one TAV implanted (yes/no) 
• 
Patency of coronary arteries post-implant (yes/no) 
• 
Estimated contrast volume used 
• 
Total procedural time(minutes): time in procedure room to exit from procedure room 
• 
Information on use of resheath/recapture featureviii 
• 
Occurrence of adverse events 
• 
If TAV implantation not attempted, reason why 
 
                                                                 
v ii For this trial, the use of pre-deployment BAV is per the discretion of the implanting physician. It will not be considered a deviation if pre-
deployment BAV is not performed. 
v iii Definitions of resheath/recapture use are provided in Appendix IV. 

 
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3.3.13 Implant Procedure (SAVR) 
Surgical aortic valve replacement should be performed according to the implanting surgical team’s standard 
routine. Procedural aspects specific to the bioprosthesis should be performed according to the Instructions 
for Use for the respective bioprosthesis. The following variables will be collected regarding the SAVR 
implantation procedure: 
• 
Name of primary surgeon 
• 
Valve size implanted 
• 
Manufacturer of implanted valve 
• 
Valve positioning (supra-annular, intra-annular, sub-annular) 
• 
Concomitant procedures performed 
• 
Post-implant degree of prosthetic paravalvular regurgitation by TEE, if performed 
• 
Post-implant degree of prosthetic transvalvular regurgitation by TEE, if performed 
3.3.14 Clinical Assessment 
Clinical assessment is required at the following post-implant intervals: discharge, 30 days, 6 months, 1 year, 
18 months, 2 years, 3 years, 4 years, 5 years, 7 years and 10 years. The following variables will be 
documented at each protocol-required follow-up interval: 
• 
Follow-up status 
• 
NYHA functional classification (except at discharge) 
• 
Modified Rankin Score (except at years 6 through 10) 
• 
Prescribed antithrombotic medications (except at years 6 through 10) 
• 
KCCQ (except at discharge, 18 months, and years 6 through 10) 
• 
EQ-5D (except at discharge, 18 months, and years 2 through 10) 
• 
Documentation of any adverse events  
o Adverse Events will be collected via telephone at 6 year, 8 year, and 9 year visits 
3.3.15 Echocardiography 
Transthoracic echocardiography (TTE) is required at the following intervals: pre-implant, 18 hours to 7 days 
(for device success), 30 days, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years and 10 years. 
Exams will be sent to the Echo Core Lab for central assessment. Further details of the echocardiography 
methods are provided in APPENDIX I: ECHOCARDIOGRAPHY PROCEDURES. Sites will acquire the necessary 
views and measurements in order for the Echo Core Lab to assess the following variables at each protocol-
required exam: 
• 
Height (cm or in) and weight (kg or lb) 
• 
Heart rate 
• 
Left ventricular outflow tract (LVOT) diameter in mid systole 
• 
Max aortic/prosthetic valve velocity (V2) by CW Doppler 
• 
Aortic valve velocity time integral (VTI) by CW Doppler 
• 
Mean gradient across aortic valve (MGV2) by CW Doppler 
• 
LVOT VTI by PW Doppler 
• 
Grade of aortic/prosthetic transvalvular regurgitation (post-implant only) 

 
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• 
Grade of aortic/prosthetic paravalvular regurgitation (post-implant only) 
• 
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
• 
Grade of mitral regurgitation 
• 
Grade of tricuspid regurgitation 
• 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
• 
Left ventricular internal dimension at end diastole 
• 
Left ventricular internal dimension at end systole 
• 
Interventricular septal thickness at end diastole 
• 
Left ventricular posterior wall thickness at end diastole 
• 
Left atrial diameter (anterior-posterior linear dimension) at systole 
• 
Left ventricular ejection fraction by visual estimate 
• 
Grade of diastolic dysfunction (if present) 
In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the site: 
• 
Body surface area (Dubois and Dubois)56 
• 
Peak aortic pressure gradient 
• 
Aortic valve area (AVA)/effective orifice area (EOA) by continuity equation 
• 
Aortic valve area index (AVAI)/effective orifice area index (EOAI) 
• 
Doppler Velocity Index (DVI) 
• 
Estimated right ventricular systolic pressure (RVSP) 
Derived variables will be displayed on the eCRF upon entry of the appropriate raw measurements. The pre-
implant qualifying AVA or AVAI must be based on the site reported variables for LVOT diameter, LVOT VTI, 
aortic valve VTI, height, and weight. 
3.3.16 Missed Follow-up Visits 
Every effort should be made to ensure subjects return to the clinic for all protocol required follow-ups. If 
the subject is unable to return for an in-person clinic visit, the Investigator, or designee, should document in 
the subject record the reason the subject was unable to complete the visit and, if applicable, follow the 
requirements for deviation reporting as outlined in section 3.3.18 
Protocol Deviations. 
The investigator should also make every effort to contact the subject within the visit window to collect the 
subject’s vital status as well as information related to potential adverse events, safety data, and 
hospitalizations. 
3.3.17 Unscheduled Follow-up Visits 
If a subject returns to the study site or is contacted via telephone between their scheduled follow-up visits 
for an event potentially related to a study endpoint, the visit  or telephone call will be treated as an 
unscheduled follow-up, and the assessments completed at this visit will be conducted at the discretion of 
the investigator. eCRFs are provided for unscheduled visits. 

 
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3.3.18 Protocol Deviations 
A protocol deviation is defined as an event where the clinical investigator or site personnel did not conduct 
the study according to the protocol or the Investigator Agreement. Examples of protocol deviations include 
but are not limited to the following: 
• 
Failure to obtain informed consent prior to participation 
• 
Incorrect version of the informed consent form used 
• 
Failure to obtain IRB approval before the start of the study 
• 
Implanted subject did not meet inclusion/exclusion criteriaix 
• 
Required testing and/or measurements not done or incorrectly done 
• 
Subject does not attend follow-up visit or follow-up visit outside window 
• 
Unauthorized use of investigational devices 
• 
Adverse events not reported in the required time frame as required by regulation or as specified in the 
CIP 
• 
Control of study devices not maintained 
• 
Source data permanently lost 
• 
Enrollment of patients during lapse of IRB approval 
• 
Enrollment limits exceeded 
Investigators should obtain prior approval from Medtronic before initiating any change or deviation from 
the CIP, except where necessary to protect the life or physical well-being of a subject in an emergency 
situation. Such approval shall be documented in writing and maintained in the Investigator Site File. Prior 
approval is generally not expected in situations where unforeseen circumstances are beyond the 
investigator’s control (eg, subject did not attend scheduled follow-up visit). 
Deviations will be reported to Medtronic regardless of whether medically justifiable, pre-approved by 
Medtronic, or taken to protect the subject in an emergency. Study deviations should be reported to 
Medtronic via the Study Deviation eCRF (one eCRF for each protocol deviation). 
Investigators should report the following deviations to Medtronic and their reviewing IRB/EC within 5 
working days of the occurrence of the deviations:  
• 
Failure to obtain written informed consent 
• 
Deviations to protect the life or physical well-being of a subject in an emergency 
In addition, Investigators are required to adhere to local IRB/EC procedures for reporting deviations.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any corrective 
and/or preventive actions that may be warranted. Repetitive or serious investigator compliance issues may 
represent a need to initiate a corrective action plan, which may include suspension of enrollment or 
termination of the investigator’s or site’s participation in the study. 
                                                                 
ix Subjects must meet all inclusion/exclusion criteria to be eligible for implantation. However, it will not be considered a protocol deviation if study 
related testing (eg. echo, MDCT, labs, coronary arteriography, Heart Team assessment, or Screening Committee assessment) of a consented subject 
identifies implantation eligibility criteria that are not met. 

 
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3.3.19 Trial Materials and Trial Specific Equipment 
Medtronic will control the supply of investigational devices and trial materials (eg, Investigator Site File, 
eCRF access). Investigational devices will not be sent to the site until the site is activated. Medtronic will not 
provide any trial-specific equipment to the sites. Equipment used for assessing study variables (eg, 
echocardiographic systems) should be maintained per the site’s standard procedures. 
3.3.20 Device Accountability 
The Evolut R TAV, the EnVeo R DCS with EnVeo InLine Sheath, the EnVeo R LS, the EnVeo PRO DCS, the 
EnVeo PRO LS, and the  Evolut PRO TAV, DCS, and LS are not approved for use in low risk patients, and 
therefore are considered investigational devices. As such, they should be stored as labeled and in a secure 
location. The method of storage should prevent the use of these investigational devices for applications 
other than mentioned in this CIP. The investigator shall maintain adequate records of the receipt and 
disposition of all investigational devices. 
Centers are required to maintain investigational device records that contain the following information: 
• 
Investigational device name 
• 
TAV serial number 
• 
Lot number (for delivery catheter system and loading system only) 
• 
Date of receipt of device 
• 
Name of person receiving the device 
• 
Name of person using the device 
• 
Date of implant or use 
• 
ID number of subject receiving or using the device 
• 
Disposition (implanted, disposed of, or returned to Medtronic) 
For devices that are returned to Medtronic or disposed of, centers are required to document the following 
information: 
• 
TAV serial numbers 
• 
Lot numbers (for delivery catheter system and loading system only) 
• 
The quantity and reason for the device being returned to Medtronic or disposed of 
• 
Name of the person who returned or disposed of each device 
• 
Date of shipment back to Medtronic 
At the trial closeout visit, the investigator must return to Medtronic any unused devices and a copy of the 
completed device inventory. The investigator’s copy of the device reconciliation records must document 
any unused devices that have been returned to Medtronic as well as all product usage including opened but 
non-implanted devices. 
 

 
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3.3.21 Device Malfunction or Explant 
In the event of a device malfunction of the Medtronic TAVR system prior to implant, or in the event a TAV 
or surgical bioprosthesis is explanted after implant (due to reintervention or autopsy), the TAV or surgical 
bioprosthesis, and/or affected components Medtronic TAVR system should be sent to Medtronic at the 
following address: 
Medtronic  
Attn: Explant Lab [PE#] 
1851 E. Deere Avenue 
Santa Ana, CA 92705-5720 
Additional details surrounding the device return process are contained within the Medtronic explant kit 
that will be provided upon notification of a device malfunction or explant.  
3.3.22 Subject Withdrawal or Discontinuation 
All subjects will be encouraged to remain in the trial through the last follow-up visit at 10 years. Subjects 
who discontinue participation prematurely will be included in the analysis of results (as appropriate) and 
will not be replaced in the enrollment of total trial subjects. If a subject is discontinued from the trial early, 
the reason for discontinuation should be documented in the subject file and a Trial Exit eCRF must be 
completed. 
The study trial site will make every effort to have all subjects complete the follow up visit schedule. A 
subject will not be considered lost to follow-up unless all efforts to obtain compliance are unsuccessful. At a 
minimum, the effort to obtain follow-up information must include 3 attempts to make contact via 
telephone and if contact via phone is not successful, a traceable letter from the investigator should be sent 
to the subject’s last known address. Should both telephone and mail efforts to contact the subject be 
unsuccessful, the subject’s primary physician should be contacted. Subjects will then be deemed lost to 
follow up. All contact efforts to obtain follow-up must be documented in both the subject’s medical records 
and on the trial eCRFs. 
If a subject discontinues the trial at any time, is withdrawn from the trial early, or completes all protocol 
required follow-up they should continue to be followed by the implanting site according to their routine 
clinical practice for aortic valve patients. If, for any reason, this is not possible for a particular subject, or if a 
subject needs to change their follow-up site at any time point after conclusion of the trial, investigators 
should refer subjects to a local site with appropriate training and experience in managing patients with 
implanted aortic valves.  
 

 
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3.3.23 Early Suspension or Termination of the Trial 
Medtronic may decide to suspend or prematurely terminate the trial (eg, if information becomes available 
that the risk to study subject is higher than initially indicated, if interim analysis indicates that the results 
significantly differ from the clinical study objectives or statistical endpoints). If the trial is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators and regulatory 
authorities of the termination or suspension and the reason(s) for this. The investigator shall then promptly 
inform the reviewing IRB/EC. Medtronic will, as soon as possible, provide a written statement to the 
investigators to enable prompt notification of the IRB/ECs. If trial enrollment is terminated early, follow-up 
visits will continue for all enrolled subjects. 
3.3.24 Early Suspension or Termination of a Trial Site 
Medtronic may decide to suspend or prematurely terminate an investigation site (eg, in case of expiring 
approval of the reviewing IRB/EC, non-compliance to the CIP, or lack of enrollment). If an investigation site 
is suspended or prematurely terminated, Medtronic shall promptly inform the investigator(s) of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform the 
reviewing IRB/EC. 
3.3.25 Revisions or Amendments to the Clinical Investigational Plan 
The investigator may propose any appropriate modification(s) of the CIP or investigational device or 
investigational device use. Medtronic will review this proposal and decide whether the modification(s) will 
be implemented. 
Medtronic will submit any significant amendment to the CIP, including a justification for the amendment, to 
all affected regulatory agencies and to the investigators to obtain approval from their IRB/EC. The 
investigator will only implement the amendment after approval of the IRB/EC, regulatory agencies, and 
Medtronic. Administrative amendments to the CIP will be submitted to the IRB/EC for notification. 
Furthermore, investigators shall sign any approved amendment for agreement. 
 
 

 
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3.3.26 Adverse Events, Adverse Device Effects, and Device Deficiencies 
3.3.26.1 Definitions 
The definitions to be applied for the purposes of reporting adverse events are provided in Table 4. 
Table 4. Adverse event definitions for reporting requirements 
Event Type 
Definition 
Adverse Event (AE)  
 
(ISO14155:2011 3.2) 
 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other parties, 
whether or not related to the investigational medical device.57 
NOTE 1: This definition includes events related to the investigational medical device or 
the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other parties, this definition is restricted to events related to 
investigational medical devices. 
Serious Adverse Event 
(SAE)  
 
(ISO14155:2011 3.37) 
 
 
Adverse event that  
a) 
led to death, 
b) 
led to a serious deterioration in the health of the subject, resulting in  
1) 
a life-threatening illness or injury, or  
2) 
a permanent impairment of a body structure or a body function, or 
3) 
in-patient or prolonged hospitalization, or  
4) 
medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
c) 
led to fetal distress, fetal death or a congenital abnormality or birth defect.57  
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by 
the CIP, without serious deterioration in health, is not considered a serious adverse 
event. 
Adverse Device Effect 
(ADE) 
or Device Related 
Adverse Event 
(ISO14155:2011 3.1) 
Adverse event related to the use of an investigational medical device. 
NOTE 1: This definition includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or operation, 
or any malfunction of the investigational medical device.57  
NOTE 2: This definition includes any event resulting from an error use or from 
intentional misuse of the investigational medical device. 
Serious Adverse Device 
Effect (SADE) 
(ISO14155:2011 3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
Serious Adverse Event.57, 58  
Unanticipated Adverse 
Device Effect 
(UADE) 
(21 CFR 812.3) 
 
Any serious adverse effect on health or safety of a patient, or any life-threatening 
problem or death caused by or associated with the device, if the effect, problem, or 
death has not been previously identified in nature, severity, or degree of incidence in 
the investigational plan or application, (including a supplementary plan or application), 
or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects.59 
 

 
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Table 3. Adverse event definitions for reporting requirements (continued) 
 
3.3.26.2 Evaluation and Documentation of Adverse Events and Device Deficiencies 
Investigators are required to evaluate and document in the subject’s medical records all adverse events 
(AE) and device deficiencies (per the definitions in Table 4) observed in trial subjects from the time they are 
enrolled until they are exited from the trial. All AE should be followed through their resolution. 
All AEs that occur during the trial need to be reported to Medtronic via the AE eCRF. Documented pre-
existing conditions are not considered to be reportable unless there is a change in the nature or severity of 
the condition. Pre-existing events should be reported as AE in the situation where a new treatment has to 
Event Type 
Definition 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
(ISO14155:2011 3.42) 
Serious adverse device effect which by its nature, incidence, severity or outcome has 
not been identified in the current version of the risk analysis report,57 
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its 
nature, incidence, severity or outcome has been identified in the risk analysis report. 
Device Deficiency 
 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance.57  
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
Mandatory Problem 
Reporting Incident  
(SOR/98-282 59-61.1(2)) 
An incident that (a) is related to a failure of the device or a deterioration in its 
effectiveness, or any inadequacy in its labeling or in the directions for use, and (b) has 
led to the death or a serious deterioration in the state of health of a patient, user or 
other person, or could do so were it to recur.  
NOTE: this definition and reporting requirement pertains to events that occur within 
Canada only. 
Significant Safety    Issue 
(SSI) 
(NHMRC Safety 
monitoring and reporting 
in clinical trials involving 
therapeutic goods 
November 2016) 
   A safety issue that could adversely affect the safety of participants or materially 
impact on the continued ethical acceptability or conduct of the trial. 
 
Urgent Safety Measure 
(USM) 
(NHMRC Safety 
monitoring and reporting 
in clinical trials involving 
therapeutic goods 
November 2016) 
A measure required to be taken in order to eliminate an immediate hazard to a 
participant’s health or safety. 
Note: This type of significant safety issue can be instigated by either the investigator 
or sponsor and can be implemented before seeking approval from Human Research 
Ethics Committees (HREC) or institutions. 
 

 
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be started or an existing treatment has to be changed to treat the adverse event and the event is 
accompanied with signs and symptoms. In addition, after the subject has completed his/her two year 
follow-up visit, only SAE and device-related AEs need to be reported to Medtronic. 
Unavoidable events are conditions which do not fulfill the definition of an Adverse Event, meaning those 
medical occurrences, clinical signs (including toward abnormal laboratory findings), diseases or injuries that 
are not untoward in nature; specifically those resulting from the intended injury such as the index SAVR or 
TAVR procedure. The events listed in Table 4 are expected for patients undergoing SAVR or TAVR, and do 
not need to be reported as AE, unless they occur outside of the stated timeframe, are otherwise considered 
to be an AE according to the treating investigator, or are suspected or confirmed to be device-related. 
 
Table 4.  Non-reportable medical occurrences associated with the index implant procedure 
Event 
Timeframe (hours) 
from the Index 
Procedure 
Short transient episode of arrhythmia (including ventricular fibrillation) during 
index procedure 
0 
Confusion, anxiety and/or disorientation (other than TIA/stroke) starting 
within 48 hours with or without medical intervention 
120 (5 days) 
Temporary change in mental status (other than TIA/stroke) not requiring 
additional medical interventions or new medical assessments (eg, CT) 
72 
Dizziness and/or lightheadedness with or without treatment  
24 
Headache with or without treatment 
72 
Sleep problems or insomnia with or without treatment 
120 (5 days) 
Mild dyspnea or cough with or without treatment 
72 
Oxygen supply after extubation/“forced breathing therapy” 
48 
Diarrhea with or without treatment 
48 
Obstipation/Constipation with or without treatment 
72 
Anesthesia-related nausea and/or vomiting with or without treatment  
24 
Low-grade fever (<101.3°F or <38.5°C) without confirmed infection 
48 
Low body temperature 
6 
Pain (eg, back, shoulder) related to laying on the procedure table with or 
without treatment 
72 
Incisional pain (pain at access site) with or without standard treatment and 
patient not returning to clinic to have additional treatment 
No time limit 
Pain in throat and/or trachea due to intubation 
72 
Mild to moderate bruising or ecchymosis 
168 (7 days) 
Atelectasis/Pleural Effusion not requiring punctuation 
168 (7 days) 
Edema resulting in weight increase up to 4 kg/9lbs from baseline 
168 (7 days) 
 

 
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For all observed AEs, investigators should assess and document the following information on the Adverse 
Event eCRF: 
• 
Date of onset or first observation 
• 
AE code number 
• 
Description of the event 
• 
Seriousness of the event 
• 
Causal relationship of the event to the TAV or surgical valve 
• 
Causal relationship of the event to the EnVeo R DCS and/or LS 
• 
Causal relationship of the event to the EnVeo PRO DCS and/or LS 
• 
Causal relationship of the event to the SAVR or TAVR implant procedure 
• 
Treatment required 
• 
Outcome or status of the event 
• 
Date of resolution 
 
For all deaths, investigators should assess and document the following information on the Death and 
Adverse Event eCRF 
• 
Date of death 
• 
Primary death category 
• 
Causal relationship of the event to the TAV or surgical valve 
• 
Causal relationship of the event to the EnVeo R DCS and/orLS 
• 
Causal relationship of the event to the EnVeo PRO DCS and/or LS 
• 
Causal relationship of the event to the implant procedure 
In addition, for all endpoint-related adverse events and deaths, sites should submit relevant, de-identified 
source documents to Medtronic for the Clinical Events Committee (CEC) members to use in their 
adjudication of the event. The CEC may request source documentation on additional events, at their 
discretion and according to the CEC Charter. 
Definitions of safety endpoints, the AE code list, and guidelines for accessing causal relationships are 
provided in APPENDIX V: DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS.  
3.3.26.3 Anticipated Adverse Events 
Adverse events that are anticipated for subjects participating in this trial are described in Section 4.2, Risks. 
 
 

 
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3.3.26.4 Adverse Event Reporting Requirements for Clinical Sites 
Adverse events and device deficiencies that occur during this trial are required to be reported to Medtronic 
via the AE or device deficiency eCRF, as soon as possible after the event occurs, but no later than the 
timeframes listed in Table 5 or local requirements, whichever is more stringent. 
 
Table 5. Required timeframes for adverse event reporting to Medtronic 
Event Type 
Timeframe for Reporting 
Adverse Event (AE) 
No later than 10 working days of the investigator’s/site’s first 
knowledge of the event 
Serious Adverse Event (SAE) 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Adverse Device Effect (ADE) or Device 
Related Adverse Event 
Immediately, but no later than 72 hours  of the investigator’s/site’s 
first knowledge of the event 
Serious Adverse Device Effect (SADE) 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Unanticipated Adverse 
Device Effect 
(UADE) 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Unanticipated Serious Adverse Device 
Effect (USADE) 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Device Deficiency 
No later than 72 hours of the investigator’s/site’s first knowledge of 
the event 
Device Deficiency that might have led to a 
SADE 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Additional event types 
Additional Time Frame for Reporting 
Mandatory Problem Reporting Incident  
(Canada ONLY) 
No later than 72 hours of the investigator’s/site’s first knowledge of 
the event, to Health Canada 
Significant Safety Issue (SSI) 
(Australia ONLY) 
No later than 72 hours of the investigator’s/site’s first knowledge of 
the event 
Urgent Safety Measure (USM) 
(AustraliaONLY) 
Immediatley, but no later than 24 hours of the investigator’s/site’s 
first knowledge of the event 
In addition, Investigators are obligated to report adverse events in accordance with the requirements of 
their reviewing IRB/EC and local regulations. 
The Sponsor is obligated to report adverse events and device deficiencies that occur during this trial to the 
Regulatory Authorities and IRB/EC as per local requirements. The applicable timeframes are described in 
the Safety Plan associated with this trial. 
3.3.26.5 Documentation and Reporting of Device Deficiencies 
Device deficiency information will be collected throughout the trial and reported to Medtronic. Device 
deficiencies that led to an AE are reported on the AE eCRF. Device deficiencies that did not lead to an AE 
should be reported on a Device Deficiency eCRF (one for each Device deficiency). 
Device deficiencies that did not lead to an adverse event but might have led to an SADE if: 

 
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a) a suitable action had not been taken, or  
b) an intervention had not been made, or  
c) circumstances had been less fortunate,  
should be reported to Medtronic as soon as possible but no later than 72 hours after the investigator first 
learns of the event.  
3.3.26.6 Emergency Contact Details for Reporting SAE, SADE, UADE, and Device Deficiencies 
Investigators should contact their Medtronic clinical trial monitor if they have any questions regarding 
reportable AEs. Medtronic will provide and maintain a listing of current contact details for each site. 
3.3.27 Clinical Events Committee 
A Clinical Events Committee (CEC) will provide independent medical review and adjudication of adverse 
event data used in the safety assessment of the investigational device. The CEC will adjudicate all deaths 
and safety endpoint-related adverse events reported by the investigators. The CEC will follow the 
recommendations of VARC II49 for classifying adverse events that relate to clinical safety endpoints. The 
analysis of the trial safety data will be based on CEC adjudicated events. Safety endpoint definitions are 
provided in APPENDIX V: DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS. 
The CEC members will be free from bias towards the trial and will be independent from both the trial and 
investigators and Medtronic. The committee will consist of at least 3 independent experts (non-Medtronic 
employed physicians) with expertise relevant to the trial. This may include experience in the areas of: 
• Cardiac surgery 
• Interventional cardiology 
• Neurology 
• Electrophysiology 
A CEC charter will be developed and approved by Medtronic prior to the first subject enrollment. 
3.3.28 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will assess interim trial data and provide recommendations to 
Medtronic regarding trial conduct, should they identify any issues that may affect the safety of the trial 
subjects. DSMB members will be free from bias towards the trial and will be independent from both the 
study and investigators and Medtronic. The DSMB will consist of a minimum of 3 members:  
1) a cardiologist with expertise in the management of aortic stenosis  
2) a cardiothoracic surgeon with expertise in aortic valve replacement 
3) a statistician 
A DSMB charter will be developed and approved by Medtronic and the DSMB members prior to the first 
subject enrollment. 
The DSMB will meet (via teleconference or in person) prior to the first subject enrollment to establish 
procedures for safety data review, chairman appointment, and guidelines for trial recommendations. The 
DSMB will meet on a periodic basis to perform a comprehensive data review, including at a minimum, all 
SAEs and deaths, and will meet more frequently when needed. Safety-related endpoints may also be 

 
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reviewed at these meetings. DSMB meetings may consist of both open and closed sessions. Medtronic 
personnel may facilitate the DSMB meeting but will not have voting privileges. 
Following each meeting, the DSMB will report to Medtronic in writing and may recommend changes in the 
conduct of the study. The DSMB recommendations may include recommendations on trial status such as 
continuing the trial without modifications, continuing the trial with modifications, stopping or suspending 
enrollment, or recommendations regarding trial conduct including recommendations around enrollment or 
protocol deviations. 
In the case of UADEs, if Medtronic and the DSMB determine that the event presents an unreasonable risk 
to the participating subjects, Medtronic must terminate the clinical trial within 5 working days after making 
that determination and no later than 15 working days after Medtronic first receives notice of the effect. All 
clinical sites will be notified of this action. 
The DSMB may call additional meetings if, at any time, there is concern about any aspect of the trial. All 
data presented at the meetings will be considered confidential.  
3.3.29 Role of Sponsor Representatives 
Representatives from Medtronic will provide confirmation of anatomical criteria prior to implant of each 
subject. In addition, representatives from Medtronic may provide technical support during the implant 
procedures to the implanting physicians and trial site staff relative to the use of the investigational devices. 
3.3.30 Data and Quality Management Procedures 
3.3.30.1 Data Collection 
Trial sites will assign a unique ID number to each subject. Records of the subject/subject ID relationship will 
be maintained by the trial site. Individual subject medical information obtained as a result of this trial will 
be considered confidential. 
This trial will utilize an Oracle Clinical Remote Data Capture (RDC) system that is the property of Medtronic. 
Required data will be recorded on electronic case report forms (eCRFs) by authorized site personnel as 
indicated on the Delegation Task List (DTL). Trial personnel delegated for eCRF completion and/or approval 
per the DTL will be trained on the use of the RDC system and thereafter provided with a user name and 
password to access the system. The eCRFs must be completed and/or updated to reflect the latest 
observations on the subjects participating in the trial. The investigator (or approved sub-investigator) will 
electronically sign the appropriate pages of each eCRF. 
Data from the core lab will be entered into the Oracle Clinical RDC system by core lab personnel per their 
procedures established for the trial. The core lab cardiologist will approve core lab eCRFs. 
The Oracle Clinical RDC system maintains an audit trail of entries, changes, and corrections in eCRFs. If a 
person only authorized to complete eCRFs makes changes to an already signed eCRF, the investigator shall 
re-approve this eCRF. 
All trial-related documents must be retained until notified by Medtronic that retention is no longer 
required. Medtronic will inform the investigator/institution when these documents are no longer required 
to be retained. 

 
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No trial document or image should be destroyed without prior written agreement between Medtronic and 
the investigator. Should the investigator wish to assign the trial records to another party or move them to 
another location, advance written notice must be given to Medtronic. 
3.3.30.2 Time Windows for Completion and Submission of eCRFs 
The Device Use Notification eCRF should be completed as soon as possible after device use. All other eCRFs 
should be completed and approved within 2 weeks of the applicable follow-up visit. 
3.3.30.3 Data Review and Processing 
Medtronic will be responsible for the processing and quality control of the data. Data review, database 
cleaning and issuing and resolving data queries will be done according to Medtronic internal SOPs and the 
Data Management Plan for this trial.The trial database will be developed and validated per the Data 
Management Plan for this trial, and will employ validation programs (eg, range and logic checks) on entered 
data to identify possible data entry errors and to facilitate data validation. The trial database will maintain 
an audit trail of all changes made to the eCRFs. 
3.3.30.4 Source Documents 
Entered data must be traceable to source documents. Source documentation is defined as the first time the 
data appear and may include all clinical records, hospital records, procedural reports, autopsy reports, and 
any other material that contains original information used for trial data collection or adverse event 
reporting. Identified descrepancies between source documents and the eCRFs will be resolved through the 
on-line query resolution process per the Data Management plan. 
The eCRFs may not serve as source documents. Source documentation for data elements not routinely 
captured in medical records (eg, echocardiography variables, MDCT variables, cath and surgical procedural 
data variables, local heart team assessment, Modified Rankin Score) may vary from center to center: the 
site may use technical worksheets if identified as source documents. 
Source documents must be retained by the investigational site for a period of two years after trial 
conclusion (or longer as required by local law) and made available for monitoring or auditing by the 
sponsor’s representative or representatives of the FDA and other applicable regulatory agencies or IRB/EC.  
The Investigator must ensure the availability of source documents from which the information on the eCRFs 
was derived. Where printouts of electronic medical records, are provided as source documents, or where 
copies of source documents are retained as source documents, they should be signed and dated by a 
member of the investigation site team indicating they are a true reproduction of the original source 
document. 
Copies of source documents will be requested to support event adjudication by the Clinical Events 
Committee. In Japan, availability of source documentation may be limited due to hospital policies. If a 
specific source document is not available, necessary information may be transcribed onto the relevant CRF 
page. 
In addition, the medical records of trial subjects should be marked or flagged in such a way to indicate their 
participation in the trial. 

 
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3.3.30.5 Subject Confidentiality 
All information and data sent to parties involved in trial conduct concerning subjects or their participation 
in this trial will be considered confidential. Trial sites will assign a unique subject ID number (SID) to each 
subject. Records of the subject/SID relationship will be maintained by the trial site. The SID is to be 
recorded on all trial documents to link them to the subject’s medical records at the site. To maintain 
confidentiality, the subjects’ name or any other personal identifiers should not be recorded on any trial 
document other than the informed consent form. In the event a subject’s name is included for any reason, 
it will be masked as applicable. In the event of inability to mask the identification (eg, digital media), it will 
be handled in a confidential manner by the authorized personnel. 
3.3.31 Records and Reports 
3.3.31.1 Responsibilities of the Investigator 
The Investigator is responsible for the preparation, review, and signature (as applicable), and retention of 
the following records: 
• 
All essential correspondence that pertains to the investigation 
• 
Device use/disposition records 
• 
Records of each subject’s case history and exposure to the device. Case histories include the eCRFs and 
supporting data (source documentation), including, for example: 
- 
Signed and dated consent forms 
- 
Medical records, including, for example, progress notes of the physicians, the subject’s hospital 
chart(s) and the nurses’ notes 
- 
All adverse event/device deficiency information  
- 
A record of the exposure of each subject to the investigational device (eg, date of implant 
procedure and follow-up assessment dates) 
• 
Documentation of any deviation from the CIP, including the date and the rationale for such deviation 
• 
Signed Investigator Agreement, signed and dated curriculum vitae of the PI, sub-investigator(s) and key 
members, signed Delegated Task List 
• 
The approved CIP, Patient Information/Informed Consent Form, Investigator Brochure, and any 
amendments 
• 
Insurance certificate, where applicable 
• 
IRB/EC Approval documentation and voting list 
• 
Regulatory authority notification and approval documentation 
• 
List of sponsor contacts and monitoring contact list 
• 
List of investigation sites 
• 
Training records 
• 
Disclosure of conflict of interest 
• 
Records indicating of adequacy of echocardiography equipment 
• 
Lab certificate/lab normal ranges 
• 
Subject ID and enrollment log 
• 
Sponsor’s statistical analyses and clinical investigation report 

 
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The Investigator may withdraw from responsibility to maintain records by transferring custody to another 
person, who will accept responsibility for record and report maintenance. The Investigator is responsible 
for the preparation, review, signature, and submission of the reports listed in Table 6,  
 

 
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Table 7, Table 8, and Table 9 for their respective geographies. These are also subject to inspection by 
government agencies and must be retained. Reports will be submitted to regulatory authorities per local 
reporting requirements/regulations. Requirements for reporting Adverse Events to Medtronic are 
described in Table 5. 
Table 6. Investigator records and reporting responsibilities applicable to the United States 
Report 
Submit To 
Description/Constraints 
Withdrawal of IRB 
approval (either 
suspension or termination) 
Sponsor 
An investigator shall report to the sponsor, within 5 working 
days, a withdrawal of approval by the reviewing IRB of the 
investigator's part of an investigation. (21 CFR 812.150(a)(2)). 
Progress report  
Sponsor and IRB 
The investigator must submit this report to the sponsor and 
IRB at regular intervals, but in no event less than yearly. (21 
CFR 812.150 (3)).  
Study deviations  
Sponsor and IRB 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon 
as possible, but no later than 5 working days after the 
emergency occurred. (21 CFR 812.150(a)(4)) 
Failure to obtain IC prior to 
investigational device use 
Sponsor and IRBs 
If an investigator uses a device without obtaining informed 
consent, the investigator shall report such use within 5 
working days after device use. (21 CFR 812.150(a)(5)) 
Final investigator report 
Sponsor, IRB s and 
Relevant Authorities 
This report must be submitted within 3 months of study 
completion or termination of the investigation or the 
investigator’s part of the investigation. (21 CFR 812.150(a)(6)) 
Other 
IRB and FDA 
An investigator shall, upon request by a reviewing IRB, FDA or 
any other regulatory agency, provide accurate, complete, and 
current information about any aspect of the investigation. (21 
CFR 812.150(a)(7)) 
 
 

 
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Table 7. investigator reports applicable to Europe 
Report 
Submit To 
Description/Constraints 
Withdrawal of MEC 
approval 
Sponsor 
The investigator must report a withdrawal of approval by the 
reviewing MEC of the investigator’s part of the investigation 
within 5 working days of the date of withdrawal. (Medtronic 
Requirement) 
Progress Report  
Sponsor and Ethics 
Board 
Provide if required by local law or MEC.  
(ISO 14155:2011) 
Trial Deviations  
Sponsor and Ethics 
Board and 
Regulatory 
Authority 
Any deviation from the CIP shall be recorded together with an 
explanation for the deviation. Deviations shall be reported to 
the sponsor who is responsible for analyzing them and 
assessing their significance.  
Note: When relevant, MECs, competent authorities or the 
appropriate regulatory bodies should be informed. (ISO 
14155:2011) 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon 
as possible, but no later than 5 working days after the 
emergency occurred. (Medtronic Requirement) 
Final investigator report 
Ethics Boards and 
Relevant Authorities 
This report must be submitted within 3 months of trial 
completion or termination of the investigation or the 
investigator’s part of the investigation. (Medtronic 
Requirement) 
Table 8. Investigator reports applicable to Canada 
Report 
Submit To 
Description/Constraints 
Withdrawal of REB 
approval 
Sponsor 
The investigator must report a withdrawal of approval by the 
reviewing REB of the investigator’s part of the investigation 
within 5 working days of the date of withdrawal. (Medtronic 
Requirement) 
Trial Deviations  
Sponsor and REB 
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation. 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon 
as possible, but no later than 5 working days after the 
emergency occurred. (Medtronic Requirement) 
Final Report 
REB, Relevant 
Authorities 
This report must be submitted within 3 months of trial 
completion or termination of the investigation or the 
investigator’s part of the investigation. (Medtronic 
Requirement) 
 
 

 
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Table 9. Investigator reports applicable to Australia and New Zealand 
Events to 
Report 
Reporting Requirement and Timeframe 
Submit 
to 
All SAEs and DDs with 
potential SADE 
Without unjustified delay. 
All SAEs should be reported immediately to the sponsor except those 
that the protocol or other document (eg, IB) identifies as not 
requiring immediate reporting. The immediate reports should be 
followed promptly by detailed, written reports. 
(5.17.3 NHMRC Safety monitoring and reporting in clinical trials 
involving therapeutic goods November 2016 part 2 section C.2 and 
other applicable local laws and regulations) 
Sponsor 
USADE 
Report to their institution without undue delay and no later than 72 
hours of the Principal Investigator becoming aware of the event. 
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.2.g) 
HREC, Institution 
Significant Safety 
Issues 
 
 
• Urgent Safety Measure (USMs): Within 24 hours 
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.2.c) 
• All other significant safety issues: without undue delay and 
no later than 72 hours of the principal investigator becoming 
aware of the event 
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.2.g) 
Sponsor 
 HREC, Institution 
Death 
For reported deaths, the investigator should supply the sponsor 
and the HREC with any additional requested information (e.g., 
autopsy reports and terminal medical reports). 
(According to applicable local laws and regulations) 
Sponsor/HREC 
 
 

 
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3.3.31.2 Responsibilities of the Sponsor 
The Sponsor will maintain the following records, including but not limited to: 
• 
All essential correspondence related to the clinical trial 
• 
Signed Investigator Agreement 
• 
Signed and dated current curriculum vitae for each Investigator 
• 
Records of device shipment and disposition (shipping receipts, material destruct records, etc.) 
• 
Adverse event and device deficiency information  
• 
Device complaint documentation 
• 
All data forms, prepared and signed by the Investigators, and received source documentation and core 
lab reports 
• 
CIP, investigator brochure, and subsequent amendments 
• 
Site monitoring reports 
• 
Financial disclosure information 
• 
Trial training records for site participants and internal trial staff members 
• 
Contact lists of all participating investigators/investigative sites, Ethics Board information, trial monitors 
and Sponsor staff members; Sponsor will maintain these lists and provide updates to the necessary 
parties.  
• 
Sample of device labeling attached to investigational device 
• 
Insurance certificates 
• 
Ethics Board approval documentation and voting list 
• 
Regulatory authority notification and approval documentation 
• 
Lab certificates /Lab normal ranges 
• 
Statistical analyses 
• 
Clinical investigation report 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, the review of and 
the submission of the reports listed in Table 10, Table 11, Table 13, and Table 14. 
 
 

 
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Table 10: Sponsor records and reporting responsibilities applicable to the United States 
Report 
Submit To 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, IRB, 
and Relevant 
authorities 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011), (MHLW Ordinance 36, Article 32)  
Unanticipated 
Adverse Device Effect 
Investigators, IRB, 
FDA, and relevant 
authorities 
Notification within ten working days after the sponsor first receives 
notice of the effect. (21 CFR 812.150(b)(1)) 
Withdrawal of IRB 
approval 
Investigators, IRB, 
FDA, and relevant 
authorities 
Notification within five working days after receipt of the 
withdrawal of approval. (21 CFR 812.150(b)(2))  
Withdrawal of FDA 
approval 
Investigators, IRB, 
and relevant 
authorities 
Notification within five working days after receipt of notice of the 
withdrawal of approval. (21 CFR 812.150(b)(3)) 
Investigator List 
FDA 
Submit at 6-month intervals, a current list of the names and 
addresses of all investigators participating in the investigation. (21 
CFR 812.150(b)(4)) 
Progress Reports 
IRB and FDA 
Progress reports will be submitted at least annually. (21 CFR 
812.150(b)(4)(5), 812.36(f)  
Recall and device 
disposition 
Investigators, IRB, 
relevant authorities, 
and FDA 
Notification within 30 working days after the request is made and 
will include the reasons for any request that an investigator return, 
repair, or otherwise dispose of any devices. (21 CFR 812.150(b)(6)) 
Failure to obtain IC  
FDA 
Investigator’s report will be submitted to FDA within five working 
days of notification. (21 CFR 812.150(b)(8)) 
Final Report 
Investigators, IRB, 
Regulatory 
authorities upon 
request, and FDA 
Medtronic will notify FDA within 30 working days of the completion 
or termination of the investigation. A final report will be submitted 
to the FDA, investigators, and IRBs within six months after 
completion or termination of this study. (21 CFR 812.150(b)(7)) 
Trial deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case report 
forms and the final report of the clinical investigation.  
Site specific study deviations will be submitted to investigators 
quarterly. (ISO 14155:2011) 
 
 

 
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Table 11: Sponsor records and reporting responsibilities applicable to Europe 
Report 
Submit To 
Description/Constraints 
Unanticipated 
Serious Adverse 
Device Effects 
(USADE) 
MEC, Investigators, 
Competent Authorities 
Medtronic will notify investigators and MEC in all geographies 
as soon as possible, but not later than 10 working days after the 
sponsor first learns of the effect.  
For reporting to Regulatory authorities, all UADEs are classified 
as SADEs and should follow the applicable reporting 
requirements. (ISO 14155:2011) and Note for Guidance on 
Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting (CPMP/ICH/377/95 3.A.1). Reporting 
timeframe as per local competent authority. (ISO 14155:2011 
3.42) 
Serious Adverse 
Event (SAE) 
MEC ,Competent 
Authorities 
Submit to MEC per local reporting requirement. Submit to 
Competent Authority per local reporting requirement. Reports 
will be in compliance with MDD 93/42/EEC and MEDDEV 2.7/3 
requirements. 
Serious Adverse 
Device Effects 
(SADE) 
MEC ,Competent 
Authorities 
Submit to MEC per local requirement (ISO 14155:2011). Submit 
to regulatory authority as per local competent authority 
reporting timelines. 
Device Deficiency 
that might have led 
to an SADE 
MEC, Competent 
Authorities 
Submit to MEC per local requirement .Submit to regulatory 
authority as per local competent authority requirement. 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, MEC, 
Relevant Authority 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011)  
Withdrawal of MEC 
approval 
Investigators, MEC, 
Relevant Authority 
All applicable investigators will be notified only if required by 
local laws or by the MEC. 
Withdrawal of 
Competent 
Authority approval 
Investigators, MEC, and 
Regulatory Authority 
Investigators and MECs will be notified only if required by local 
laws or by the MEC. 
Progress Reports 
MEC, Regulatory 
Authority (per local 
reporting 
requirements/regulations) 
This will be submitted to the MEC and/or Regulatory Authority 
only if required.  
Final Report 
CA, Investigators, MEC, 
and Regulatory Authority 
(per local reporting 
requirements/regulations) 
The investigator shall have the opportunity to review and 
comment on the final report. If a clinical investigator does not 
agree with the final report, his/her comments shall be 
communicated to the other investigator(s). The principal 
clinical investigator in each center shall sign the report. (ISO 
14155:2011) 
Trial deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case 
report forms and the final report of the clinical investigation. 
Site specific study deviations will be submitted to investigators 
quarterly. (ISO 14155:2011) 
 
 

 
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Table 12: Sponsor records and reporting responsibilities applicable to Europe (continued) 
 
 
 
Significant new 
information 
MEC and Regulatory 
Authority 
Ensure that the MECs and Regulatory Authorities are informed 
of significant new information about the clinical investigation 
(ISO 14155:2011) 
 
 

 
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Table 13: Sponsor records and reporting responsibilities applicable to Canada 
Report 
Submit To 
Description/Constraints 
Unanticipated Serious 
Adverse Device 
Effects (USADE) 
REB, Investigators, 
Health Canada 
Medtronic will notify investigators and Ethics Boards in all 
geographies as soon as possible, but not later than 10 working days 
after the sponsor first learns of the effect.  
Preliminary and final reporting to the Canadian Ministry of Health of 
events occurring inside (always) or outside Canada (in case of 
corrective actions) that is related to a failure of the device or a 
deterioration in its effectiveness, or any inadequacy in its labeling or 
its directions for use and has led to the death or a serious 
deterioration in the state of health of a patient, user or other person 
or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in 
the state of health of a patient, user or other person b) within 30 
days, if incident has not led to death or a serious deterioration in the 
state of health of a patient, user or other person, but could do so 
were it to recur c) as soon as possible, if incident occurred outside of 
Canada and is related to a corrective action. (Canada Medical Device 
Regulations, SOR/98-282; Mandatory Problem Reporting 59(1) , 
59(2), 60 (1)) 
Serious Adverse 
Device Effects (SADE) 
REB, Health Canada 
Submit to Ethics Boards per local requirement (ISO 14155) 
Preliminary and final reporting to the Canadian Ministry of Health of 
events occurring inside (always) or outside Canada (in case of 
corrective actions) that is related to a failure of the device or a 
deterioration in its effectiveness, or any inadequacy in its labeling or 
its directions for use and has led to the death or a serious 
deterioration in the state of health of a patient, user or other person 
or could do so were it to recur. Report a) within 10 days after 
awareness, if incident has led to death or a serious deterioration in 
the state of health of a patient, user or other person b) within 30 
days, if incident has not led to death or a serious deterioration in the 
state of health of a patient, user or other person, but could do so 
were it to recur c) as soon as possible, if incident occurred outside of 
Canada and is related to a corrective action. (Canada Medical Device 
Regulations, SOR/98-282; Mandatory Problem Reporting 59(1) , 
59(2), 60 (1)) 
Device Deficiency that 
might have led to an 
SADE 
REB, Investigators, 
Health Canada 
Submit to Ethics Board per local requirement. Submit to regulatory 
authority as per local requirement.  
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, REB, 
Health Canada 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011) 
Recall and device 
disposition 
Investigators, Head 
of Institution, REB, 
Health Canada 
Notification within 30 working days of the request and will include 
the reasons for any request that an investigator return, repair, or 
otherwise dispose of any devices. (Medical Devices Regulation 
Mandatory Problem Reporting 63 – 65.1) 
 
 

 
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Table 13. Sponsor records and reporting responsibilities applicable to Canada (continued) 
Report 
Submit To 
Description/Constraints 
Final Report 
Investigators, REB, 
and Health Canada 
The investigator shall have the opportunity to review and comment 
on the final report. If a clinical investigator does not agree with the 
final report, his/her comments shall be communicated to the other 
investigator(s). The principal clinical investigator in each center shall 
sign the report. (ISO 14155:2011) 
Trial deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case report 
forms and the final report of the clinical investigation.  
Site specific study deviations will be submitted to investigators 
quarterly. (ISO 14155:2011) 
Significant new 
information 
Ethics Board and 
Health Canada 
Ensure that the Ethics Boards and Regulatory Authorities are 
informed of significant new information about the clinical 
investigation (ISO 14155:2011) 
 
 

 
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Table 14. Sponsor reports applicable to Australia and New Zealand  
Events to Report 
Submit to 
Reporting Requirement and Timeframe 
Fatal or life-
threatening 
Australian USADEs  
TGA 
No later than 7 calendar days after being made aware of the case with any 
follow up information within a further 8 calendar days. 
(ARGMD, v1.1, May 2011, Access to unapproved therapeutic goods- clinical 
studies in Australia October 2004, NHMRC Safety monitoring and reporting 
in clinical trials involving therapeutic goods November 2016 part 2 section 
C.1.f and other applicable local laws and regulations) 
 
Other Australian 
USADEs 
TGA 
No later than 15 calendar days after being made aware of the case.  
(ARGMD, v1.1, May 2011, Access to unapproved therapeutic goods- clinical 
studies in Australia October2004, NHMRC Safety monitoring and reporting 
in clinical trials involving therapeutic goods November 2016 part 2section 
C.1.f and other applicable local laws and regulations) 
Significant Safety 
Issue 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TGA  
 
Urgent Safety Measure (USMs): Without undue delay and no later than 
72 hours of the measure being taken. 
Reasons for the urgent safety measure, Measures taken, Further 
actions planned 
Contact the TGA within 24 hours of the measure being taken.  
Other significant safety measures: Without undue delay and no later 
than 15 calendar days of the sponsor being aware of the issue. 
Details of significant safety issue, Further actions planned 
Temporary halt of a trial for safety reasons: Without undue delay and 
no later than 15 calendar days of the sponsor’s decision to halt the 
trial. 
Reasons for the halt, The scope of the halt, Measures taken, Further 
actions planned  
Early termination of a trial for safety reasons: Without undue delay and 
no later than 15 calendar days of the sponsor’s decision to termination 
the trial. 
Reasons for the termination, Measures taken, Further actions planned  
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.1.k) 
Other New 
information 
TGA 
Rapidly communicate information that has an important bearing on the 
benefit-risk assessment of the investigational product or that would be 
sufficient to consider changes to the overall conduct of the clinical study. 
Such information may arise as a result of the sponsor's monitoring of the 
study, including an internal statistical analysis of data. 
(Access to unapproved therapeutic goods- clinical studies in Australia 
October 2004, and other applicable local laws and regulations) 
 
 
 

 
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Table 15. Sponsor reports applicable to Australia and New Zealand (continued) 
Significant safety 
issue 
Any Australian 
Investigator 
and HREC 
Urgent Safety Measure (USMs): Without undue delay and no later than 
72 hours of the measure being taken. 
Reasons for the urgent safety measure, Measures taken, Further 
actions planned 
Other significant safety measures: Without undue delay and no later 
than 15 calendar days of the sponsor being aware of the issue. 
Details of significant safety issue, Further actions planned 
Temporary halt of a trial for safety reasons: Without undue delay and 
no later than 15 calendar days of the sponsor’s decision to halt the 
trial. 
Reasons for the halt, The scope of the halt, Measures taken, Further 
actions planned  
Early termination of a trial for safety reasons: Without undue delay and 
no later than 15 calendar days of the sponsor’s decision to termination 
the trial. 
Reasons for the termination, Measures taken, Further actions planned  
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.1.k) 
USADEs for Australia 
and international / 
Safety Report / 
updated IB / 
approved Product 
Information 
HREC and 
Investigator 
Per EC requirements, but at least annually: 
 Annual safety report including; a summary of the evolving safety 
profile of the trial, a brief description and analysis of new/relevant 
findings, implications of safety data to the risk-benefit ratio for the 
trial, a description of any measures taken or proposed to minimize 
risks  
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.1.i) 
An updated/addenda of IB, or IFU, if appropriate (eg, in a study for a 
product approved in Australia or where an IB is no longer 
maintained). 
(NHMRC Safety monitoring and reporting in clinical trials involving 
therapeutic goods November 2016 part 2 section C.1.h) 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
Medsafe 
The New Zealand sponsor is required to report all fatal or life-threatening 
suspected unexpected serious adverse reactions occurring in New Zealand 
trial participants where the treatment is known. 
Reports must be sent to Medsafe within 7 days of the sponsor receiving an 
investigator or life-threatening  
Adverse reactions occurring in a clinical trial participants are considered to 
be unexpected if they are not outlined in the protocol and investigatorial 
participants where the trned study end-points (eg, death or 
hospitalisation).  
(Guideline on the Regulation of Therapeutic Products in New Zealand – Part 
11- Edition 1.2 section 5.4.2) 
Reporting Other 
Adverse Events 
Medsafe 
The New Zealand sponsor is required to hold reports of all (worldwide) 
USADEs. These reports should not be routinely sent to Medsafe, but must 
be held in an accessible form and made available to Medsafe on request.  
(Guideline on the Regulation of Therapeutic Products in New Zealand – Part 
11- Edition 1.2 section 5.4.3) 

 
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Note: When determining whether a USADE has occurred, where the sponsor’s causality assessment 
conflicts with the assessment made by the site investigator, the site investigator’s assessment cannot be 
downgraded by the sponsor (ie, altered from ‘related’ to ‘not related’). In this case, if an investigator’s 
judgment triggers the reporting of a USADE, the opinion of both the investigator and the sponsor should be 
provided with any report sent to the TGA. 
Note: It is the responsibility of the sponsor to provide the investigator with reportable events for HREC 
reporting purposes. 

 
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3.3.31.3 Record Retention 
The investigator must retain the Investigator Site File, source documents, and the records listed in Section 
3.3.30.1, until informed by Medtronic they no longer need to be retained. At a minimum, the investigator 
must retain records for at least 2 years (or for 15 years if required by local law) after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications, or at least 
two years have elapsed since the formal discontinuation of clinical development of the investigational 
devices. The investigator should take measures to prevent accidental or early destruction of the trial 
related materials. 
3.3.31.4 Additional Contact Information 
The following contact information will be provided to the clinical site under a separate cover: 
• 
The name, address, and telephone number of the monitor 
• 
The name, title, address, and telephone numbers of the study Co-Principal Invesigators 
• 
The name, title, address, and telephone number of the sponsor’s medical expert for the study. 
 
 

 
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4.0 
RISK/BENEFIT ANALYSIS 
4.1 Description of Risk Analysis 
Medtronic has determined the Medtronic TAVR system to be a significant risk medical device. Therefore, 
Medtronic is sponsoring this clinical trial to support approvals for an expanded indication for the Medtronic 
TAVR system to patients with aortic stenosis at low risk for 30-day mortality for SAVR. 
In the United States, Medtronic will obtain an Investigational Device Exemption from the United States 
Food and Drug Administration. Medtronic will obtain approval from country-specific authorities in Europe, 
Canada, Australia, New Zealand, and Japan. 
Risk Analysis procedures were completed in accordance with ISO 14971:2012, and the results are provided 
in the Investigators Brochure. 
4.2 
Risks 
As with any TAVR or SAVR procedure, there are risks associated with participation in this trial. However, the 
risks to a patient for participation in this trial are not materially different than those a patient would incur if 
they underwent TAVR or SAVR outside of this trial. 
TAVR has been associated with serious complications, including death. In addition, complications may occur 
at varying intervals necessitating re-intervention or surgical replacement of the TAV. Known complications 
that may result from TAVR include but are not limited to the following: 
• 
Death 
• 
Cardiac arrest 
• 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
• 
Urgent surgery (eg, coronary artery bypass, heart valve replacement, valve explant) 
• 
Multi-organ failure 
• 
Heart failure or low cardiac output 
• 
Myocardial infarction  
• 
Cardiogenic stroke 
• 
Respiratory insufficiency or respiratory failure 
• 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricles, myocardium, 
or valvular structures that may require intervention) 
• 
Perforation of the myocardium or a vessel 
• 
Stroke or other neurological deficits 
• 
Transient ischemic attack 
• 
Permanent disability 
• 
Urgent need for balloon valvuloplasty (note that BAV during implantation is expected) 
• 
Urgent need for Percutaneous Coronary Intervention (PCI) 
• 
Major or minor bleeding that may or may not require transfusion or intervention (including life-
threatening or disabling bleeding) 
• 
Respiratory insufficiency or respiratory failure 
• 
Cardiac tamponade 
• 
Ascending aorta trauma 
• 
Disturbances in the electrical system of the heart that may result in the permanent placement of a 
device (pacemaker) 

 
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- 
Atrio-ventricular node block  
- 
Bundle branch block  
- 
Asystole  
• 
Cardiac arrhythmias  
• 
Thrombosis (including valve thrombosis) 
• 
Valve migration/embolization 
• 
Ancillary device embolization 
• 
Prosthetic valve dysfunction including but not limited to: 
- 
Fracture 
- 
Bending (out-of-round configuration) of the valve frame 
- 
Under-expansion of the valve frame 
- 
Calcification  
- 
Pannus 
- 
Wear, tear, prolapse or retraction in the valve leaflet 
- 
Poor valve coaptation 
- 
Suture breaks or disruption 
- 
Leak 
- 
Mal-sizing (prosthesis-patient mismatch) 
- 
Malposition (either too high or too low) 
- 
Valve regurgitation (paravalvular or transvalvular) 
- 
Valve stenosis 
• 
Mitral valve regurgitation or injury 
• 
Hypotension or hypertension 
• 
Renal insufficiency or renal failure (including acute kidney injury) 
• 
Allergic reaction to antiplatelet agents, contrast medium, or anesthesia 
• 
Infection (including septicemia or endocarditis)  
• 
Vascular access site or access related complications, including but not limited to: 
- Dissection 
- Perforation 
- Pain 
- Bleeding 
- Hematoma  
- Pseudoaneurysm 
- Irreversible nerve injury 
- Compartment syndrome 
- Arteriovenous fistula 
- Stenosis 
• 
Tissue erosion 
• 
Encephalopathy 
• 
Pulmonary edema 
• 
Pericardial effusion 
• 
Pleural effusion 
• 
Myocardial ischemia 
• 
Peripheral ischemia 
• 
Bowel ischemia 
• 
Heart murmur 
• 
Hemolysis 

 
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• 
Cerebral infarction-asymptomatic 
• 
Non-emergent reoperation 
• 
Inflammation 
• 
Fever 
• 
Syncope 
• 
Dyspnea 
• 
Anemia 
• 
Angina 
• 
Abnormal lab values (including electrolyte imbalance) 
• 
Exposure to radiation through fluoroscopy and angiography 
• 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic valve and 
prolonged procedural time. 
Each of these complications has the potential to be life-threatening, and some could lead to the need for 
open heart surgery. 
4.3 Measures to Mitigate Risks to Trial Subjects 
The following measures will be implemented to minimize risks to the trial subjects: 
• 
Implanting physicians will have considerable experience with TAVR 
• 
Study sites will have significant experience with surgical SAVR and TAVR 
• 
Patients will undergo thorough imaging assessment during their pre-implant workup 
• 
Patients will be rigorously followed over the course of the trial 
• 
An independent DSMB will review adverse events and interim results in order to advise Medtronic 
regarding trial conduct, should safety concerns be identified. 
4.4 Benefits 
The primary potential benefit to subjects participating in the trial is restored function of their diseased 
(stenotic) aortic valve. TAVR with the Medtronic TAVR system has been shown to be a safe and effective 
treatment for patients with symptomatic severe aortic stenosis who are at high risk through extreme risk 
for operative mortality with SAVR. 
4.5 Alternatives 
Presently, therapeutic alternatives for patients with the expanded clinical indication targeted for the 
Medtronic TAVR System include the following: 
• 
Medical therapy 
• 
Balloon aortic valvuloplasty 
• 
Surgical aortic valve replacement 
• 
TAVR with another device 
4.6 Results from the Risk Analysis and Justification for the Trial 
TAVR is now established as a safe and effective treatment option for patients with symptomatic severe 
aortic stenosis who are at high or extremely high risk for surgical aortic valve replacement. The Medtronic 
CoreValve bioprosthesis has been in widespread use since receiving the CE Mark in 2007, and there is now 
extensive published experience demonstrating the CoreValve system is fulfilling its intended role with a 

 
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favorable risk/benefit ratio.21-24 Rigorous clinical trials have established its safety and effectiveness, with 
improved mortality and quality of life compared with medical therapy in extreme risk patients,2 and even 
superiority to SAVR among high operative risk patients.4, 25  
A comprehensive protocol of bench and animal testing has indicated the Evolut R system is equivalent to 
the CoreValve system in terms of structural integrity, hydrodynamic performance, and valve durability. 
Clinical studies of the Evolut R system have confirmed the safety and efficacy of the Evolut R system to be 
equivalent to the CoreValve system, with no new clinical risks associated with the use of the 
resheath/recapture feature. Further, no new Class III risks were identified through Risk Analysis.60 
This trial is designed to evaluate the safety and effectiveness of the Medtronic TAVR system in patients who 
are at low predicated risk of mortality at 30 days. Although there are risks to the subjects for participation 
in the trial, they are anticipated to be similar to the risks of undergoing TAVR or SAVR outside of the trial. 
The trial endpoints are clinically relevant for the patient population targeted for the indication expansion, 
and consistent with the trial objectives. Therefore the trial as described is justified. 
 
 

 
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5.0 DESCRIPTION OF INVESTIGATIONAL DEVICES 
5.1 Evolut R System 
The Evolut R System is a transcatheter aortic valve implantation system comprised of the following three 
components: 
1. Evolut R Transcatheter Aortic Valve (TAV) 
2. EnVeo R Delivery Catheter System (DCS) with EnVeo R InLine Sheath or EnVeo PRO Delivery Catheter 
System (DCS) 
3. EnVeo R Loading System (LS) or EnVeo PRO Loading System (LS) 
All of the Evolut R system components are considered investigational in each of the study geographies for 
the low risk patient population . These components are provided separately for the procedure. All 
components are provided sterile and are intended for single use only. The Evolut R TAV is loaded into the 
EnVeo R or EnVeo PRO delivery catheter system using the EnVeo R or EnVeo PRO loading system 
immediately prior to implantation. 
The Evolut R TAV is intended as a permanent implant throughout the patient’s life, unless there is clinical 
indication to replace it with another prosthetic valve. The delivery catheter system is in contact with the 
body only during the device introduction and deployment phase of the implant procedure, typically less 
than 90 minutes. 
The system components and associated model numbers for the clinical trial are shown in Table 15. A 
detailed description of the system components is provided in Sections 5.1.1 through 5.1.5. 

 
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Table 16. Evolut R System Components 
Component 
US Model 
Number 
OUS Model 
Number 
ANZ Model 
Number 
TAV Size (mm) 
Aortic Annulus 
Diameter 
(mm) 
Evolut R TAV 
EvolutR-23-C 
EVOLUTR-23 
EVOLUTR-23 
23 
18 – 20 
EvolutR-26-C 
EVOLUTR-26 
EVOLUTR-26 
26 
20 – 23 
EvolutR-29-C 
EVOLUTR-29 
EVOLUTR-29 
29 
23 – 26 
EvolutR-34-C 
EVOLUTR-34 
EVOLUTR-34 
34 
26 – 30  
EnVeo R Catheter 
Delivery System with 
EnVeo InLine Sheath 
(18 Fr) 
EnVeoR-L-C 
ENVEOR-L-GC 
ENVEOR-L 
23, 26, and 29 
Not applicable 
EnVeo R Catheter 
Delivery System with 
EnVeo InLine Sheath 
(20 Fr) 
EnVeoR-N-C 
ENVEOR-N-GC 
ENVEOR-N 
34 
Not applicable 
EnVeo PRO Catheter 
Delivery System (14eFr)i 
ENVPRO-14-C 
Not applicable 
Not applicable 
23,26, and 29 
Not applicable 
EnVeo PRO Catheter 
Delivery System (16eFr)i   
ENVPRO-16-C 
Not applicable 
Not applicable 
34 
Not applicable 
EnVeo R Loading 
System 
LS-EnVeoR-23-C 
LS-ENVEOR-23-GC 
LS-ENVEOR-23 
23 
Not applicable 
EnVeo R Loading 
System 
LS-EnVeoR2629-C 
LS-ENVEOR2629GC 
LS-ENVEOR-
2629 
26 and 29 
Not applicable 
EnVeo R Loading 
System 
LS-EnVeoR-34-C 
LS-ENVEOR-34-GC 
LS-ENVEOR-34 
34 
Not applicable 
EnVeo PRO Loading 
System (14eFr) i 
LS-ENVPRO-14-C 
Not applicable 
Not applicable 
23,26, and 29 
Not applicable 
EnVeo PRO Loading 
System (16eFr) i 
LS-ENVPRO-16-C 
Not applicable 
Not applicable 
34 
Not applicable 
i iThe EnVeo PRO Delivery Catheter System and EnVeo PRO Loading System are limited to clinical investigation only with sites located in the 
United States in scope of this Clinical Investigation Plan. 
5.1.1 
Evolut R TAV 
The Evolut R TAV is available in four sizes (23, 26, 29, and 34 mm) for this trial, covering an aortic annulus 
diameter of 18 to 30 mm. The TAV is comprised of three leaflets and a sealing skirt constructed from 
gluteraldehyde-fixated porcine pericardium, sewn to a compressible and self-expandable Nitinol support 
frame (Figure 2A). The TAV is processed with an anti-mineralization treatment of alpha-amino oleic acid 
(AOA), a compound derived from oleic acid, a naturally occurring long-chain fatty acid. 

 
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5.1.2 
EnVeo R Catheter Delivery System with EnVeo InLine Sheath 
The EnVeo R catheter delivery system facilitates the placement of the TAV within the annulus of the aortic 
valve (Figure 2B). The catheter assembly is flexible and compatible with a 0.035 in (0.889 mm) guidewire. 
The distal (deployment) end of the system features an atraumatic, radiopaque catheter tip and a capsule 
that covers and maintains the bioprosthesis in a crimped position. The capsule includes a distal flare to 
enable full recapture of the bioprosthesis after partial deployment. A stability layer is fixed at the handle 
and extends down the outside of the catheter shaft. It provides a barrier between the retractable catheter 
and the introducer sheath and vessel walls, thus enabling the catheter to retract freely. 
The EnVeo R InLine Sheath is assembled over the stability layer, which functions as a hemostatic introducer 
sheath and minimizes the access site size to the capsule diameter. The EnVeo R InLine Sheath is also 
compatible with an 18 Fr introducer. 
The delivery catheter system consists of a catheter with an integrated handle to provide the user with 
accurate and controlled deployment. The handle is on the proximal end of the catheter and is used to load, 
deploy, recapture, and reposition the bioprosthesis. The handle features a gray front grip used to stabilize 
the system. The blue actuator turns to deploy the bioprosthesis precisely. Arrows on the actuator indicate 
the direction of rotation required to deploy the bioprosthesis. If desired, the blue actuator can be turned in 
the opposite direction to recapture the bioprosthesis if the radiopaque capsule marker band has not yet 
reached the distal end of the spindle. The blue actuator also features a trigger, which can be engaged to 
make macro adjustments to the capsule position. A blue hand rest connects to the blue actuator. The end 
of the handle features a tip-retrieval mechanism, which can be used to withdraw the catheter tip to meet 
the capsule after the device has been fully deployed. 
The catheter packaging contains an integrated loading bath and a removable tray with 3 rinsing bowls for 
loading and rinsing the bioprosthesis. The integrated loading bath features a mirror, which aids in accurate 
placement of the bioprosthesis frame paddles during loading. In addition, the device packaging is swiveled 
and secured to facilitate the bioprosthesis loading procedure. 
5.1.3 
EnVeo PRO Catheter Delivery System  
The EnVeo PRO DCS is a single use, intravascular “over the wire” delivery catheter that is sterilized using a 
validated Ethylene Oxide (EO) sterilization process.  The EnVeo PRO DCS is available in two sizes; the EnVeo 

 
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PRO 14eFr DCS and EnVeo PRO 16eFr DCS (
 
Figure 2C). The EnVeo PRO 14eFr DCS has an 18 Fr crossing profile and is designed to be compatible with 
commercially available 0.035” intravascular wires and 18 Fr introducers. The EnVeo PRO 16eFr DCS has a 20 
Fr crossing profile and is designed to be compatible with commercially available 0.035” intravascular wires 
and 20 Fr introducers. Changes to the EnVeo PRO DCS include manufacturing process changes to form the 
capsule frame as a single piece nitinol capsule, introducing the option for either a single piece or two-piece 

 
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capsule to be used. Additionally, the distal tip of the DCS required dimensional changes to increase the 
amount of material on the proximal end of the tip which then decreases the open space between the tip 
and the distal end of the TAV when encapsulated in the DCS. This minor tip redesign optimizes the bending 
stiffness of the device as it tracks through the patient anatomy. Furthermore, the snap component of the 
inline sheath (ILS) hub was updated on the pad printing and color of the sizing nomenclature (14eFr or 
16eFr) of the DCS to improve product differentiation.  

 
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5.1.4 
EnVeo R Loading System 
The EnVeo R loading system facilitates manual loading of the TAV into the deployment sheath capsule of 
the catheter delivery system by gradually reducing the diameter of the bioprosthesis radially to an optimal 
 
diameter (Figure 2D). The manual loading is performed during the procedure prior to implantation. The 
loading procedure is performed while immersing the loading system, the TAV, and the distal end of the 
catheter delivery system in cold sterile saline. 

 
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5.1.5 EnVeo PRO Loading System 
The EnVeo PRO LS is a system of reduction cones and tubing designed to gradually reduce the diameter of 
the TAV radially to an optimal diameter to facilitate manual loading of the Evolut R TAV or Evolut PRO TAV 
into the deployment sheath capsule of the EnVeo R DCS or EnVeo PRO DCS. The EnVEo PRO loading system 
was modified to consolidate the number of loading systems from five to three (
 

 
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Figure 2E).  Minor modifications include a change to the capsule guide tube (CGT) to include a locking collar 
which reduces the ability of the user to load the TAV with a paddle in the incorrect position by preventing 
movement of the frame paddles once positioned in the spindle pockets. Additionally, there was a more 
robust manufacturing process and a minor design and material change, including the color differentiation 
between the two loading system sizes, implemented on the tip guide tube (TGT) components. A third 
modification is to the inner diameter of the inflow ring designed to allow multiple TAVs to seat securely into 
the inflow ring.  
Note: In the United States, in the event that product delivery timelines (per sponsor process) cannot 
support supplying investigational labeled Evolut XL system components (TAV, DCS, and LS) in time for a 
scheduled case and using medical judgment, the site investigator and screening committee determine that 
the Evolut R 34 mm TAV is the most viable option for the subject, the study subject may receive commercial 
devices distributed by Medtronic. In this case, no site-specific protocol deviation would be required.  
 

 
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Figure 2 (A) Evolut R TAV (B) EnVeo R catheter delivery system and EnVeo R InLine sheath (C) EnVeo PRO delivery catheter system 
(D) EnVeo R loading system (E) EnVeo PRO loading system 
 

 
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5.2 Medtronic Evolut PRO System 
The Medtronic Evolut PRO System (commercially referred to as the Medtronic Evolut PRO System) is a 
TAVR implantation system comprised of the following three components (Table 16): 
1. Medtronic Evolut PRO TAV 
2. Medtronic Evolut PRO DCS with InLine Sheath or EnVeo R Delivery Catheter System (DCS) with EnVeo R 
InLine Sheath or EnVeo PRO Delivery Catheter System (DCS) 
3. Medtronic Evolut PRO LS or EnVeo PRO Loading System (LS) 
All of the Evolut PRO system components are considered investigational in each of the study geographies 
for the low risk patient population. The system components for the clinical study are shown in Figure3A 
detailed description of the system components is provided in Sections 5.2.1 through 5.2.6. 
 
Table 16. Evolut PRO System Components 
Component 
US Model Number 
OUS Model 
Number 
ANZ Model 
Number 
Size (mm) 
Aortic Annulus 
Diameter (mm) 
Medtronic Evolut PRO 
TAV 
TAV-MDT2-23-C 
TAV-MDT2-23-C 
EVOLUTPRO-
23 
23 
18 – 20  
TAV-MDT2-26-C 
TAV-MDT2-26-C 
EVOLUTPRO-
26 
26 
20 – 23 
TAV-MDT2-29-C 
TAV-MDT2-29-C 
EVOLUTPRO-
29 
29 
23 – 26 
Medtronic Evolut PRO 
DCS with InLine 
Sheath 
DS-MDT2-C 
DS-MDT2-GC 
ENVEOR-N 
23, 26, and 
29 
Not applicable 
EnVeo R Catheter 
Delivery System with 
EnVeo InLine Sheath 
(20 Fr) 
EnVeoR-N-C 
ENVEOR-N-GC 
ENVEOR-N 
23, 26, and 
29 
Not applicable 
EnVeo PRO Catheter 
Delivery System 
(16eFr)i 
ENVPRO-16-C 
Not applicable 
Not applicable 
23,26, and 29 
Not applicable 
Medtronic Evolut PRO 
LS 
LS-MDT2-23-C 
LS-MDT2-23-GC 
LS-MDT2-23 
23 
Not applicable 
LS-MDT2-2629-C 
LS-MDT2-2629-GC 
LS-MDT2-2629 
26 and 29 
Not applicable 
EnVeo PRO Loading 
System (16eFr)i 
 
LS-ENVPRO1623C 
Not applicable 
Not applicable 
23 
Not applicable 
LS-ENVPRO-16-C 
Not applicable 
Not applicable 
26 and 29 
Not applicable 
i iThe EnVeo PRO Delivery Catheter System and EnVeo PRO Loading System are limited to clinical investigation only with sites located in the 
United States in scope of this Clinical Investigation Plan. 

 
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Figure 3. (A) Evolut PRO TAV; (B) Evolut PRO DCS and inline sheath; (C) EnVeo R catheter delivery system and EnVeo R InLine sheath 
(D) EnVeo PRO delivery catheter system (E) Evolut PRO loading system (F) EnVeo PRO loading system 

 
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5.2.1 Medtronic Evolut PRO Transcatheter Aortic Valve 
The Evolut PRO TAV is available in 3 sizes (23, 26, 29 mm), covering an aortic annulus diameter of 18 to 26 
mm. If the patient’s annulus diameter is within 0.5 mm of the upper or lower bound of the range, use of the 
larger valve size can be considered, provided additional dimensional criteria as outlined in the CIP are met. 
The TAV is comprised of 3 leaflets, a sealing skirt, and outer tissue wrap constructed from gluteraldehyde-
fixated porcine pericardium, sewn to a compressible and self-expandable Nitinol support frame. The TAV is 
processed with an anti-mineralization treatment of AOA, a compound derived from oleic acid, a naturally 
occurring long-chain fatty acid. 
5.2.2 Medtronic Evolut PRO Delivery Catheter System 
The Evolut PRO DCS facilitates the placement of the TAV within the annulus of the aortic valve. The 
catheter assembly is flexible and compatible with a 0.035 in (0.889 mm) guidewire. The distal (deployment) 
end of the system features an atraumatic, radiopaque catheter tip and a capsule that covers and maintains 
the bioprosthesis in a crimped position. The capsule includes a distal flare to enable full recapture of the 
bioprosthesis after partial deployment. A stability layer is fixed at the handle and extends down the outside 
of the catheter shaft. It provides a barrier between the retractable catheter and the introducer sheath and 
vessel walls, thus enabling the catheter to retract freely. 
The InLine Sheath is assembled over the stability layer, which functions as a hemostatic introducer sheath 
and minimizes the access site size to the capsule diameter. The InLine Sheath for the 23 mm, 26 mm, and 
29 mm system is compatible with a 20 Fr introducer.  
The DCS consists of a catheter with an integrated handle to provide the user with accurate and controlled 
deployment. The handle is on the proximal end of the catheter and is used to load, deploy, recapture, and 
reposition the bioprosthesis. The handle features a gray front grip used to stabilize the system. The blue 
actuator turns to deploy the bioprosthesis precisely. Arrows on the actuator indicate the direction of 
rotation required to deploy the bioprosthesis. If desired, the blue actuator can be turned in the opposite 
direction to recapture the bioprosthesis if the radiopaque capsule marker band has not yet reached the 
distal end of the spindle. The blue actuator also features a trigger, which can be engaged to make macro 
adjustments to the capsule position. A blue hand rest connects to the blue actuator. The end of the handle 
features a tip-retrieval mechanism, which can be used to withdraw the catheter tip to meet the capsule 
after the device has been fully deployed. 
The catheter packaging contains an integrated loading bath and a removable tray with 3 rinsing bowls for 
loading and rinsing the bioprosthesis. The integrated loading bath features a mirror, which aids in accurate 
placement of the bioprosthesis frame paddles during loading. In addition, the device packaging is swiveled 
and secured to facilitate the bioprosthesis loading procedure. 
5.2.3 
EnVeo R Catheter Delivery System with EnVeo InLine Sheath 
The EnVeo R catheter delivery system facilitates the placement of the TAV within the annulus of the aortic 
valve (Figure 3C). The catheter assembly is flexible and compatible with a 0.035 in (0.889 mm) guidewire. 
The distal (deployment) end of the system features an atraumatic, radiopaque catheter tip and a capsule 
that covers and maintains the bioprosthesis in a crimped position. The capsule includes a distal flare to 
enable full recapture of the bioprosthesis after partial deployment. A stability layer is fixed at the handle 

 
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and extends down the outside of the catheter shaft. It provides a barrier between the retractable catheter 
and the introducer sheath and vessel walls, thus enabling the catheter to retract freely. 
The EnVeo R InLine Sheath is assembled over the stability layer, which functions as a hemostatic introducer 
sheath and minimizes the access site size to the capsule diameter. The EnVeo R InLine Sheath is also 
compatible with an 18 Fr introducer. 
The delivery catheter system consists of a catheter with an integrated handle to provide the user with 
accurate and controlled deployment. The handle is on the proximal end of the catheter and is used to load, 
deploy, recapture, and reposition the bioprosthesis. The handle features a gray front grip used to stabilize 
the system. The blue actuator turns to deploy the bioprosthesis precisely. Arrows on the actuator indicate 
the direction of rotation required to deploy the bioprosthesis. If desired, the blue actuator can be turned in 
the opposite direction to recapture the bioprosthesis if the radiopaque capsule marker band has not yet 
reached the distal end of the spindle. The blue actuator also features a trigger, which can be engaged to 
make macro adjustments to the capsule position. A blue hand rest connects to the blue actuator. The end 
of the handle features a tip-retrieval mechanism, which can be used to withdraw the catheter tip to meet 
the capsule after the device has been fully deployed. 
The catheter packaging contains an integrated loading bath and a removable tray with 3 rinsing bowls for 
loading and rinsing the bioprosthesis. The integrated loading bath features a mirror, which aids in accurate 
placement of the bioprosthesis frame paddles during loading. In addition, the device packaging is swiveled 
and secured to facilitate the bioprosthesis loading procedure. 
5.2.4 EnVeo PRO Delivery Catheter System 
The EnVeo PRO DCS is a single use, intravascular “over the wire” delivery catheter that is sterilized using a 
validated Ethylene Oxide (EO) sterilization process.  The EnVeo PRO DCS is available in two sizes; the EnVeo 
PRO 14eFr DCS and EnVeo PRO 16eFr DCS. The EnVeo PRO 14eFr DCS has an 18 Fr crossing profile and is 
designed to be compatible with commercially available 0.035” intravascular wires and 18 Fr introducers. 
The EnVeo PRO 16eFr DCS has a 20 Fr crossing profile and is designed to be compatible with commercially 
available 0.035” intravascular wires and 20 Fr introducers. Changes to the EnVeo PRO DCS include 
manufacturing process changes to form the capsule frame as a single piece nitinol capsule, introducing the 
option for either a single piece or two-piece capsule to be used. Additionally, the distal tip of the DCS 
required dimensional changes to increase the amount of material on the proximal end of the tip which then 
decreases the open space between the tip and the distal end of the TAV when encapsulated in the DCS. 
This minor tip redesign optimizes the bending stiffness of the device as it tracks through the patient 
anatomy. Furthermore, the snap component of the inline sheath (ILS) hub was updated on the pad printing 
and color of the sizing nomenclature (14eFr or 16eFr) of the DCS to improve product differentiation. 
5.2.5 Medtronic Evolut PRO Loading System 
The Evolut PRO LS facilitates manual loading of the TAV into the deployment sheath capsule of the DCS by 
gradually reducing the diameter of the bioprosthesis radially to an optimal diameter. The manual loading is 
performed during the procedure prior to implantation. The loading procedure is performed while 
immersing the LS, the TAV, and the distal end of the DCS in cold sterile saline. 

 
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The Evolut PRO LS was designed with ribs on the interior surface of the cone designed to decrease the 
friction between the TAV tissue wrap on the inflow cone during loading. There are two loading system 
models; one for the 23 mm TAV and another for the 26 mm and 29 mm TAV sizes. 
5.2.6 EnVeo PRO Loading System 
Similar to the EnVeo R LS, the EnVeo PRO LS is a system of reduction cones and tubing designed to 
gradually reduce the diameter of the TAV radially to an optimal diameter to facilitate manual loading of the 
Evolut R TAV or Evolut PRO TAV into the deployment sheath capsule of the EnVeo R DCS or EnVeo PRO DCS. 
The EnVEo PRO loading system was modified to consolidate the number of loading systems from five to 
three.  Minor modifications include a change to the capsule guide tube (CGT) to include a locking collar 
which reduces the ability of the user to load the TAV with a paddle in the incorrect position by preventing 
movement of the frame paddles once positioned in the spindle pockets. Additionally, there was a more 
robust manufacturing process and a minor design and material change, including the color differentiation 
between the two loading system sizes, implemented on the tip guide tube (TGT) components. A third 
modification is to the inner diameter of the inflow ring designed to allow multiple TAVs to seat securely into 
the inflow ring.   
5.3 Manufacturer of the Investigational Devices 
The manufacturer and design site of the Evolut R and Evolut PRO systems is as follows: 
Medtronic CoreValve LLC 
1851 E Deere Avenue 
Santa Ana, CA 92705  
USA 
5.4 Comparator Devices 
The comparator devices used in the SAVR control arm are any surgical aortic valve bioprostheses (stented 
or stentless) that are approved for commercial use in both the United States and the geography in which 
the study center is located. As such, the comparator devices are not investigational in this trial. 
 
 

 
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6.0  
MONITORING AND AUDITING 
6.1 Monitoring 
Investigational sites will be monitored to ensure compliance with the trial protocol, adherence to applicable 
regulations, and accuracy of trial data. Monitoring visits will be conducted primarily to ensure the safety 
and well-being of the subjects is preserved. Monitoring visits will also be used to verify that trial data 
submitted on case report forms are complete and accurate with respect to the subject clinical records and 
to verify device accountability. Sites should provide appropriate access to the source data. Site personnel 
will complete eCRFs following each subject visit. Trial data submitted will be reviewed against subject 
charts and other sources containing original records of subject data. Source document verification will 
occur in accordance to a Monitoring Plan. 
The progress of the trial will be monitored by: 
• 
On-site review, as deemed appropriate by Medtronic 
• 
Telephone communications between the site personnel (eg, investigator, trial coordinator) and trial 
monitors 
• 
Review of eCRFs and the associated clinical records 
• 
Review of regulatory documents 
Monitoring and monitoring oversight will be provided by Medtronic (8200 Coral Sea St NE, Mounds View, 
MN 55112). Representatives of Medtronic (ie, contractors and designees) may also act as trial monitors. 
Under the Japan GCP Ordinance, the sponsor or a designee will conduct regular monitoring. This monitoring 
includes one or more pre-study visits prior to enrollment. During interim visits, the monitor will check for 
compliance of the study with the “3.1.1 Statement(s) of Compliance”, and will compare the eCRF with the 
source data (source data verification).  The monitor will also check the device storage/management 
conditions at appropriate timing. 
All monitoring activities shall be documented and include a summary of what the monitor reviewed and the 
observations with regard to the completion of previous action items, significant findings, facts, deviations, 
conclusions, and recommended actions to be taken to secure compliance. Additionally, the monitor will 
confirm periodic testing, calibration and maintenance of equipment used for study assessments according 
to local standard of practice. 
6.2 Auditing 
Medtronic may conduct audits at participating clinical sites. The purpose of an audit is to verify the 
performance of the monitoring process and the trial conduct, independent of the personnel directly 
involved in the trial. Regulatory bodies, such as the Food and Drug Administration may also perform 
inspections at participating sites. The investigator and/or institution shall permit Medtronic and regulatory 
bodies direct access to source data and documents. 
6.3 Trial Closure 
Upon completion of the trial, Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 
After the trial has been completed, medical care will be provided to the subjects upon the discretion of the 
treating physician. 

 
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7.0 LABELING 
Labeling of the Medtronic TAVR system will be provided in English and the local language, if needed 
according to local requirements. The labeling will indicate that the device is for investigational use only, and 
only to be used by qualified investigators, and consistent with the requirements of the geographies where 
the trial is conducted. 
The Instructions for Use for the Medtronic TAVR System used in this trial will be provided as a separate 
document. If changes are made to the labeling, they will be provided under separate cover to the 
appropriate authorities per local requirements. 
8.0 CONSENT MATERIALS 
A sample informed consent form for the trial is attached in APPENDIX VI: SAMPLE INFORMED CONSENT 
FORM. 
9.0 INVESTIGATOR BROCHURE AND REPORT OF PRIOR INVESTIGATIONS 
An Investigator Brochure for this trial will be provided under separate cover to the relevant sites and 
regulatory agencies. Medtronic will update the Investigator Brochure in accordance with ISO14155:2011, 
and provide those updates to sites and regulatory agencies. For geographies under ISO14155:2011, 
documentation of receipt of the Investigator Brochure by each site’s Ethics Board is required for all versions 
of the Investigator Brochure. Report of Prior Investigations requirements (21 CFR 812.27) are included in 
the Investigator Brochure.  
10.0 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE INFORMATION 
Information on each participating Institutional Review Board/Ethics Committee will be maintained in a 
separate document. A definitive list of all participating IRB/ECs will be maintained and provided in clinical 
reports. 
11.0 
OTHER INSTITUTIONS AND PROFESSIONAL SERVICES 
This trial will utilize an Echo Core Lab, an MDCT Core Lab, an Explant Pathology Core Lab, a Clinical Events 
Committee, and a Data Safety Monitoring Board. Information and contact details for each of these parties 
will be maintained in a separate document and provided to the study sites. A definitive list of all 
participating parties will be provided in clinical reports. In addition, a list of the names and addresses of 
participating institutions will maintained and provided to the sites. 
12.0 
PUBLICATION POLICY 
Medtronic is committed to the widespread dissemination of all primary and secondary endpoint results. A 
Publication Plan will be implemented and followed. At the conclusion of the trial, a multisite abstract 
reporting the primary results will be prepared by the Principal Investigators (in collaboration with others 
including but not limited to the echo core lab physicians, and the CEC/DSMB). A multisite publication will 
similarly be prepared for publication in a reputable scientific journal. The publication of the principal results 
from any single site experience within the trial is not allowed until both the preparation and publication of 
the multisite results, and then only with written permission from Medtronic. 

 
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Following analysis and presentation of the endpoint results, active participation of all participating 
investigators, CEC/DSMB committee members, and core laboratory personnel will be solicited for data 
analysis and abstract and manuscript preparation. Submission of all abstracts and publications regarding 
the primary endpoint and secondary endpoints from the trial requires approval by the Principal 
Investigators after review by the Publications Committee. 
A separate Publication Plan will provide detailed information about the publication committee, authorship, 
publication proposals, and requests for data. 
13.0 
SPONSOR TRIAL PERSONNEL 
A list of sponsor personnel (including monitors, safety representatives, and the medical expert) and their 
contact details will be maintained in a separate document and provided to the trial centers. 
14.0 
INSURANCE/SUBJECT INDEMNIFICATION 
Medtronic (including all wholly owned subsidiaries) maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with applicable law and custom 
concerning specific insurance coverage. If required, a Clinical Trial Insurance statement/certificate will be 
provided to the IRB/EC if required. 
 
 

 
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APPENDIX I: ECHOCARDIOGRAPHY PROCEDURES 
1.0 Required Exams 
Transthoracic echocardiography is required at the following intervals: 
Interval 
Time Window 
Baseline (Pre-implant) 
Within 12 weeks prior to submission to Screening Committee 
Device Success 
Between 18 hours and 7 days post-procedure 
30 days 
Between 30 and 45 days post procedure 
6 months 
Between 183 and 213 days post procedure 
1 year 
Between 365 and 395 days post procedure 
2 Year 
Between 730 and 760 days post procedure 
3, 4, 5, 7 and 10  years 
Between implant anniversary date and +/-60 days after 
2.0 General Imaging and Recording Procedures 
• 
A list of recommended images is provided in Section 2.1, List of Recommended Images. 
• 
The subject’s ID number and exam interval should be annotated on the image. 
• 
A simultaneous ECG with a clearly defined R-wave should be displayed on all clips. 
• 
Digital cine clips should be a minimum of two cardiac cycles in length (preferably three cycles) 
• 
Color Doppler images should be obtained at a minimum frame rate of 20 Hz through optimization of 
sector width and depth settings. 
• 
Still frames of measured variables (eg, LVOT diameter, velocities) should be captured. In addition, still 
frames of spectral Doppler tracings without the measurements should be captured to facilitate analysis 
by the Echo Core Lab. Still frames of spectral Doppler tracings should contain a minimum of 3 cardiac 
cycles for subjects in sinus rhythm, and a minimum of 5 cardiac cycles for subjects in atrial fibrillation 
(two sequential frames per variable may be necessary). 
• 
Spectral Doppler waveforms should be recorded at a minimum sweep speed of 50 mm/sec. 
• 
Echocardiograms should be recorded and archived on a DICOM digital format for transmission to the 
Echo Core Lab. 
• 
Exams will be transmitted to the Echo Core Lab via compact disc (CD-R) or Web-based picture archiving 
and communication system. Details of the image transmission process for each site will be established 
during site initiation process. 
• 
Exams sent to the Echo Core Lab via CD-R should be DICOM files in a true or pure DICOM format. 
• 
The following information should be documented on any CD-R disks sent to the Echo Core Lab: 
- Trial site ID number 
- Subject ID number 
- Exam date 
- Trial interval 
 
 

 
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2.1 List of Recommended Images 
Parasternal long-axis window 
1. 2D gray scale standard view (LV in a sagittal section) 
2. 2D color Doppler for mitral regurgitation (MR) 
3. 2D color Doppler of aortic (native or prosthetic) regurgitation (AR) 
4. If AR is present, ZOOM & narrow sector with focus on vena contracta of regurgitant jet  
5. 2D gray scale ZOOM for LV outflow tract diameter (LVOT)  
6. Frozen image of measured LVOT diameter 
7. 2D gray scale; ZOOM at an intercostal space higher for aortic root/aortic prosthesis  
Parasternal short-axis window 
8. 2D grayscale LV at mitral valve level 
9. 2D grayscale LV at papillary muscle level  
10. Frozen image of measured LV dimensions (without measurements) 
11. 2D grayscale LV at apical level 
12. 2D grayscale aortic valve level 
13. 2D color Doppler of AR: post-implant start scanning from highest position and record first visible AR jet, scan 
more downwards and look for additional jets – confirm origin of AR jets from PLAX 
Parasternal long-axis view (RV inflow) 
14. 2D color Doppler of tricuspid regurgitation (TR) 
15. If TR is present, CW Doppler of TR jet (frozen image without measurements) 
16. Frozen image of TR jet velocity with measurements 
Apical 4-Chamber window 
17. 2D grayscale standard view  
18. 2D color Doppler of MR  
19. If MR is present, ZOOM & narrow sector 
20. If MR is present, CW Doppler of MR jet (frozen image) 
21. 2D color Doppler of TR 
22. If TR is present, CW Doppler of TR jet (frozen image without measurement) 
23. Frozen image of TR jet velocity with measurements 
24. 2D grayscale focussed on LV with decreased depth 
25. PW Doppler of transmitral flow at mitral valve tips (frozen image) 
26. Tissue Doppler of the septal mitral annulus (frozen image) 
27. Tissue Doppler of the lateral mitral annulus (frozen image) 
Apical long–axis view 
28. 2D grayscale standard view 
29. 2D color Doppler of AR 
30. If AR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
31. If AR is present, CW Doppler of AR jet (frozen image without measurement) 
32. Frozen image of CW Doppler of AR jet (with measurements) 
33. CW Doppler of aortic/prosthetic valve (frozen image without measurement) 
34. Frozen image of measured aortic/prosthetic valve velocity 

 
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35. PW Doppler LVOT (native aortic valve): within 0.5 – 1 cm below native aortic valve (frozen image without 
measurements 
36. PW Doppler LVOT (post –implant) immediately proximal to inflow of stent or valve (frozen image without 
measurements) 
37. Frozen image: measured LVOT velocity 
Apical 2-Chamber view 
38. 2D grayscale standard view 
39. 2D grayscale focused on LV with decreased depth 
Sub-costal Position 
40. 2D grayscale; long-axis view 
41. 2D grayscale; short-axis view 
42. 2D grayscale: IVC and hepatic vein 
43. If TR moderate by color Doppler, PW Doppler of hepatic vein (frozen image) 
44. IF AR mild by color Doppler, PW Doppler from descending aorta (frozen image) 
Supra-Sternal Position 
45. CW Doppler of aortic valve velocity non-imaging probe (frozen image without measurements) 
46. Frozen image: measured aortic valve velocity 
47. If AR mild by color Doppler, PW Doppler from descending aorta (frozen image) 
Right Parasternal Position 
48. CW Doppler of aortic valve velocity; non-imaging probe (frozen image without measurements) 
49. Frozen image: measured aortic valve velocity 
Results Reporting 
50. Screen prints of all results pages 
 
 

 
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3.0 Data Requirements 
Sites should obtain the appropriate images and Doppler recordings in order for the Echo Core Lab to assess 
and report the variables listed below. Procedures for acquiring key variables are described in Section 4, 
Acquisition of Key Variables. 
• 
Height (cm) and Weight (kg) 
• 
Heart rate 
• 
Left ventricular outflow tract (LVOT) diameter in mid systole 
• 
Max aortic/prosthetic valve velocity (V2) by CW Doppler 
• 
Aortic valve velocity time integral (VTI) by CW Doppler 
• 
Mean gradient across aortic valve (MGV2) by CW Doppler 
• 
LVOT VTI by PW Doppler 
• 
Grade of aortic/prosthetic transvalvular regurgitation (post-implant only) 
• 
Grade of aortic/prosthetic paravalvular regurgitation (post-implant only) 
• 
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
• 
Grade of mitral regurgitation 
• 
Grade of tricuspid regurgitation 
• 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
• 
Left ventricular internal dimension at end diastole 
• 
Left ventricular internal dimension at end systole 
• 
Interventricular septal thickness at end diastole 
• 
Left ventricular posterior wall thickness at end diastole 
• 
Left atrial diameter (anterior-posterior linear dimension) at systole 
• 
Left ventricular ejection fraction by visual estimate 
• 
Grade of diastolic dysfunction (if present) 
In addition, the following variables will be derived by the central database from the appropriate 
measurements reported on the site eCRF. 
• 
Body surface area (Dubois and Dubois)55 
• 
Peak aortic pressure gradient 
• 
Aortic valve area (AVA)/effective orifice area (EOA) by continuity equation 
• 
Aortic valve area/effective orifice area index (EOAI) 
• 
Doppler Velocity Index 
• 
Estimated right ventricular systolic pressure (RVSP) 
Derived variables will be displayed on the eCRF upon entry of the appropriate raw measurements. The pre-
implant qualifying AVA must be based on the site reported variables for LVOT diameter, LVOT VTI, aortic 
valve VTI, height, and weight. 
 
 

 
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4.0 Acquisition of Key Variables 
4.1 LVOT Diameter 
Pre-implant LVOT diameter is measured from the inner edge to inner edge of the septal endocardium, and 
the anterior mitral leaflet in mid-systole (Figure A and B).61, 62. Following implantation of the TAV, LVOT 
diameter is measured from the parasternal long-axis view, immediately proximal to the inflow aspect of the 
stent, and in mid systole (Figure C and D).61-63 Post surgical valve implantation, LVOT diameter is measured 
from the junction of the anterior sewing ring and the ventricular septum to the junction of the sewing ring 
and the anterior mitral valve leaflet (Figure 4E and F).61  
 
 
Figure 4. (A) and (B) Examples of measurement of pre-implant LVOT diameter. LVOT diameter is measured from the white-black 
interface of the septal endocardium to the anterior mitral leaflet, parallel to the aortic valve plane, approximately 0.5 cm below the 
level of the aortic annulus, and in mid systole (C) and (D) Post TAV implantation, LVOT diameter measurement is from outer edge to 
outer edge of the inflow aspect of the stent (E) and (F) post surgical valve implantation, LVOT diameter is measured from the 
junction of the anterior sewing ring and the ventricular septum to the junction of the sewing ring and the anterior mitral valve 
leaflet. 

 
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4.2 LVOT Velocity 
LVOT velocity is recorded with PW Doppler from the apical position, in either the apical long-axis view or in 
the anteriorly angulated four-chamber view (or “5-chamber view”). For pre-implant exams, the PW sample 
volume should be positioned just proximal to the aortic valve, with care to avoid the zone of pre-valve 
acceleration (usually 0.5 to 1.0 cm proximal to the cusps, Figure A).61 
Post TAV implantation, the sample volume should be placed proximal to the inflow aspect of the stent.64 
Full-screen imaging of the TAV should be used to verify positioning of the sample volume below the stent 
before switching to spectral Doppler mode (Figure C and D).64, 65 Post surgical valve implantation, the 
sample volume should be placed proximal to the inflow aspect of the sewing ring. 
The LVOT VTI is measured by tracing the modal velocity (middle of the dense signal) for use in the 
continuity equation.61 
            
 
Figure 5 (A) Sample volume placement just proximal to zone of pre-valve acceleration (illustration by Mayo Clinic, used with 
permission) (B) Optimal LVOT velocity signal showing a smooth spectral Doppler recording with a narrow velocity range at each 
time point (C) Illustration showing correct sample volume placement just proximal to inflow of TAV stent (D) Full-screen imaging of 
stent to ensure positioning of sample volume below the TAV stent. 
 
 

 
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4.3 Aortic Valve Velocities 
Aortic valve velocity should be interrogated with CW Doppler from a minimum of 2 transducer positions 
(apical and either a parasternal or suprasternal position). The position that provides the highest velocity is 
used for measurements. A smooth velocity curve with a clear outer edge and maximal velocity should be 
recorded. The maximal velocity is measured at the outer edge of the dark signal; fine linear signals at the 
peak should not be included in measurements. The outer edge of the dark “envelope” of the velocity curve 
is traced to provide both the VTI for the continuity equation and the mean gradient (Figure ).61 
 
Figure 6. (A) Aortic valve velocities interrogated from multiple transducer positions (illustration by Mayo Clinic, used with 
permission) (B) CW Doppler of severe aortic stenosis showing tracing of the velocity curve from mean gradient and VTI, and 
measurement of max velocity. 
4.4 Assessment of Prosthetic Aortic Regurgitation 
An integrated exam approach using color flow, pulsed-wave (PW), and continuous-wave (CW) Doppler is 
used to assess the severity of transvalvular and paravalvular aortic regurgitation (AR). Color flow Doppler 
imaging should be performed from the parasternal long and short-axis views, and the apical long-axis 
and/or 5-chamber views. In the short axis view, color imaging should be performed at multiple levels (from 
level of the leaflets to below the skirt and frame to assess paravalvular regurgitation, and at the coaptation 
point of the leaflets for transvalvular (central) regurgitation.66, 67 
If AR is seen by color Doppler, a CW Doppler recording of the regurgitant signal should be obtained for 
measurement of pressure half-time and assessment of jet density. If the degree of AR by color Doppler 
appears more than mild by visual estimate, the velocity in the proximal descending aorta should be 
recorded with PW Doppler.  
The degree of transvalvular, paravalvular, and total (transvalvular plus paravalvular) AR will be graded as 
none, trace, mild, mild to moderate, moderate, moderate to severe, and severe based on the synthesis of 
the Doppler parameters shown in Table 17.67 The category of “trace” should be used in cases where 
regurgitation is barely detectable by color Doppler. Regurgitant signals observed to originate within the 
stent will be considered transvalvular, and regurgitant signals observed to originate outside the stent will 
be considered paravalvular.

 
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Table 17. Parameters for evaluation of the severity of aortic regurgitation 
3-class Grading Scheme 
Trace 
Mild 
Mild 
Moderate 
Moderate 
Severe 
Unifying 5-Class Grading Scheme 
Trace 
Mild 
Mild-to-Moderate 
Moderate 
Moderate-to-severe 
Severe 
Doppler parameters (qualitative or 
semiquantitiative) 
 
 
 
 
 
 
 Jet Features 
 
 
 
 
 
 
   Extensive/wide jet origin 
Absent 
Absent 
Absent 
Present 
Present 
Present 
   Multiple jets 
Possible 
Possible 
Often present 
Often present 
Usually present 
Usually present 
   Jet path visible along stent 
Absent 
Absent 
Possible 
Often present 
Usually present 
Usually present 
   Proximal flow convergence visible 
Absent 
Absent 
Absent 
Possible 
Often present 
Often present 
 Vena contracta width (mm) 
<2 
<2 
2-4 
4-5 
5-6 
>6 
 Vena contracta area (mm2) 
<5 
5-10 
10-20 
20-30 
30-40 
>40 
 Jet width at origin (% LVOT diameter) 
Narrow (<5) 
Narrow (5-15) 
Intermediate (15-30) 
Intermediate (30-45) 
Large (45-60) 
Large (>60) 
 Jet density: CW Doppler 
Incomplete or faint 
Incomplete or 
faint 
Variable 
Dense 
Dense 
Dense 
 Pressure half-time (ms): CW Doppler 
Slow (>500) 
Slow (>500) 
Slow (>500) 
Variable (200-500) 
Variable (200-500) 
Steep (<200) 
 Diastolic flow reversal in descending aorta 
Absent 
Absent or brief 
early diastolic 
Intermediate 
Intermediate 
Holodiastolic (end-
diast. Vel. >20 cm/s) 
Holodiastolic 
(end-diast. Vel. 
>25 cm/s) 
 Circumferential extent of PVR (%) 
<10 
<10 
10-20 
20-30 
>30 
>30 
Doppler parameters (quantitiative) 
 
 
 
 
 
 
 Regurgitant volume (ml/beat) 
<15 
<15 
15-30 
30-45 
45-60 
>60 
 Regurgitant fraction (%) 
<15 
<15 
5-10 
10-20 
20-30 
>30 
 Effective regurgitant orifice area (mm2) 
<5 
<5 
5-10 
10-20 
20-30 
>30 

 
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4.5 Assessment of Mitral Regurgitation 
Color flow Doppler imaging of the left atrium should be performed from the parasternal long-axis view, and 
from the apical 4, 2, and long axis views. 
Mitral regurgitant (MR) jets should be recorded with CW Doppler using a velocity scale that allows 
assessment of the density, shape, duration, and peak velocity of the MR jet. If the severity appears 
moderate or greater by visual assessment, pulmonary vein velocities should be recorded with PW Doppler 
to assess for the presence of systolic flow reversal. Grading of the severity of mitral regurgitation should be 
integrative using the parameters in Table 18.68 
Table 18. Parameters for evaluation of the severity of mitral regurgitation 
Parameter 
Mild 
Moderate 
Severe 
Color flow jet area 
Small, central jet 
(usually <4 cm2 or 
<20% of LA area) 
Variable 
Large central jet 
(usually >10 cm2 or 
>40% of LA area), or variable wall-
impinging jet swirling in the LA 
Jet density (CW) 
Incomplete or faint 
Dense 
Dense 
Jet contour (CW) 
Parabolic 
Usually parabolic 
Early peaking, triangular 
Pulmonary vein flow 
Systolic dominance 
Systolic blunting 
Systolic flow reversal 
4.6 Assessment of Tricuspid Regurgitation 
Color flow imaging of the right atrium should be performed from the apical 4-chamber view, the 
parasternal long-axis view of the RVOT, and the parasternal short-axis view at the level of the aortic valve. 
Tricuspid regurgitant (TR) jets should be recorded with CW Doppler using a velocity scale that allows 
assessment of the density, shape, duration, and peak velocity of the TR jet. If the severity appears 
moderate or greater by visual assessment, hepatic vein velocities should be recorded with PW Doppler to 
assess for the presence of systolic flow reversal. Grading of the severity of tricuspid regurgitation should be 
integrative using the parameters in Table 19.68  
Table 19. Parameters for evaluation of the severity of tricuspid regurgitation 
Parameter 
Mild 
Moderate 
Severe 
Jet area (cm2) 
<5 
5 – 10 
>10 
VC width (cm) 
Not defined 
Not defined, but <0.7 
≥0.7 
PISA Radius (cm) 
≤0.5 
0.6 – 0.9 
>0.9 
Jet density & contour 
Soft & parabolic 
Dense, variable contour 
Dense, triangular, with early 
peaking 
Hepatic vein flow  
Systolic dominance 
Systolic blunting 
Systolic flow reversal 
 
 

 
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4.7 Assessment of Left Ventricular Function and Left Atrial Size 
Dimensions of the left ventricle and left atrium should be obtained by either 2-D linear measurements or 
using 2-D guided m-mode from either the parasternal long or short axis views (Figure 3). Left ventricular 
chamber dimensions, septal thickness, and posterior wall thickness are measured using the American 
Society of Echocardiography (ASE) measurement convention69 (blood-tissue interface). In addition, 
standard 2-D views of the left ventricle should be obtained from parasternal and apical transducer positions 
for visual estimation and quantitative assessment of left ventricular ejection fraction using the modified 
Simpson’s rule, and for assessment of regional wall motion. 
 
Figure 3. Measurements of the left ventricle (A) and left atrium (B) using 2-D guided m-mode. 
 
4.8 Assessment of Left Ventricular Diastolic Function 
A spectral Doppler recording of mitral inflow should be obtained with PW Doppler in the apical 4-chamber 
view, using a 1 to 3 mm sample volume placed between the mitral leaflet tips during diastole (Figure 4). The 
spectral gain and wall filter settings should be optimized to clearly display the onset and cessation of left 
ventricular inflow. The following variables should be measured: 
• 
Mitral inflow “A” velocity 
• 
Mitral inflow “E” velocity 
• 
Mitral inflow E-wave deceleration time 
 
 
 
A 
B 

 
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Figure 4. Positioning of the sample volume for recording of mitral inflow velocities. 
 
 
Mitral annular velocities should be obtained from the lateral and septal aspects of the mitral annulus using 
PW tissue Doppler (DTI) performed in the apical 4-chamber view. The sample volume should be positioned 
at or 1 cm within the septal and lateral insertion sites of the mitral leaflets and adjusted as necessary 
(usually 5 to 10 mm) to cover the longitudinal excursion of the mitral annulus in both systole and diastole. 
Minimal angulation (<20 degrees) should be present between the ultrasound beam and the plane of cardiac 
motion. The following variables should be measured: 
• 
Mitral annular tissue Doppler systolic velocity (septal and lateral) 
• 
Mitral annular tissue Doppler early diastolic velocity (septal and lateral) 
• 
Mitral annular tissue Doppler late diastolic velocity (septal and lateral) 
Diastolic function should be categorized as normal, mild dysfunction (impaired relaxation pattern), 
moderate dysfunction (pseudonormal filling), or severe dysfunction (restrictive filling) per the 2009 
American Society of Echocardiography recommendations.70 
 
5.0 Core Lab Analysis 
Protocol-required echocardiograms will be sent to the Echo Core lab for assessment: the data generated by 
the Echo Core Lab will be the primary data used for analysis and reporting. Received echocardiograms will 
be logged in and analyzed by the Echo Core Lab according to their procedures determined for this trial.  
The Echo Core Lab will report the following variables: 
• 
Heart rate 
• 
Left ventricular outflow tract (LVOT) diameter in mid systole 
• 
Max aortic/prosthetic valve velocity (V2) by CW Doppler 
• 
Aortic valve velocity time integral (VTI) by CW Doppler 
• 
Mean gradient across aortic valve (MGV2) by CW Doppler 
• 
LVOT VTI by PW Doppler 

 
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• 
Grade of aortic/prosthetic transvalvular regurgitation (post-implant only) 
• 
Grade of aortic/prosthetic paravalvular regurgitation (post-implant only) 
• 
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
• 
Grade of mitral regurgitation 
• 
Grade of tricuspid regurgitation 
• 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
• 
Left ventricular internal dimension at end diastole 
• 
Left ventricular internal dimension at end systole 
• 
Interventricular septal thickness at end diastole 
• 
Left ventricular posterior wall thickness at end diastole 
• 
Left atrial diameter (anterior-posterior linear dimension) at systole 
• 
Left ventricular ejection fraction by visual estimate 
• 
Grade of diastolic dysfunction (if present) 
Qualitative grading of valvular regurgitation will be performed using the criteria described in Sections 4.4 
through 4.7. For reporting the degree of prosthetic regurgitation, the grading classes may be collapsed 
according to the 3-class grading scheme recommended by the American Society or Echocardiography (ASE)-
European Association of Cardiovascular Imaging Guidelines (Table 16).68, 71 
 
 

 
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In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the Echo Core Lab: 
• 
Peak Pressure Gradient (Peak ∆ P) Across the Aortic Valve in mmHg 
Peak ∆ P = 4 x (V22) 
Where: V2 is the peak velocity across the prosthesis in m/sec 
• 
Aortic Valve Area (AVA) in cm2 
AVA = LVOT diameter in cm2 x 0.785 x (VTIV1/VTIV2) 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 is the velocity time 
integral of the native aortic valve in cm 
• 
Aortic Valve Area Index (AVAI) in cm2/m2 
AVAI = AVA/BSA 
Where: AVA is the native aortic valve area in cm2, and BSA is the body surface area in m2 x 
• 
Effective Orifice Area (EOA) in cm2 
EOA = LVOT diameter2 x 0.785 x (VTIV1/VTIV2) 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 is the velocity time 
integral of the aortic prosthesis in cm 
• 
Effective Orifice Area Index (EOAI) in cm2/m2 
EOAI = EOA/BSA 
Where: EOA is the effective orifice area in cm2, and BSA is the body surface area in m2 
• 
Doppler Velocity Index (DVI) 
DVI= VTIV1/VTIV2 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 is the time velocity 
integral of the prosthetic aortic valve in cm 
• 
Left Ventricular Mass (LVM) in grams 
LVM = 0.83 x [(LVIDD + LVPW + IVS)3 - (LVIDD)3] +0.6 
Where: LVIDD is the left ventricular internal dimension at end diastole in cm, LVPW is the left ventricular posterior 
wall thickness at end diastole in cm, and IVS is the interventricular wall thickness at end diastole in cm. 
• 
Left Ventricular Mass Index (LVMI) in g/m2 body surface area 
LVMI = LVM/BSA 
Where: LVM is left ventricular mass in g, and BSA is body surface area in m2 
• 
Estimated Right Ventricular Systolic Pressure (RVSP) in mmHg 
RVSP = (4 x MVTR jet2) + 10 
Where: MV TR jet is the max velocity of the tricuspid regurgitant jet, and 10 = the assumed mean right atrial 
pressure in mmHg 
• 
Body Surface Area (BSA) in m2 
BSA = 0.007184 x (height in cm0.725 x weight in kg0.425) 
 
 
                                                                 
x BSA derived from height and weight reported on the site eCRF 

 
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APPENDIX II: MDCT ACQUISTION GUIDELINES: PRE-TAVR PLANNING 
1.0 Introduction 
Multi-Detector Computed Tomography (MDCT) is used to evaluate aortic valve anatomy, determine aortic 
root dimensions for device sizing, and to evaluate peripheral vessel dimensions and anatomy. The following 
sections are intended as guidelines for acquiring the images for assessing anatomical suitability for 
implantation with the Medtronic TAVR systems. 
2.0 General Requirements 
• 
Multi-detector CT scanner (64-slice minimum) with ECG-gating capability. 
• 
ECG-gated contrast enhanced aortic root (slice thickness of ≤1.0 mm) 
• 
Temporal resolution should be optimized to reduce motion artifact. 
• 
Spatial resolution should be as high as possible (goal is smallest isotropic voxel size) 
3.0 ECG-gated Contrast Enhanced Scan of Aortic Root 
Retrospective ECG-gated scans are recommended, which allows for reconstruction in various phases of the 
cardiac cycle and optimal evaluation of anatomic dimensions and valve morphology. Recommended scan 
parameters are listed in Table 20. 
Prospective ECG-gated sequential scans (step-and-shoot) and high-pitch spiral scans with ECG-gating (flash 
spiral) are also acceptable. The following parameters are important to the optimum scan: 
• 
Detector collimation 0.4-0.625 mm. 
• 
Slice thickness ≤1.0 mm. 
• 
The recommended coverage area is from superior to the aortic arch to inferior to the cardiac apex. The 
minimum required coverage area is from 50 mm above the aortic annulus to 10 mm below the aortic 
annulus. 
• 
The recommended slice overlap is 0.4 mm (will result in isotropic voxels with a 20 cm field of view). 
3.1 Post-processing 
• 
Retrospective ECG-gated scans 
- 
Verify heart rate ECG triggers are at consistent place in cardiac cycle, edit if necessary. Additional 
editing/removal of arrhythmias may be performed. 
- 
Reconstruct at multiple phases (10 increments of 10%), with ≤1.0 mm slice thickness. If the system 
has the capability, also reconstruct a “best systolic” and “best diastolic” phase. 
• 
Prospective ECG-gated scans (including flash spiral) 
- 
Reconstruct with medium soft kernel and slice thickness ≤1.0 mm (slice overlap of 0.4 mm 
recommended) 
 
 

 
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Table 20. Recommended MDCT parameters for pre TAVR planning 
Parameter 
Recommendation 
IV injection with iodine 
contrast 
80-100 (320mg/ml or higher), modify per patient as appropriate 
Injection rate 
4-6 mL/sec 
Bolus tracking, delay 
Delay time calculated using protocol for current scanner (bolus tracking or similar) with 
peak of contrast concentration in the ascending aorta during acquisition. 
ECG-gating 
Retrospective 
Scan direction 
Cranial-caudal 
Scan coverage 
From above the aortic arch to past the cardiac apex 
Detector collimation 
0.4 – 0.625 mm 
Pitch 
0.2–0.43 adapted to the heart rate 
Dose modulation 
Modulation and full current between 30 and 80% of the cardiac cycle 
Slice thickness 
0.8 mm 
Slice overlap 
0.4 mm 
Reconstruction kernel 
Medium Smooth 
Post-processing 
Retrospective ECG gating reconstruction algorithm that minimizes motion artifact. 
Reconstruct at multiple phases (10 minimum). Reconstructed slice thickness ≤0.8 mm. 
3.2 Required Aortic Root Measurements 
The following measurements of the aortic root are obtained for assessing anatomical suitability for the 
Evolut R TAV: 
• 
Annulus perimeter (measured at systole if retrospective gating is used) 
• 
Sinus of Valsalva diameters (measured at diastole) 
• 
Sinus of Valsalva heights (measured at diastole) 
 
 
For the Evolut PRO TAV, the following measurements of the aortic root are obtained for assessing 
anatomical suitability: 
• 
Major aortic annulus (measured at systole if retrospective gating is used) 
• 
Orthogonal minor aortic annulus diameter (measured at systole if retrospective gating is used) 
• 
Annulus perimeter (measured at systole if retrospective gating is used) 
• 
Sinus of Valsalva diameters (measured at diastole) 
• 
Sinus of Valsalva heights (measured at diastole) 
 
Dimensional sizing criteria for the Evolut R and Evolut PRO are provided in Tables 20 and 21. 
 
 

 
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3.2.1 
Reformatting of Images  
Reformatting of the images is as follows: 72 
• 
Site image cross-hairs on aortic root in all windows where it is visible. Lock cross-hairs so they remain 
orthogonal for all steps. 
• 
In the coronal window, rotate cross-hairs (horizontal line) counter-clockwise to align with virtual basal 
plane, (Figure 95, upper left panel). 
• 
In the sagittal window, the horizontal line is rotated clockwise or counter-clockwise to align with virtual 
basal plane (Figure 95, lower left panel). 
• 
On the newly defined double-oblique axial image, scroll up and down through the aortic root until the 
most caudal attachment points of the three native leaflets come into view (indicated by arrowheads in 
Figure 6). If one of the leaflets comes into view at a more cranial or caudal slice, adjust the coronal or 
sagittal cross-hairs until all three leaflets come into view on the same axial slice. 
• 
For confirmation of the correct aortic annulus plane, scroll through the double oblique axial images 
starting in the mid sinus and ending at the level of the aortic annulus. The sinuses should appear to be 
relatively the same size at the level of the mid-sinus and the leaflets should all disappear equally at the 
level of the annulus. 
 
 
Figure 95. Example images in original orientation (axial, coronal, and sagittal). Red curved arrow and line indicate adjustment of 
coronal and sagittal planes to align with aortic basal annulus. 
Sagittal 
Coronal 
Axial 

 
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Figure 6. Example images of reformatted oblique coronal (upper left), oblique sagittal (lower left), double oblique axial (upper 
right), and 3D reconstruction (lower right). Yellow arrowheads indicate most caudal attachment of three leaflets of the aortic 
valve). 
3.2.2 
Aortic Annulus Measurements 
• 
Choose the cleanest systolic images for the aortic annulus measurements, either automatically (eg, best 
systolic) or by manually identifying. Measurement on a diastolic image is also acceptable. 
• 
Aortic annulus measurements should be completed on the properly reformatted double-oblique axial 
image at aortic annulus level, as described in Section 3.2.1, Reformatting of Images. 
• 
Trace the perimeter of the basal annulus (Figure 7, left). Place cross-hairs at site of basal annulus, 
create major diameter through the site, create minor diameter defined as perpendicular to major and 
through site (Figure 7, right). 
 
Figure 7. Example of perimeter measurement (left) and major and minor diameter measurements (right). 
Oblique 
Coronal 
Oblique 
Sagittal 
Double-oblique axial 

 
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3.2.3 
Sinus of Valsalva Measurements 
Choose the best diastolic images for measurement of sinus of Valsalva diameters and heights from images 
using the same reformatting technique as described in Section 3.2.1. 
Sinus of Valsalva Diameters 
• 
Select the double oblique axial image where the widest portion of the three sinuses is visible. 
• 
Measure a diameter from each commissure through the site of the root to the opposite sinus. 
Complete for all three sinuses (Figure 8).  
 
Figure 8. Example of sinus of Valsalva diameters 
Sinus of Valsalva Heights 
• 
The sinotubular junction is typically not co-planar with the aortic annulus. Therefore, a sinus of Valsalva 
height must be measured for each of the three sinuses. This height is defined as the distance between 
the aortic annular plane and the tallest point in the sinus. 
• 
Choose the double oblique axial image so that it is located at the level of the aortic annulus. The 
reformatting line representing the double oblique axial image should now be visible in the oblique 
coronal and oblique sagittal images at the level of the aortic annulus.  
• 
For the left coronary and non coronary heights, use the oblique coronal image. For the right coronary 
height, use the oblique sagittal image. 
• 
To complete the measurement, scroll through the oblique coronal or sagittal image (depending on 
which sinus you are measuring) and locate the heights location of the sinotubular junction. On that 
image, measure the distance along the path of the aortic root from the aortic annular plane, marked by 
the reformatting line, to the sinotubular junction (Figure 9). 

 
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Figure 9. Examples of sinus of Valsalva heights (A) left coronary (B) non coronary (C) right coronary 
4.0 Evolut R and Evolut PRO TAV Sizing Matrix 
Table 21. Dimensional sizing criteria for Evolut R TAV 
Device 
Size 
Aortic Annulus 
Sinus of Valsalva 
Perimeter 
(mm) 
Mean Diameter 
(mm) 
Mean Diameter 
(mm) 
Mean Height 
(mm) 
23 mm 
56.5 – 62.8 
18 – 20 
≥25 
≥15 
26 mm 
62.8 – 72.3 
20 – 23 
≥27 
≥15 
29 mm 
72.3 – 81.6 
23 – 26 
≥29 
≥15 
34 mm 
81.7 – 94.2 
26 - 30 
≥31 
≥16 
 
Table 22. Dimensional sizing criteria for Evolut PRO TAV 
Device 
Size 
Aortic Annulus 
Sinus of Valsalva 
Perimeter 
(mm) 
Mean Diameter 
(mm) 
Mean Diameter 
(mm) 
Mean Height 
(mm) 
23 mm 
56.5 – 62.8 
18 – 20 
≥25 
≥15 
26 mm 
62.8 – 72.3 
20 – 23 
≥27 
≥15 
29 mm 
72.3 – 81.6 
23 – 26 
≥29 
≥15 
 

 
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APPENDIX III: DEFINITIONS OF STS FACTORS AND OTHER CO-MORBIDITIES 
1.0 STS Factors 
http://riskcalc.sts.org/stswebriskcalc/#/calculate, Risk Model and Variables - STS Adult Cardiac Surgery Database 
Version 2.81 
Factor 
Definition 
Heart Failure 
Physician documentation or report that the patient has been in a state of heart failure 
within the past 2 weeks. Heart failure is defined as physician documentation or report of 
any of the following clinical symptoms of heart failure described as unusual dyspnea on 
light exertion, recurrent dyspnea occurring in the supine position, fluid retention; or the 
description of rales, jugular venous 
Distension, pulmonary edema on physical exam, or pulmonary edema on chest x-ray 
presumed to be cardiac dysfunction. A low ejection fraction alone, without clinical 
evidence of heart failure does not qualify as heart failure. An elevated BNP without other 
supporting documentation should not be coded as CHF. 
Diabetes 
History of diabetes diagnosed and/or treated by a healthcare provider. The American 
Diabetes Association criteria include documentation of the following: 
1. Hemoglobin A1c ≥6.5%; or 
2. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L); or 
3. 2-h Plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or 
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L) 
This does not include gestational diabetes. 
Dialysis 
Subject currently (prior to surgery) undergoing dialysis 
Hypertension 
Any of the following: 
• 
documented history of hypertension diagnosed and treated with medication, diet 
and/or exercise, 
• 
prior documentation of blood pressure >140 mmHg systolic or 90 mmHg diastolic for 
patients without diabetes or chronic kidney disease, or prior documentation of 
blood pressure >130 mmHg systolic or 80 mmHg diastolic on at least 2 occasions for 
patients with diabetes or chronic kidney disease 
• 
currently on pharmacologic therapy to control hypertension 
Immunocompromise 
Indicate whether immunocompromise is present due to immunosuppressive medication 
therapy within 30 days preceding the operative procedure or existing medical condition. 
This includes, but is not limited to systemic steroid therapy, anti-rejection medications 
and chemotherapy. This does not include topical steroid applications, one time systemic 
therapy, inhaled steroid therapy or preprocedure protocol. 
Arrhythmia 
History or preoperative arrhythmia (sustained ventricular tachycardia, ventricular 
fibrillation, atrial fibrillation, atrial flutter, third degree heart block, second degree heart 
block, sick sinus syndrome) that has been treated with any of the following modalities: 
• 
ablation therapy 
• 
AICD 
• 
pacemaker 
• 
pharmacologic treatment 
• 
electrocardioversion, defibrillation 

 
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1.0 
STS Factors (continued) 
Factor 
Definition 
Atrial fibrillation/atrial 
flutter 
Presence of atrial fibrillation or flutter within 30 days of the procedure 
Myocardial infarction 
History of at least one documented myocardial infarction at any time prior this surgery 
Endocarditis 
Indicate whether the patient has a history of endocarditis. Endocarditis must meet at 
least 1 of the following criteria: 
1. Patient has organisms cultured from valve or vegetation. 
2. Patient has 2 or more of the following signs or symptoms: fever (>38°C or >100.4°F), 
new or changing murmur*, embolic phenomena*, skin manifestations* (ie, petechiae, 
splinter hemorrhages, painful subcutaneous nodules), congestive heart failure*, or 
cardiac conduction abnormality. 
*with no other recognized cause and at least 1 of the following: 
a. organisms cultured from 2 or more blood cultures 
b. organisms seen on Gram’s stain of valve when culture is negative or not done 
c. valvular vegetation seen during an invasive procedure or autopsy 
d. positive laboratory test on blood or urine (eg, antigen tests for H mmunocom, S 
mmunocom, N mmunocompro, or Group B Streptococcus) 
e. evidence of new vegetation seen on echocardiogram and if diagnosis is made 
antemortem, physician institutes appropriate antimicrobial therapy. 
 
Chronic lung disease 
Presence of lung disease and severity level as follows: 
None 
Mild: FEV1 60% to 75% of predicted, and/or on chronic inhaled or oral bronchodilator 
therapy. 
Moderate: FEV1 50% to 59% of predicted, and/or on chronic steroid therapy aimed at 
lung disease. 
Severe: FEV1 <60 or Room Air pCO2 >50. 
CLD present, severity not documented 
Unknown 
A history of chronic inhalation reactive disease (asbestosis, mesothelioma, black lung 
disease or pneumoconiosis) may qualify as chronic lung disease. Radiation induced 
pneumonitis or radiation fibrosis also qualifies as chronic lung disease. (if above criteria 
is met) A history of atelectasis is a transient condition and does not qualify. Chronic lung 
disease can include patients with chronic obstructive pulmonary disease, chronic 
bronchitis, or emphysema. It can also include a patient who is currently being chronically 
treated with inhaled or oral pharmacological therapy (eg, beta-adrenergic agonist, anti-
inflammatory agent, leukotriene receptor antagonist, or steroid). Patients with asthma 
or seasonal allergies are not 
considered to have chronic lung disease. 
 
 

 
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1.0 
STS Factors (continued) 
Factor 
Definition 
Peripheral vascular 
disease 
History of peripheral arterial disease (includes upper and lower extremity, renal, 
mesenteric, and abdominal aortic systems). This can include: 
• 
claudication , either with exertion or at rest 
• 
amputation for arterial vascular insufficiency 
• 
vascular reconstruction, bypass surgery, or percutaneous intervention to the 
extremities (excluding dialysis fistulas and vein stripping) 
• 
documented aortic aneurysm with or without repair 
• 
positive noninvasive test (eg, ankle brachial index ≤0.9, ultrasound, magnetic 
resonance or computed tomography imaging of >50% diameter stenosis in any 
peripheral artery, ie, renal, subclavian, femoral, iliac), or angiographic imaging 
*Excludes disease in the carotid cerebrovascular arteries, or thoracic aorta. PVD does not 
include deep vein thrombosis 
Cerebrovascular 
disease 
Indicate whether the patient has a current or previous history of any of the following: 
a. Stroke: Stroke is an acute episode of focal or global neurological dysfunction caused 
by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction, 
where the neurological dysfunction lasts for greater than 24 hours. 
b. TIA: is defined as a transient episode of focal neurological dysfunction caused by 
brain, spinal cord, or retinal ischemia, without acute infarction, where the 
neurological dysfunction resolves within 24 hours. 
c. Noninvasive or invasive arterial imaging test demonstrating ≥50% stenosis of any of 
the major extracranial or intracranial vessels to the brain 
d. Previous cervical or cerebral artery revascularization surgery or percutaneous 
intervention. This does not include chronic (nonvascular) neurological diseases or 
other acute neurological insults such as metabolic and anoxic ischemic 
encephalopathy. 
Cerebrovascular 
accident 
History of stroke. Stroke is an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction, where the neurological dysfunction lasts for greater than 24 hours. 
Previous cardiac 
interventions 
Any previous cardiovascular intervention, either surgical or non-surgical, which may 
include those done during the current admission. 
Number of diseased 
vessels 
The number of diseased major native coronary vessel systems: LAD system, Circumflex 
system, and/or Right system with ≥50% narrowing of any vessel preoperatively. 
NOTE: Left main disease (≥50%) is counted as TWO vessels (LAD and Circumflex, which 
may include a Ramus Intermedius). For example, left main and RCA would count as three 
total. A vessel that has ever been considered diseased, should always be considered 
diseased. 
Inotropes 
Subject received IV inotropic agents within 48 hours preceding surgery. 
 
 

 
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1.0 
STS Factors (continued) 
Factor 
Definition 
Cardiogenic shock 
A sustained (>30 min) episode of hypoperfusion evidenced by systolic blood pressure 
<90 mm Hg and/or, if available, cardiac index <2.2 L/min per square meter determined 
to be secondary to cardiac dysfunction and/or the requirement for parenteral inotropic 
or vasopressor agents or mechanical support (eg, IABP, extracorporeal circulation, VADs) 
to maintain blood pressure and cardiac index above those specified levels. Note: 
Transient episodes of hypotension reversed with IV fluid or atropine do not constitute 
cardiogenic shock. The hemodynamic compromise (with or without extraordinary 
supportive therapy) must persist for at least 30 min. 
Resuscitation  
Patient required cardiopulmonary resuscitation before the start of the operative 
procedure which includes the institution of anesthetic management. Capture 
resuscitation timeframe: within 1 hour or 1-24 hours pre-op 
Incidence 
Indicate if this is the patient's: 
• 
first surgery 
• 
first re-op surgery 
• 
second re-op surgery 
• 
third re-op surgery 
• 
fourth or more re-op surgery. 
Surgery is defined as cardiothoracic operations (heart or great vessels) surgical 
procedures performed with or without cardiopulmonary bypass (CPB). Also include lung 
procedures utilizing CPB or tracheal procedures utilizing CPB. Reoperation increases risk 
due to the presence of scar tissue and adhesions. 
 
 

 
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1.0 
STS Factors (continued) 
Factor 
Definition 
Cardiac presentation 
on admission 
Indicate the patient’s cardiac symptoms at the time of this admission. 
No Symptoms: No Symptoms, no angina. 
Stable Angina: Angina without a change in frequency or pattern for the prior 6 weeks. 
Angina is controlled by rest and/or oral or transcutaneous medications. 
Unstable Angina: There are three principal presentations of unstable angina: 1. Rest 
angina (occurring at rest and prolonged, usually >20 minutes); 2. New-onset angina 
(within the past 2 months, of at least Canadian Cardiovascular Society Class III severity); 
or 3. Increasing angina (previously diagnosed angina that has become distinctly more 
frequent, longer in duration, or increased by 1 or more Canadian Cardiovascular Society 
class to at least CCS III severity). 
–Non-ST Elevation MI (Non- STEMI): The patient was hospitalized for a non-ST elevation 
myocardial infarction (STEMI) as documented in the medical record. Non-STEMIs are 
characterized by the presence of both criteria: 
a. Cardiac biomarkers (creatinine kinase-myocardial band, Troponin T or I) exceed the 
upper limit of normal according to the individual hospital’s laboratory parameters 
with a clinical presentation which is consistent or suggestive of ischemia. ECG changes 
and/or ischemic symptoms may or may not be present. 
b. Absence of ECG changes diagnostic of a STEMI  
–ST Elevation MI (STEMI): The patient ’presented with a ST elevation myocardial 
infarction (STEMI) or its equivalent as documented in the medical record. STEMIs are 
characterized by the presence of both criteria: 
a. ECG evidence of STEMI: New or presumed new ST segment elevation or new left 
bundle branch block not documented to be resolved within 20 minutes. ST segment 
elevation is defined by new or presumed new sustained ST-segment elevation at the 
J-point in two contiguous electrocardiogram (ECG) leads with the cutoff points: ≥0.2 
mV in men or ≥0.15mV in women in leads V2-V3 and/or ≥0.1 mV in other leads and 
lasting greater than or equal to 20 minutes. If no exact ST-elevation measurement is 
recorded in the medical chart, physician’s written documentation of ST elevation or Q 
waves is acceptable. If only one ECG is performed, then the assumption that the ST 
elevation persisted at least the required 20 minutes is acceptable. Left bundle branch 
block (LBBB) refers to new or presumed new LBBB on the initial ECG. 
b. Cardiac biomarkers (creatinine kinase-myocardial band, Troponin T or I) exceed the 
upper limit of normal according to the individual hospital’s laboratory parameters a 
clinical presentation which is consistent or suggestive of ischemia. 
Angina equivalent 
Other: Presentation/symptom not listed above. 
 
 

 
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STS Factors (continued) 
Factor 
Definition 
Status of the procedure 
Elective: The patient's cardiac function has been stable in the days or weeks prior to the 
operation. The procedure could be deferred without increased risk of compromised 
cardiac outcome.  
Urgent: Procedure required during same hospitalization in order to minimize chance of 
further clinical deterioration. Examples include but are not limited to: Worsening, 
sudden chest pain, CHF, acute myocardial infarction (AMI), anatomy, IABP, unstable 
angina (USA) with intravenous (IV) nitroglycerin (NTG) or rest angina.  
Emergent: Patients requiring emergency operations will have ongoing, refractory 
(difficult, complicated, and/or unmanageable) unrelenting cardiac compromise, with or 
without hemodynamic instability, and not responsive to any form of therapy except 
cardiac surgery. An emergency procedure is one in which there should be no delay in 
providing operative intervention. The patient’s clinical status includes any of the 
following: a. Ischemic dysfunction (any of the following): (1) Ongoing ischemia including 
rest angina despite maximal medical therapy (medical and/or IABP)); (2) Acute Evolving 
Myocardial Infarction within 24 hours before surgery; or (3) pulmonary edema requiring 
intubation. b. Mechanical dysfunction (either of the following): (1) shock with circulatory 
support; or (2) shock without circulatory support. 
Emergent Salvage: The patient is undergoing CPR en route to the OR or prior to 
anesthesia induction or has ongoing ECMO to maintain life. 
 
 

 
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2.0 Other Factors Not Captured by Traditional Risk Score49 
Co-morbidity 
Definition/Criteria 
Porcelain aorta or 
severely 
atherosclerotic aorta 
Heavy circumferential calcification or severe atheromatous plaques of the entire 
ascending aorta extending to the arch such that aortic cross-clamping is not feasible. 
Frailty 
Slowness, weakness, exhaustion, wasting and malnutrition, poor endurance and 
inactivity, loss of independence 
Criteria:  
• 
5 meter walking time 
• 
Grip strength  
• 
BMI <20 kg/m2 and/or weight loss 5 kg/yr  
• 
Serum albumin <3.5 g/dL  
• 
Cognitive impairment or dementia  
Sever liver 
disease/cirrhosis 
Any of the following: 
• 
Child-Pugh class C  
• 
MELD score ≥10  
• 
Portal-caval, spleno-renal, or transjugular intrahepatic portal shunt  
• 
Biopsy proven cirrhosis with portal hypertension or hepatocellular dysfunction  
Hostile chest 
Any of the following or other reasons that make redo operation through sternotomy or 
right anterior thoracotomy prohibitively hazardous:  
• 
Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease)  
• 
Complications from prior surgery  
• 
Evidence of severe radiation damage (eg, skin burns, bone destruction, muscle loss, 
lung fibrosis or esophageal stricture)  
• 
History of multiple recurrent pleural effusions causing internal adhesions  
IMA or other critical 
conduit(s) crossing 
midline and/or 
adherent to posterior 
table of sternum  
 
A patent IMA graft that is adherent to the sternum such that injuring it during re-
operation is likely. A patient may be considered extreme risk if any of the following are 
present:  
• 
The conduit(s) are radiographically indistinguishable from the posterior table of the 
sternum.  
• 
The conduit(s) are radiographically distinguishable from the posterior table of the 
sternum but lie within 2-3 mm of the posterior table. 
Severe pulmonary 
hypertension  
Severe right 
ventricular 
dysfunction  
Primary or secondary pulmonary hypertension with PA systolic pressures greater than 
2/3 of systemic pressure  
Criteria as defined by the guidelines (eg, TAPSE <15mm, RV end-systolic area >20 cm2) 
 
 

 
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APPENDIX IV: RESHEATH AND RECAPTURE DEFINITIONS 
The following definitions are applicable to the data elements on the Implant eCRF that address the use of the 
resheath and recapture feature. 
Resheath attempt 
An attempt to intentionally resheath only a portion of the TAV (including the 
frame) into the capsule of the delivery catheter (eg, with the intent to 
reposition of the valve during deployment). 
Recapture attempt 
An attempt to intentionally fully resheath the entire TAV (including the frame) 
into the capsule of the delivery catheter until there is no gap between capsule 
and the tip (eg, with the intent to enable re-crossing of the aortic valve or 
retrieval of the system, Figure 14D). 
Reposition 
Repositioning of the TAV proximally or distally before final deployment 
Retrieve 
Retrieval of a partially deployed TAV 
 
 
Figure 10. (A) Between 0 and 1/3 of the valve length outside of the capsule (B) between 1/3 and 2/3 of the valve length outside of 
the capsule (C) Point of no return: capsule marker in alignment with the spindle marker (D) Full recapture: entire valve resheathed 
into the capsule until there is no gap between capsule and the tip. 

 
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APPENDIX V: DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS 
Definitions of adverse events to be evaluated as clinical safety endpoints, other related complications, and 
efficacy events are provided in Sections 1.0, 2.0, and 3.0, respectively. 49 The CEC and site investigators will 
code safety endpoint events according to these definitions, using the associated code list provided on 
Section 4.0, Event Code List. 
1.0 Safety Endpoint Definitions  
Mortality 
Cardiovascular 
mortality 
Any of the following criteria: 
1) Death due to proximate cardiac cause (eg, myocardial infarction, cardiac tamponade, 
worsening heart failure) 
2) Death caused by non coronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other 
vascular disease 
3) All procedure-related deaths, including those related to a complication of the 
procedure or treatment for a complication of the procedure 
4) All valve-related deaths including structural or nonstructural valve dysfunction or 
other valve-related adverse events 
5) Sudden or unwitnessed death 
6) Death of unknown cause 
Non-cardiovascular 
mortality 
Any death in which the primary cause of death is clearly related to another condition (eg, 
trauma, cancer, suicide). 

 
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1.0 
Safety Endpoints (continued) 
Myocardial Infarction 
Periprocedural MI 
(≤72 h after the 
index procedure) 
New ischemic symptoms (eg, chest pain or shortness of breath), or new ischemic signs (eg, 
ventricular arrhythmias, new or worsening heart failure, new ST-segment changes, 
hemodynamic instability, new pathological Q-waves in at least 2 contiguous leads, imaging 
evidence of new loss of viable myocardium or new wall motion abnormality) AND 
Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the index procedure, 
consisting of at least 1 sample post procedure with a peak value exceeding 15x as the 
upper reference limit for troponin or 5x for CK-MB. If cardiac biomarkers are increased at 
baseline (>99th percentile), a further increase in at least 50% post procedure is required 
AND the peak value must exceed the previously stated limit. 
Spontaneous MI 
(>72 h after the 
index procedure) 
Any of the following criteria: 
1) Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 1 
value above the 99th percentile URL, together with the evidence of myocardial 
ischemia with at least 1 of the following: 
• 
Symptoms of ischemia 
• 
ECG changes indicative of new ischemia (new ST-T changes or new left bundle 
branch block (LBBB)) 
• 
New pathological Q-waves in at least 2 contiguous leads 
• 
Imaging evidence of a new loss of viable myocardium or new wall motion 
abnormality 
2) Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, 
or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at 
autopsy, but death occurring before blood samples could be obtained, or at a time 
before the appearance of cardiac biomarkers in the blood. 
3) Pathological findings of an acute myocardial infarction  
 
 

 
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Safety Endpoints (continued) 
Stroke and TIA 
Diagnostic criteria 
1) Acute episode of a focal or global neurological deficit with at least 1 of the following:  
• 
change in the level of consciousness 
• 
hemiplegia, hemiparesis 
• 
numbness or sensory loss affecting 1 side of the body 
• 
dysphasia or aphasia 
• 
hemianopia 
• 
amaurosis fugax 
• 
other neurological signs or symptoms consistent with stroke 
Stroke: duration of a focal or global neurological deficit ≥24 h; OR <24 h if available neuroimaging documents 
a new hemorrhage or infarct; OR the neurological deficit results in death 
TIA: duration of a focal or global neurological deficit <24 h, any variable neuroimaging does not demonstrate 
a new hemorrhage or infarct 
2) No other readily identifiable non-stroke cause for the clinical presentation (eg, brain tumor, trauma, infection, 
hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in conjunction with the 
neurologist 
3) Confirmation of the diagnosis by at least 1 of the following: 
• 
Neurologist or neurosurgical specialist 
• 
Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds alone 
Stroke Definitions 
Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least 1 mRS category from an 
individual’s pre-stroke baseline 
Non-disabling stroke: an mRS score of <2 at 90 days or one that does not result in an increase in at least 1 mRS 
category from an individual’s pre-stroke baseline 
Stroke Classifications 
Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central 
nervous system tissue 
Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, 
intraventricular, or subarachnoid hemorrhage 
Undetermined: insufficient information to allow categorization as ischemic or hemorrhagic 
 
 

 
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Safety Endpoints (continued) 
Bleeding Complications 
Life-threatening or 
disabling bleeding 
1) Fatal bleeding (BARC type 5) OR 
2) Bleeding in a critical organ, such as intracranial, intraspinal, 
intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with 
compartment syndrome (BARC type 3b and 3c) OR 
3) Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors 
or surgery (BARC type 3b) OR 
4) Overt source of bleeding with drop in hemoglobin ≥5 g/dL or whole blood or packed 
red blood cells (RBCs) transfusion ≥4 units* 
(BARC type 3b) 
Major bleeding 
(BARC type 3a) 
1) Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 
g/dL or requiring transfusion of 2 or 3 units of whole blood/RBC, or causing 
hospitalization or permanent injury, or requiring surgery AND 
2) Does not meet criteria of life-threatening or disabling bleeding 
Minor bleeding 
(BARC type 2 or 3a, 
depending on the 
severity) 
Any bleeding worthy of clinical mention (eg, access site hematoma) that does not qualify 
as life-threatening, disabling, or major 
*Given one unit of packed RBC typically will raise hemoglobin concentration by 1 g/dL, an estimated decrease in 
haemoglobin will be calculated; BARC: Bleeding Academic Research Consortium29; RBC: red blood cell  
Note: With respect to blood transfusions, it is critical to acknowledge that a bleeding complication has to be the result of overt 
bleeding and cannot be adjudicated based on blood transfusions alone. 
 
Acute Kidney Injury (up to 7 days post procedure) 
Stage 1 
1) Increase in serum creatinine to 150%-199% (1.5-1.99 x increase compared with 
baseline) OR increase of ≥0.3 mg/dL (≥26.4 mmol/L) OR 
2) Urine output <0.5 mL/kg/h for >6 but <12 h 
Stage 2 
1) Increase in serum creatinine to 200%-299% (2.0-2.99 x increase compared with 
baseline) OR 
2) Urine output <0.5 mL/kg/h for >12 but <24 h 
Stage 3 
1) Increase in serum creatinine to ≥300% (>3 x increase compared with baseline) OR 
serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute increase of at least 0.5 
mg/dL (44 mmol/L) OR 
2) Urine output <0.3 ml/kg/h for ≥24 h OR 
3) Anuria for ≥12 h 
 
 

 
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Safety Endpoints (continued) 
Vascular Access Site and Access Related Complications 
Major vascular 
complication 
1) Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or 
new apical aneurysm/pseudoaneurysm OR 
2) Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve 
injury, compartment syndrome, percutaneous closure device failure) leading to 
death, life-threatening or major bleeding, visceral ischemia, or neurological 
impairment OR 
3) Distal embolization (noncerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage OR 
4) The use of unplanned endovascular or surgical intervention associated with death, 
major bleeding, visceral ischemia or neurological impairment OR 
5) Any new ipsilateral lower extremity ischemia documented by patient symptoms, 
physical exam, and/or decreased or absent blood flow on lower extremity 
angiogram OR 
6) Surgery for access site-related nerve injury OR 
7) Permanent access site-related nerve injury 
Minor vascular 
complication 
1) Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneuysms, hematomas, percutaneous 
closure device failure) not leading to death, life-threatening or major bleeding*, 
visceral ischemia, or neurological impairment OR 
2) Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage OR 
3) Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication OR 
4) Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
Percutaneous 
closure device 
failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
*Refer to VARCII bleeding definitions49 
VALVE DYSFUNCTION REQUIRING REPEAT PROCEDURE 
Any valve dysfunction that requires repeat procedure (eg, balloon valvuloplasty, TAVR, snare repositioning, 
placement of vascular plug paravalvular leak, or surgical AVR) 
Note: Repeat procedures are reported on the appropriate eCRF (Surgical Intervention or Catheter Reintervention) 
 
 

 
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2.0 Other Related Complications 
Complication 
Definition 
Conversion to open surgery 
Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications 
Unplanned use of 
cardiopulmonary bypass 
Unplanned use of CPB for hemodynamic support at any time during the TAVI 
procedure 
Coronary artery obstruction 
Angiographic or echocardiographic evidence of a new, partial or complete, 
obstruction of a coronary ostium, either by the TAV prosthesis itself, the 
native leaflets, calcifications, or dissection, occurring during or after the 
TAVR procedure. 
Ventricular septal perforation 
Angiographic or echocardiographic evidence of a new septal perforation 
during or after the TAVR procedure 
Mitral valve apparatus damage or 
dysfunction 
Angiographic or echocardiographic evidence of new damage (chordae, 
papillary muscle, or leaflet) to the mitral valve apparatus or dysfunction (eg, 
restrictions due to the TAV of the mitral valve during or after the TAVR 
procedure 
Cardiac tamponade 
Evidence of new pericardial effusion associated with hemodynamic 
instability and clearly related to the TAVI procedure 
Prosthetic valve thrombosis 
Any thrombus attached to or near an implanted valve that occludes part of 
the blood flow path, interferes with valve function, or is sufficiently large to 
warrant treatment. 
Valve-associated thrombus identified at autopsy in a patient whose cause of 
death was not valve related should not be reported as valve thrombosis. 
Valve migration 
After initial correct positioning, any observed movement (upward or 
downward) of the TAV within the aortic annulus from its initial position, with 
or without consequences. 
Valve embolization 
The TAV moves during or after deployment such that it loses contact within 
the aortic annulus 
Ectopic valve deployment 
Permanent deployment of the TAV in a location other than the aortic root 
TAV in TAV deployment 
Additional valve prosthesis is implanted within a previously implanted TAV 
because of sub-optimal device position and/or function, during or after the 
index procedure. 
Hemolysis 
Red cell destruction confirmed by lab data 
Minor hemolysis: No intervention required 
Major hemolysis: Requires intervention (eg, iron supplements, transfusion, 
invasive intervention). 
Frame fracture 
Visual evidence on radiography or at explant of loss of contact between 
elements (cells) of the stent. 
Minor frame fracture: Does not require intervention, or is not associated 
with prosthetic valve dysfunction. 
Major frame fracture: Intervention required (eg, reoperation, catheter re-
intervention) or is associated with prosthetic valve dysfunction 
 
 

 
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Other TAVR-Related Complications (continued) 
PROSTHETIC VALVE ENDOCARDITIS 
Any of the following: 
1) Fulfillment of the following Duke criteria for definite endocarditis: 74 
• 
Histologic and/or microbiologic evidence of infection at surgery or autopsy, or 
• 
2 major criteria, or 
• 
1 major criteria or 3 minor criteria, or  
• 
5 minor criteria 
Major and minor criteria are as follows: 
Major Criteria: 
• 
Blood cultures positive for Infective Endocarditis (IE) 
o 
Typical microorganisms consistent with IE isolated from two separate blood cultures, as noted 
below 
• 
Viridans streptococci, Streptococcus bovis, Staphylcoccus aureus, or HACEK group 
• 
Community-acquired enterococci in the presence of a primary focus 
o 
Microorganisms consistent with IE isolated from persistently positive blood cultures defined as: 
• 
At least two positive cultures or blood samples obtained >12 hours apart, or 
• 
All of three, or a majority of four or more separate cultures of blood, the first and last 
sample obtained > one hour apart 
o 
Single blood culture positive for Coxiella burnetti or an antiphase I IG antibody titer >1:800 
• 
Evidence of endocardial involvement 
o 
Positive results of echocardiography for IE defined as: 
• 
Oscillating intracardiac mass on a valve or supporting structures in the path of regurgitant 
jets or on implanted material in the absence of an anatomic explantation, or 
• 
Abscess, or 
• 
New partial dehiscence of a valvular prosthesis 
o 
New valvular regurgitation (worsening or changing or pre-existing murmur not sufficient) 
Minor Criteria: 
 
• 
Predisposition: predisposing heart condition or intravenous drug use 
• 
Fever: temperature >38◦C 
• 
Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial 
hemorrhage, conjunctival hemorrhages, and Janeway’s lesions 
• 
Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor 
• 
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 infectious endocarditis. 
• 
Echocardiographic findings: consistent with IE but do not meet a major criterion as noted above 
If only 1 major and 1-2 minor criteria are fulfilled, or if only 3-4 minor criteria are fulfilled, the event will be 
coded as “possible endocarditis” 
2) Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary to infection by histological 
or bacteriological studies during a re-operation 
3) Findings of abscess, pus, or vegetation involving the TAV or surgical bioprosthesis at autopsy 
 
 

 
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Efficacy Event Definitions 
PROSTHETIC VALVE DYSFUNCTION 
Stenosis: moderate/severe 
Any of the following  
1) Peak aortic velocity >4 m/s OR mean aortic gradient >40 mmHg, 
AND EOA <0.8 cm2. 
2) Peak aortic velocity >4 m/s OR mean aortic gradient >40 mmHg, 
AND EOA ≥0.8 cm2, and DVI <0.25, 
3) Peak aortic velocity ≤4 m/s and mean aortic gradient ≤ 40 mmHg, 
AND EOA <0.8 cm2, and DVI <0.25 
Paravalvular regurgitation: moderate 
Moderate paravalvular regurgitation (per echo criteria in Table 17, 3 
grade scheme) 
Paravalvular regurgitation: severe 
Severe paravalvular regurgitation (per echo criteria in Table 17, 3 grade 
scheme) per echo criteria in CIP) 
Transvalvular regurgitation: moderate 
Moderate paravalvular regurgitation (per echo criteria in Table 17, 3 
grade scheme)  
Transvalvular regurgitation: severe 
Severe transvalvular regurgitation (per echo criteria in Table 17, 3 grade 
scheme) 
Total regurgitation: moderate 
Moderate total regurgitation (per echo criteria in Table 16, 3 grade 
scheme) 
Total regurgitation: severe 
Severe total regurgitation (per echo criteria in Table 16, 3 grade scheme) 
Notes: 
 
1. 
DVI = Doppler Velocity Index (LVOT VTI/valve VTI) 
2. 
For subjects with BSA <1.6 m2, the EOA criteria for significant (moderate or severe) stenosis is <0.6 cm2 
3. 
For subjects with LVOT diameter >2.5 cm, the DVI criteria for significant (moderate or severe) stenosis is <0.2 cm2 
4. 
Reporting of prosthetic valve dysfunction will be based on core lab results. 
5. 
Prosthetic valve dysfunction events are not reported as adverse events, unless the dysfunction is accompanied with clinical 
sequelae at the time of event detection, and the clinical sequelae are chronologically and physiologically associated with the 
dysfunction. However, prosthetic dysfunctions that are associated with adverse events, and that meet the definition of a 
serious adverse event, should be reported as such. 
 

 
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4.0 Event Code List 
Myocardial Infarction 
100 
Peri-procedural myocardial infarction 
101 
Spontaneous myocardial infarction 
 
Stroke and TIA 
102 
Disabling stroke: ischemic 
103 
Disabling stroke: hemorrhagic 
104 
Disabling stroke: undetermined origin 
105 
Non-disabling stroke: ischemic 
106 
Non-disabling stroke: hemorrhagic 
107 
Non-disabling stroke: undetermined origin 
108 
Transient ischemic attack 
 
Bleeding Complications 
110 
Life threatening or disabling bleed event 
111 
Major bleeding event  
112 
Minor bleeding event 
 
Acute Kidney Injury 
113 
Acute kidney injury: stage 1 
114 
Acute kidney injury: stage 2 
115 
Acute kidney injury: stage 3 
 
Vascular Access and Access Site Complications 
Major 
120 
Major vascular complication: aortic dissection, aortic 
rupture, LV perforation, or new apical 
aneurysm/pseudoaneurysm 
121 
Major vascular complication: access site or access site-
related vascular injury (dissection, stenosis, 
perforation, etc) 
122 
Major vascular complication: distal embolization from 
vascular source 
123 
Unplanned endovascular or surgical intervention 
124 
New ipsilateral lower extremity ischemia 
125 
Surgery for access site-related nerve injury 
126 
Permanent access site-related nerve injury 
127 
Other major vascular complication 
Minor 
130 
Minor vascular complication: access site or access site-
related vascular injury 
131 
Minor vascular complication: distal embolization from 
vascular source 
132 
Unplanned endovascular stenting or unplanned 
surgical intervention not meeting criteria for major 
complication 
133 
Vascular repair or need for vascular repair 
134 
Other minor vascular access site complication 
140 
Failure of closure device leading to alternative 
treatment 
 
 
Other TAVR-Related Complications 
150 
Conversion to open surgery 
151 
Unplanned used of CPB 
152 
Coronary artery obstruction 
153 
Ventricular septal perforation 
154 
Mitral valve apparatus damage 
155 
Cardiac tamponade 
156 
Prosthetic valve thrombosis 
157 
Valve migration 
158 
Valve embolization 
159 
Ectopic valve deployment 
160 
TAV in TAV deployment 
161 
Major hemolysis 
162 
Minor hemolysis 
163 
Prosthetic valve endocarditis: definite 
164 
Prosthetic valve endocarditis: possible 
165 
Major frame fracture 
166 
Minor frame fracture 
167 
Other TAVR-related complication 
 
 
Conduction Disturbances and Arrhythmias 
170 
Atrio-ventricular block, 1° 
171 
Atrio-ventricular block, 2° 
172 
Atria-ventricular block, 3° 
173 
LBBB 
174 
RBBB 
175 
Left anterior fascicular block 
176 
Left posterior fascicular block 
180 
Atrial fibrillation 
181 
Atrial flutter 
182 
Junctional rhythm (<100 bpm) 
183 
Junctional rhythm (≥100 bpm) 
184 
Sinus bradycardia (<50 bpm) 
185 
Supraventricular tachycardia 
186 
Ventricular fibrillation 
187 
Ventricular premature beats 
188 
Ventricular tachycardia 
189 
Other arrhythmia 
 
 
Prosthetic Valve Dysfunction 
191 
Moderate/severe stenosis 
192 
Moderate paravalvular regurgitation 
193 
Severe paravalvular regurgitation 
194 
Moderate transvalvular regurgitation 
195 
Severe transvalvular regurgitation 
196 
Moderate total regurgitation 
197 
Severe total regurgitation 
 
 
 
 
 
 

 
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Other Implantation/Catheterization Procedure-Related 
Adverse Events 
200 
Brachial plexus injury 
201 
Hypovolemia 
202 
Hypotension requiring intervention 
203 
Air embolism 
204 
Venous thrombosis, definite 
205 
Venous thrombosis, suspected 
206 
Metabolic acidosis 
207 
Catheter induced arrhythmia 
208 
Hemothorax 
209 
Radiation-induced erythema 
210 
Other implantation/catheterization 
 
 
Other Cardiac Adverse Events 
300 
Cardiac arrest 
301 
Congestive heart failure 
302 
Cardiogenic shock 
303 
Valvular regurgitation, mitral 
304 
Valvular regurgitation, tricuspid 
307 
Syncope 
308 
Palpitations 
309 
Cyanosis 
310 
Chest pain 
311 
Pericardial effusion, hemorrhagic 
312 
Pericardial effusion, non-hemorrhagic 
313 
Intracardiac mass 
399 
Other cardiac event 
 
 
Respiratory/Pulmonary Adverse Events 
400 
Respiratory arrest 
401 
Pneumothorax 
402 
Chronic pulmonary disease 
403 
Bronchospasm/asthma 
404 
Pleural effusion 
405 
Hemoptysis 
406 
Respiratory failure 
407 
Atelectasis 
408 
Hemothorax 
409 
Respiratory insufficiency 
410 
Apnea/hypoventilation 
499 
Other respiratory/pulmonary 
 
 
Other Neurologic Adverse Events 
500 
Seizure(s) 
502 
Meningitis, infectious 
504 
Headaches 
505 
Dizziness 
599 
Other central nervous system 
 
 
Gastrointestinal Adverse Events 
600 
Vomiting 
601 
Diarrhea 
602 
Protein losing enteropathy 
603 
Liver disease 
604 
Liver failure 
699 
Other gastrointestinal 
 
 
Hematologic/Oncologic Adverse Events 
700 
Cancer/malignancy 
701 
Coagulopathy 
702 
Anemia (Hgb <10g or Hct <30%) 
703 
Thrombocytopenia 
704 
Transfusion reaction 
799 
Other hematologic/oncologic 
 
 
Infection Adverse Events 
801 
Fever 
802 
Sepsis, confirmed (positive blood culture) 
803 
Sepsis, suspected (by clinical findings) 
804 
Endocarditis, other than the TAV or surgical valve 
805 
Urinary tract infection 
806 
Pneumonia 
807 
Gastroenteritis 
808 
Hepatitis 
809 
Upper respiratory tract infection 
899 
Other infection 
 
 
Other Renal Adverse Events (Exclusive of AKI) 
900 
Renal insufficiency 
902 
Chronic renal failure 
903 
Proteinuria 
904 
Urinary retention 
999 
Other renal 
 
 
Allergic Reactions 
1000 Anaphylaxis 
1001 Pruritus 
1002 Rash 
1003 Contrast reaction/allergy 
1004 Medication reaction/allergy 
1099 Other allergic reaction 
 
 
Other 
1200 Multi organ failure 
1299 Other 
 

 
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5.0 
Classification of Causal Relationships 
The following definitions are intended as guidelines for classifying causal relationships between the event 
and the TAV or surgical valve, the catheter delivery system, and the TAVR or SAVR implant procedure. 
Causal relationships between event and the TAV or surgical valve 
Not related to the TAV 
or surgical valve 
The relationship to TAV or surgical valve can be excluded when: 
• 
the event is not a known side effect of the TAV or surgical valve product category 
the device belongs to or of similar devices; 
• 
The event has no temporal relationship with the TAV or surgical valve 
• 
The event does not follow a known response pattern to the TAV or surgical valve 
and is biologically implausible;  
• 
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at 
the same time. 
Unlikely to be related to 
the TAV or surgical valve 
The relationship with the TAV or surgical valve seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained. 
Possibly related to the 
TAV or surgical valve 
The relationship with the TAV or surgical valve is weak but cannot be ruled out 
completely. Alternative causes are also possible (eg, an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible. 
Probably related to the 
TAV or surgical valve 
The relationship with TAV or surgical valve seems relevant and/or the event cannot 
reasonably explained by another cause, but additional information may be obtained. 
Causal relationship 
“Related” to the TAV or 
surgical valve 
The event is associated with the TAV or surgical valve beyond reasonable doubt when:  
• 
the event is a known side effect of the TAV or surgical valve product category the 
device belongs to or of similar devices; 
• 
the event has a temporal relationship with investigational device use/application 
or procedures; 
• 
the event involves a body-site or organ that  
o 
the TAV or surgical valve is applied to;  
o 
the TAV of surgical valve has an effect on; 
• 
the event follows a known response pattern to the TAV or surgical valve; 
• 
other possible causes (eg, an underlying or concurrent illness/clinical condition or 
an effect of another device, drug, or treatment) have been adequately ruled out 
• 
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the 
same time. 
Timeframe for assessing implant procedure relationships begin when subject is being prepared for the TAVR or SAVR implant (or re-
implant) procedure. 
 
 

 
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Causal relationships between event and the TAVR delivery system 
Not related to the TAVR 
delivery system 
The relationship with the TAVR delivery system can be excluded when:  
• 
the event is not a known side effect of the TAVR delivery system product category 
the device belongs to or of similar devices; 
• 
The event has no temporal relationship with the use of the TAVR delivery system 
• 
The event does not follow a known response pattern to the TAVR delivery sysem 
and is biologically implausible;  
• 
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at 
the same time 
Unlikely to be related to 
the TAVR delivery 
system 
The relationship with the TAVR delivery sysem seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained. 
Possibly related to the 
TAVR delivery system 
The relationship with the TAVR delivery system is weak but cannot be ruled out 
completely. Alternative causes are also possible (eg, an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible. 
Probably related to the 
TAVR delivery system 
The relationship with the TAVR delivery system seems relevant and/or the event 
cannot reasonably explained by another cause, but additional information may be 
obtained. 
Causal relationship 
“Related” to the TAVR 
delivery system 
The event is associated with the TAVR delivery system reasonable beyond doubt 
when: 
• 
the event is a known side effect of the product category the device belongs to or 
of similar devices; 
• 
the event has a temporal relationship with the TAVR delivery system 
use/application; 
• 
the event involves a body-site or organ that  
o 
the TAVR delivery system is applied to;  
o 
the TAVR delivery system has an effect on; 
• 
the event follows a known response pattern to the TAVR delivery system; 
• 
other possible causes (eg, an underlying or concurrent illness/clinical condition or 
an effect of another device, drug, or treatment) have been adequately ruled out 
• 
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the 
same time. 
 
 

 
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Causal relationships between event and the TAVR or SAVR implant procedure 
Not related to the TAVR 
or SAVR implant 
procedure 
The relationship with the TAVR or SAVR implant procedure can be excluded when:  
• 
the event is not a known side effect of the TAV or SAVR implant procedure; 
• 
The event has no temporal relationship with the TAVR or SAVR implant 
relationship 
• 
The event does not follow a known response pattern to the TAVR or SAVR implant 
procedure and is biologically implausible;  
• 
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at 
the same time. 
Unlikely to be related to 
the TAVR or SAVR 
implant procedure 
The relationship with the TAVR or SAVR implant procedure seems not relevant and/or 
the event can be reasonably explained by another cause, but additional information 
may be obtained. 
Possibly related to the 
TAVR or SAVR implant 
procedure 
The relationship with the TAVR or SAVR implant procedure is weak but cannot be ruled 
out completely. Alternative causes are also possible (eg, an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible. 
Probably related to the 
TAVR or SAVR implant 
procedure 
The relationship with TAVR or SAVR implant procedure seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may 
be obtained. 
Causal relationship 
“Related” to the TAVR 
delivery system 
The event is associated with the TAVR or SAVR implant procedure beyond reasonable 
doubt when:  
• 
the event is a known side effect of the TAVR or SAVR implant procedure; 
• 
the event has a temporal relationship with the TAVR or SAVR implant procedure; 
• 
the event involves a body-site or organ that  
o 
the TAVR or SAVR is applied to;  
o 
the TAVR or SAVR implant procedure has an effect on; 
• 
the event follows a known response pattern to the TAVR or SAVR implant 
procedure; 
• 
other possible causes (eg, an underlying or concurrent illness/clinical condition or 
an effect of another device, drug, or treatment) have been adequately ruled out 
• 
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the 
same time. 
Note: Procedure related events refers to the procedure related to the initial application of the investigational medical device only and therefore not 
to any other procedures or treatments applied later throughout the clinical investigation, for instance to treat (serious) adverse events. 
 
 

 
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APPENDIX VI: SAMPLE INFORMED CONSENT FORM: MAIN TRIAL 
 
An informed consent form template will be provided under separate cover. 
 
 
 

 
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APPENDIX VII: LEAFLET THICKENING/IMMOBILITY SUB-STUDY PROTOCOL 
1.0 Synopsis 
Title 
Frequency of Leaflet Thickening/Immobility Detected By Multidetector CT 
Scanning Following Aortic Valve Replacement Sub-Study 
Purpose 
Evaluate leaflet thickening/immobility (LTI) after transcatheter and surgical aortic 
valve replacement in subjects enrolled in the Medtronic Transcatheter Aortic Valve 
(Medtronic TAVR) Low Risk Trial 
Design 
Subjects participating in the LTI Sub-Study will undergo post-procedure MDCT 
scanning. An independent MDCT Core Laboratory will evaluate scans for the 
presence of LTI. 
Study Objective 
Establish the prevalence of the LTI detected by MDCT angiography following TAVR 
and SAVR 
Investigational 
Sites 
Up to 100 Low Risk sites worldwide. All LTI sites will be participating in the Low 
Risk Trial 
Sample Size 
At least 150 evaluable TAVR subjects and at least 150 evaluable SAVR subjects will 
followed up through one year as part of the sub-study 
Subject Selection 
Criteria 
• 
Enrollment in the Medtronic TAVR Low-Risk Trial 
• 
Absence of Chronic Kidney Disease Stage IV or V (eGFR <30 ml/min) 
Study Evaluations 
and Procedures 
• 
Patients who consent to sub study participation will undergo MDCT 
angiography at 30 days and one year 
 
Professional 
Services 
MDCT Core Laboratory 
 
2.0 Background 
Recent publications75-77 have reported Multidetector Computed Tomography (MDCT) imaging findings in 
asymptomatic patients following transcatheter and surgical aortic valve replacement (TAVR and SAVR) 
referred to as leaflet thickening or immobility (LTI). The incidence of LTI in these reports ranged widely from 
4%77 to 40%,75 and frequencies across device platforms could not be established due to the small number of 
subjects studied. Similarly, no definitive correlation between LTI and patient characteristics, procedural 
factors, or clinical events could be made although it was shown that LTI can be resolved with 
anticoagulation therapy using Vitamin K Antagonists (VKAs). 
These preliminary findings highlight the need for further investigation; principally, determining the 
incidence of LTI in transcatheter and surgical aortic bioprostheses. Foundational work to understand the 
impact of LTI in terms of late clinical events is also warranted. 

 
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3.0 Sub-Study Objective 
The objective of the LTI Sub-Study is to establish the prevalence of the LTI detected by MDCT angiography 
following transcatheter and surgical aortic valve replacement. Additionally, the relationship between LTI 
and late clinical events will be explored. 
4.0 Methodology 
Patients enrolled in the LTI Sub-Study will follow all methods and procedures according to the main 
protocol. This section will provide information on methods and requirements specific to the LTI Sub-Study.  
4.1 Sub-Study Design 
Subjects will undergo MDCT scanning at 30 days and one year post-implantation. MDCT scans will be 
acquired by study-trained staff with oversight by a designated cardiovascular imaging specialist to ensure 
MDCT images are in accordance with the LTI Sub-Study protocol. An independent MDCT Core Laboratory 
will evaluate site images and determine if LTI is present or absent according to protocol definitions. 
4.2 Investigational Sites 
The LTI Sub-Study will be conducted at up to 100 investigational sites. Investigational sites must meet the 
following criteria for LTI Sub-Study participation: 
• 
Demonstrated ability to perform high quality retrospective ECG gated MDCT scans with validated CT 
equipment meeting minimum requirements for temporal resolution 
• 
Dedicated cardiac CT imaging specialist with experience acquiring and reviewing CT imaging of TAVR 
patients  
• 
Completion of MDCT Core Lab training for compliance with study imaging protocol 
• 
Participation in ongoing assessment of imaging quality 
4.3 Number of Subjects 
At least 150 evaluable patients treated with the Medtronic TAVR system bioprostheses and at least 150 
evaluable patients treated with surgical valves will be enrolled in the LTI Sub-Study. The MDCT Core 
Laboratory will determine if patients are evaluable by review of the 30 day MDCT scan. 
4.4 Subject Selection Criteria 
4.4.1 
Inclusion Criteria 
Prospective subjects for the LTI Sub-Study must meet all subject selection criteria for enrollment in the 
Medtronic TAVR Low Risk Trial (see Section 3.3.5 of the main protocol) and undergo device implantation. 
4.4.2 
Exclusion Criteria 
Subjects with history of Chronic Kidney Disease Stage IV or V (eGFR <30 ml/min) are excluded from 
participation in the LTI Sub-Study. 
Additionally if any of the following clinical findings are present at the time of MDCT, the subject is not 
eligible for image acquisition: 
1. Chronic Kidney Disease Stage IV or V (eGFR <30 ml/min) 

 
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2. Atrial fibrillation that cannot be rate controlled to ventricular response rate <60 bpm  
4.5 Informed Consent 
Prior to enrolling in the study, patients should be fully informed of the details of study participation as 
required by applicable regulations, the site’s IRB and by Medtronic. An informed consent addendum 
specific to the LTI Sub-Study will be reviewed and signed by patients participating in the LTI Sub-Study. 
4.6 Screening and Enrollment 
See section 3.3.8 and Figure 1 of main protocol for screening and enrollment information. 
4.7 Post Procedure Anti-thrombotic Therapy 
The recommended post procedure anti-thrombotic regiment for TAVR will be 30 days or more of DAPT 
followed by aspirin through 12 months. Recommended pharmacology post procedure for SAVR will be a 
VKA or aspirin in accordance with current guidelines.13 As the clinical significance of any LTI findings has not 
been established, treatment of subjects should be based on current standard of care practices. The local 
clinical site investigator should avoid empiric anticoagulation unless any of the following clinical findings are 
demonstrated: 
• 
Any neurological event 
• 
Any potential embolic event 
• 
ST segment elevation or Non ST elevation myocardial infarction 
• 
Increase in aortic regurgitation to moderate to severe 
• 
An increase by more than 50% of discharge mean aortic valve gradient or a decrease in the Doppler 
Velocity Index (DVI) by more than 50% 
4.8 Required Evaluations 
LTI Sub-Study protocol evaluations should be performed at the investigational site. The protocol required 
sub-study evaluations are as follows: 
30 days (between 30 and 45 days post procedure) 
• 
ECG if history or symptoms of atrial fibrillation are present 
• 
MDCT image acquisition 
One year (between 365 and 395 days post procedure) 
• 
ECG if history or symptoms of atrial fibrillation are present 
• 
MDCT image acquisition 
4.9 Unblinding of MDCT Core Laboratory Findings 
Images will be read in a standard fashion for cardiac and non-cardiac findings by clinical site CT imaging 
specialist. If deterioration of subject health due to suspected thrombosis occurs, the clinical site may 
request an unblinding of the MDCT Core Laboratory findings.  

 
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4.10 
Adverse Events, Clinical Events Committee, Data Safety Monitoring Board 
Investigational sites will report events related to sub-study participation as described in the main protocol 
(Section 3.3.25). The Clinical Events Committee (CEC) and Data Safety Monitoring Board (DSMB) procedures 
are found in the main protocol (Section 3.3.26 and Section 3.3.27).  
4.11 
Statistical Analysis 
Primary analysis for the LTI Sub-study will be performed after subjects have completed one year 
evaluations. Descriptive statistics will be used to identify the presence of LTI at 30 days and 1 year in 
subjects undergoing aortic valve replacement, with frequencies provided for transcatheter and surgical 
aortic valves. 
5.0 MDCT Image Acquisition 
5.1 General requirements 
5.1.1 
General requirements for CT hardware 
• 
Single source CT scanner  
- 
With 8 cm detector coverage (Toshiba Aquilion Premium, Philips iCT256)  
- 
Volume CT scanner with 16 cm detector coverage (Aquilion One/Vision; GE Revolution) 
• 
Dual Source CT scanners (Siemens Somatom Definition, Flash, Force)  
5.1.2 
General requirements for CT data acquisition 
• 
Contrast enhancement  
- 
4-6 ml/s contrast media injection rate 
• 
ECG-assisted/synchronized data acquisition  
- 
Helical/spiral data acquisition with retrospective ECG-gating  
- 
ECG-gated volume acquisition (one beat, one slab, 8 cm or 16 cm acquisition)  
- 
CAVEAT: sequential/axial data acquisition with prospective ECG-triggering or high-pitch helical 
data acquisition is not acceptable 
• 
Data acquisition covering the entire cardiac cycle  
• 
Sufficient z-axis coverage to allow for coverage of the transcatheter heart valve or surgical heart valve 
5.1.3 
General requirements for CT data reconstruction 
• 
Multiphasic, thin sliced, overlapping axial image reconstructions  
- 
≤0.625 mm slice thickness with overlap 
- 
5% or 10% increments (relative reconstruction), or 50ms increments (absolute reconstruction) 
- 
Coverage of the entire cardiac cycle 
• 
ECG-editing in case of increased heart rate variability and premature contractions when using 
retrospective ECG-gating. 
5.2 Specific recommendations  
5.2.1 
Heart rate control  
• 
Use oral or intra-venous beta-blockade for heart rate control, in particular when using single-
source/volume scanners. 

 
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• 
Indications/contraindications for administration of beta-blockade should follow institutional 
standards/guidelines 
5.2.2 
Acquisition technique 
The following table lists recommended techniques for ECG-assisted data acquisition stratified by scanner 
type: 
Scanner 
Recommendation 
GE 
GE Revolution (Volume 
scanner) 
ECG-gated, ’one-beat, one-slab’ volume acquisition (detector has 16cm coverage) 
Philips  
Philips iCT 256 
ECG-gated, ’one-beat, one-slab’ volume acquisition (detector has 8cm coverage) 
Siemens 
Siemens Dual-Source 
(Somatom Definition, Flash, 
Force) 
Helical/spiral acquisition with retrospective ECG-gating (do not use high-helical pitch 
acquisition or step-and shoot mode) 
Toshiba 
Toshiba Aquilion One/Vision 
or Aquilion Premium 
ECG-gated, ’one-beat, one-slab’ volume acquisition (detectors have 16 cm or 8 cm 
coverage) 
 
 
 

 
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5.2.3 
Acquisition settings 
The following table lists recommended settings for the ECG-assisted data acquisition: 
Parameter 
Recommendation 
Tube current 
Absolute or reference tube current settings similar to institutional settings for 
routine coronary cardiac CT 
Dose modulation 
Dose modulation is not recommended in order to allow for images of equal, 
diagnostic image quality throughout the entire cardiac cycle 
Tube voltage 
120 kVp, alternatively 140 kVp to reduce beam hardening artifacts of stent frame 
(in particular with volume-scanners); use of 100kVp or 80kVp is not recommended; 
automated algorithms for tube voltage selection may need to be overridden  
Collimation 
Thinnest possible, eg, 0.625 mm with GE and Philips hardware, 0.6 mm with 
Siemens Hardware, 0.5 mm/0.25 mm with Toshiba hardware 
5.2.4 
Contrast administration  
The following table lists recommendations for contrast administration: 
Parameter 
Recommendation 
Iodine concentration 
Iodinated contrast agent as per institutional standards 
Flow rate 
4-6 ml/sec 
Volume 
As per institutional standard for routine coronary cardiac CT, commonly 50-80 cc 
IV-access 
Antecubital vein is recommended 
Timing 
Bolus tracking to allow for peak contrast in the ascending aorta 
5.2.5 
Image reconstruction 
The following table lists recommendations for image reconstruction settings: 
Parameter 
Recommendation 
Technique 
Both, reconstructions with filtered back projection or iterative reconstruction are 
acceptable. If iterative reconstruction is used, the strength/weighting should be 
intermediate (eg, ADMIRE/SAPHIRE/IRIS strength 3, ASIR 40%)  
Slice thickness 
Thinnest possible, eg, 0.625 mm with GE and Philips hardware, 0.6 mm with 
Siemens Hardware, 0.5 mm/0.25 mm with Toshiba hardware 
Slice overlap 
Slice overlap is recommended to improve MPR quality; eg, 0.4 mm increment with 
0.6 mm slice thickness when using Siemens equipment 
Reconstruction field of 
view and matrix 
Small field of view (FOV) limited to the heart; 512 x 512 matrix 
Reconstruction kernel 
Same kernel as used for coronary CTA per institutional standard; alternatively use 
edge-pronounced kernel (‘stent’ kernel, eg, I46f) in particular with pronounced 
blooming 
Multiphasic 
reconstruction 
• 
Coverage of the entire cardiac cycle 
Volume scanner (GE Revolution, Toshiba Aquilion One/Vision): 
• 
5% or 10% increments  
Other scanner: 
• 
5% or 10% increments (relative reconstruction), or 50 ms increments 
(absolute reconstruction, not available on Philips Hardware) 
 
 

 
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6.0 MDCT Core Laboratory Data Analysis 
MDCT analysis is performed on dedicated post-processing work-stations using multiplanar reformats. 
Analysis steps resulting in either binary values or semi-quantitative, grading scale values are performed by 
two physician readers independently. In case of disagreement, arbitration will be performed by a third 
reader. Quantitative analysis resulting in continuous variables (such as caliper measurements) are 
performed by one expert physician reader. 
6.1 Assessment and documentation of image quality based on pre-defined standards 
• 
Verification that a multiphasic dataset has been provided and assessment of which parts of the cardiac 
cycle are covered by the multiphasic reconstruction. 
• 
Assessment of slice thickness and slice overlap. 
• 
Assessment of presence of sufficient contrast attenuation. 
• 
Assessment of image quality throughout cardiac cycle, with focus on presence of reconstruction with 
diagnostic image quality in mid-systole and diastole 
6.2 Leaflet thickening and immobility (LTI) assessments 
The location of the affected cusp(s) will be defined with regard to the bioprosthetic valve commissure that 
is aligned with one of the outflow tabs. This tab also has an x-ray marker ‘c’ which may be visible on the 
reformatted CT images. For surgical valves, the location of the affected cusp(s) will be defined with regard 
to the former native cusp position as right, left, or non-coronary. 
6.2.1 
Leaflet thickening  
Leaflet thickening will be assessed as follows: 
• 
Presence of hypoattentuating leaflet thickening or focal hypoattenuating abnormality attached to one 
or more prosthetic leaflets identifiable on at least two reconstructed planes  
• 
Maximum thickness of the affected cusp will be measured on the long axis of the device  
6.2.2 
Leaflet immobility 
Quantification of leaflet immobility/restriction requires systolic reconstruction phases of diagnostic image 
quality and will be evaluated using multiplane reformats (MPRs) and graded in regard to the involvement 
along the curvilinear leaflet at its center 
• 
Partial immobility limited to basal restriction (<25%) 
• 
Partial immobility, 25-75% 
• 
Immobile or largely immobile (>75%)  
6.2.3 Prosthesis position and expansion 
For the TAV stent frame expansion will be planimetrically assessed at the inflow, mid-level, and outflow 
regions of device. 
 
 

 
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7.0 Sample Informed Consent Addendum for LTI Sub-Study 
A sample informed consent addendum will be provided under separate cover. 
 
 

 
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APPENDIX VIII: Quality of Life Questionairres 
A sample Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol (EQ-5D) will be provide under 
separate cover 
 
 
 
 

 
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Clinical Investigation Plan 
Clinical Investigation Plan Title  Transcatheter Aortic Valve Replacement (TAVR) in 
Patients with the Medtronic Transcatheter Aortic Valve 
Replacement System (TAVR) in Patients at Low Risk for 
Surgical Aortic Valve Replacement (SAVR) Continued 
Access Trial 
Addendum To Transcatheter Aortic Valve Replacement With the 
Medtronic Transcatheter Aortic Valve Replacement 
System In Patients at Low Risk for Surgical Aortic Valve 
Replacement Trial Number 10234430DOC 
Study Product Name Medtronic Evolut R Transcatheter Aortic Valve (TAV) 
System 
Medtronic Evolut PRO TAV System 
Sponsor/Local Sponsor Medtronic  
Coronary and Structural Heart Clinical 
8200 Coral Sea St. NE, MVS 66 
Mounds View, MN 55112 
United States 
Document Version, Date 1A 
Document Date 25-JUL-2018 
Document Reference Number 10831957DOC 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 
 
 

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Table of Contents  
 
  
Table of Contents ...................................................................................................................... 2 
1. 
Glossary .............................................................................................................................. 5 
2. 
Synopsis ............................................................................................................................. 6 
3. 
Introduction ....................................................................................................................... 8 
3.1. Background ............................................................................................................................. 8 
3.2. Purpose ................................................................................................................................... 9 
4. 
Objectives and Endpoints ................................................................................................... 9 
4.1. Objectives ............................................................................................................................... 9 
4.1.1. 
Primary Objective .................................................................................................................... 9 
4.1.2. 
Secondary Safety Endpoints .................................................................................................... 9 
4.1.3 
Secondary Effectiveness Endpoints......................................................................................... 9 
5. 
Study Design ...................................................................................................................... 9 
5.1. Duration ................................................................................................................................ 10 
5.2. Rationale ............................................................................................................................... 10 
6. 
Product Description.......................................................................................................... 10 
6.1 Trial Materials ........................................................................................................................ 10 
6.2 Device Accountability ............................................................................................................. 10 
6.3.  Device Malfunction or Explant ................................................................................................. 11 
7. 
Selection of Subjects ........................................................................................................ 12 
7.1. Study Population .................................................................................................................... 12 
7.2. Subject Enrollment ................................................................................................................. 12 
7.3. Inclusion Criteria .................................................................................................................... 12 
7.4. Exclusion Criteria ................................................................................................................... 12 
8. 
Study Procedures ............................................................................................................. 15 
8.1. Schedule of Events ................................................................................................................. 15 
8.1.1 
Echocardiography .................................................................................................................. 17 
8.2. Subject Consent ..................................................................................................................... 17 
8.3. Subject Screening .................................................................................................................. 18 

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8.4. Subject Disposition ................................................................................................................. 19 
8.5. Assessment of Safety ............................................................................................................. 19 
8.6. Recording Data ...................................................................................................................... 19 
8.7. Time Windows for Completion and Submission of eCRFs and Data Collection Forms................... 20 
8.8. Deviation Handling ................................................................................................................. 20 
8.9. Subject Withdrawal or Discontinuation .................................................................................... 21 
9. 
Data Review Committees ................................................................................................. 21 
10. 
Risks and Benefits ......................................................................................................... 21 
11. 
Statistical Design and Methods ..................................................................................... 22 
11.1 Analysis Populations ............................................................................................................... 22 
11.1.1 Approved Population ............................................................................................................... 22 
11.2 Description of Baseline Variables ............................................................................................. 22 
11.3 Sample Size ........................................................................................................................... 22 
11.4 Subject Accountability ............................................................................................................ 22 
11.5 Analysis of Endpoints ............................................................................................................. 23 
12. 
Ethics ............................................................................................................................. 23 
12.1. 
Statement(s) of Compliance .............................................................................................. 23 
13. 
Study Administration ..................................................................................................... 24 
13.1. 
Study Training ................................................................................................................. 24 
13.2. 
Monitoring ....................................................................................................................... 24 
13.3. 
Data Management ............................................................................................................ 24 
13.4. 
Confidentiality .................................................................................................................. 24 
13.5. 
Liability ............................................................................................................................ 25 
13.6. 
CIP Amendments ............................................................................................................. 25 
13.7. 
Record Retention ............................................................................................................. 25 
13.8. 
Publication and Use of Information .................................................................................... 25 
13.9. 
Suspension or Early Termination ....................................................................................... 25 
14 
Appendices .................................................................................................................... 27 
APPENDIX I: DEFINITIONS OF STS FACTORS AND OTHER CO-MORBIDITIES ...................... 27 
1.0 
STS Factors .................................................................................................................... 27 
APPENDIX II: TVT-R DATA COLLECTION FORM IDENTIFED ADVERSE EVENTS ..................... 36 

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2.0 
Adverse Events .............................................................................................................. 36 
15 
Version History .............................................................................................................. 36 
 
 
 

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1. Glossary 
Term 
Definition 
TAVR 
Transcatheter Aortic Valve Replacement 
SAVR 
Surgical Aortic Valve Replacement 
TAV 
Transcatheter Aortic Valve 
TVT-R 
Transcatheter Valve Therapies Registry 
CMS 
Centers for Medicare & Medicaid Services 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
RDC 
Remote Data Capture 
TTE 
Transthoracic Echocardiography 
ICF 
Informed Consent Form 
MDCT 
Multi-Detector Computed Tomography 
PCI 
Percutaneous Coronary Intervention 
DTL 
Delegated Task List 
eCRFs 
Electronic Case Report Forms 
SID Number 
Subject Identification Number 
 
 

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2. Synopsis 
Title 
Transcatheter Aortic Valve Replacement (TAVR) in Patients with the 
Medtronic Transcatheter Aortic Valve Replacement System (TAVR) in 
Patients at Low Risk for Surgical Aortic Valve Replacement (SAVR) 
Continued Access Trial 
Clinical Trial Type 
Continued Access 
Product Name 
Investigational Devices 
• Evolut R 23, 26, 29, and 34 mm Transcatheter Aortic Valve (TAV) 
• Medtronic Evolut PRO TAV 23, 26, and 29 mm 
• EnVeo R Delivery Catheter System with EnVeo Inline Sheath and 
EnVeo R Loading System 
• EnVeo PRO Delivery Catheter System and EnVeo PRO Loading 
System 
Sponsor  
Medtronic  
Local Sponsor 
Coronary and Structural Heart Clinical  
8200 Coral Sea St. NE, MVS 66 
Mounds View, MN 55112 
United States 
Investigation Purpose 
Evaluate the safety and effectiveness of the Medtronic TAVR System 
in patients with severe aortic stenosis at low risk for SAVR 
Primary Objective 
Evaluate the safety and effectiveness of the Medtronic TAVR system 
as measured by the rate of all-cause mortality or all stroke at 1 year in 
subjects who have a low predicted risk of operative mortality for 
SAVR.  
Annual clinical summaries will report long term follow-up and adverse 
events (as collected through the TVT-R and Centers for Medicare & 
Medicaid Services (CMS) claims data) through 10 years post implant. 
Study Design 
Multi-center, prospective, non-randomized continued access trial. All 
heart team approved subjects will be assigned to TAVR with the 
Medtronic TAVR system  
Primary Endpoint 
All-cause mortality or all stroke at 1 year 
Secondary Endpoint 
Safety 

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• 
Composite of death, all stroke, life-threatening bleed, or major 
vascular complication at 30 days 
• 
New permanent pacemaker implantation at 30 days 
• 
Prosthetic valve endocarditis at one year 
• 
Prosthetic valve thrombosis at one year 
• 
All stroke at one year 
• 
Life-threatening bleed at one year 
• 
Valve-related dysfunction requiring repeat procedure at one year 
(surgical or interventional therapy) 
Effectiveness 
• 
Quality of Life as assessed by Kansas City Cardiomyopathy (KCCQ) 
at one year 
• 
Device Success (intra-procedure) 
Sample Size 
The sample size of the continued access phase of the TAVR in Low 
Risk Patients Trial will be determined based on FDA approval. 
Maximum sample size is not expected to exceed 3660 attempted 
implant subjects in the United States.   
Patient Population 
Subjects with severe aortic stenosis with an indication for SAVR with a 
bioprosthesis whose predicted risk of mortality at 30 days is <3% per 
multidisciplinary local heart team assessment 
Key Inclusion Criteria 
• 
Patient is considered low risk for SAVR, where low risk is defined 
as predicted risk of mortality for SAVR <3% at 30 days per 
multidisciplinary local heart team assessment  
• 
Severe aortic stenosis, defined as: 
 
Symptomatic aortic stenosis 
Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 
cm2/m2), OR mean gradient ≥40 mmHg, OR maximal aortic 
valve velocity ≥4.0 m/sec by transthoracic 
echocardiography at rest 
 
Asymptomatic aortic stenosis: 
- 
Very severe aortic stenosis with an aortic valve area of 
≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND 
maximal aortic velocity ≥5.0 m/sec, or mean gradient ≥60 
mmHg by transthoracic echocardiography at rest, OR 

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- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of 
≤0.6 cm2/m2), AND a mean gradient ≥40 mmHg, or 
maximal aortic valve velocity ≥4.0 m/sec by transthoracic 
echocardiography at rest, AND an exercise tolerance test 
that demonstrates a limited exercise capacity, abnormal 
BP response, or arrhythmia OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of 
≤0.6 cm2/m2), AND mean gradient ≥40 mmHg, or maximal 
aortic valve velocity ≥4.0 m/sec by transthoracic 
echocardiography at rest, AND a left ventricular ejection 
fraction <50%. 
• 
Indicated for SAVR with a bioprosthesis 
Key Exclusion Criteria 
• 
Bicuspid aortic valve identified by echocardiography, MDCT, or 
Magnetic Resonance Imaging  
• 
Significant ascending aortopathy 
Study Procedures and 
Assessments 
• 
Subjects will be enrolled, and if approved, and an implant is 
attempted, they will be followed via TVT-R through 1 year with 
assessments at pre-, peri- and post-procedure, discharge, 30 days 
and 1 year 
• 
Additional clinical data available from CMS claims data will be 
reported out to 10 years 
Co-Principal Investigators 
Jeffrey Popma, MD, Interventional Cardiologist 
Beth Israel Deaconess Medical Center, Boston MA 
Michael Reardon, MD, Cardiothoracic Surgeon 
Houston Methodist Hospital, Houston TX 
Vendors 
• 
ACC/STS Transcatheter Valve Therapies Registry™ 
• 
Centers for Medicare & Medicaid Services 
• 
Independent Explant Pathology Core Laboratory 
3. Introduction  
3.1. Background  
The Medtronic TAVR in Low Risk Patients Trial is a multi-center, prospective, randomized, interventional 
pre-market trial. The purpose of this trial is to evaluate the safety and effectiveness of the Medtronic 
TAVR System in patients with severe aortic stenosis at low risk for SAVR. 
The purpose of this addendum to the Medtronic TAVR in Low Risk Patients Trial protocol is to conclude 
the randomized phase of the trial and initiate the single-arm, non-randomized, continued access phase 
of the trial.  

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3.2. Purpose 
The purpose of this trial is to evaluate the safety and effectiveness of the Medtronic TAVR System in 
patients with severe aortic stenosis at low risk for SAVR. 
4. Objectives and Endpoints 
4.1. Objectives 
4.1.1. 
Primary Objective 
The primary objective is to characterize the composite event rate of all-cause mortality and all stroke at 
1 year post procedure.  
4.1.2. 
Secondary Safety Endpoints 
• 
Composite of death, all stroke, life-threatening bleed, or major vascular complication at 30 days 
• 
New permanent pacemaker implantation at 30 days 
• 
Prosthetic valve endocarditis at one year 
• 
Prosthetic valve thrombosis at one year 
• 
All stroke at one year 
• 
Life-threatening bleed at one year 
• 
Valve-related dysfunction requiring repeat procedure at one year (surgical or interventional 
therapy) 
4.1.3 Secondary Effectiveness Endpoints 
• 
Quality of Life as assessed by Kansas City Cardiomyopathy (KCCQ) change from baseline at one year. 
• 
Device Success (intra-procedure) 
5. Study Design  
The continued access trial is a multi-center, prospective, non-randomized, interventional trial conducted 
in the United States. The maximum sample size is not expected to exceed 3660 subjects with an 
attempted implant, this maximum is based on enrollment during the randomized phase of the trial and 
will be distributed in semi-annual allocations of 732 attempted implants per 6 months. No site will enroll 
more than 15% of the semi-annual allocation (ie, no site will implant > 110 subjects during any given 
allocation period) without prior authorization from Medtronic. Subjects who exit from the trial after 
implantation will not be replaced. 

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All enrolled, qualified, and heart team approved low risk subjects will be implanted with the Medtronic 
Evolut R or Evolut PRO system. Subjects that undergo an attempted implant or are implanted will be 
followed via TVT-R through 1 year with assessments at pre-, peri- and post-procedure, discharge, 30 
days and 1 year. Additional clinical data available from CMS data claims will be reported out to 10 years. 
5.1. Duration 
Subjects will be consented for follow-up through 10 years. The enrollment period for this continued 
access study will be through completion of FDA review for the PMA supplement for the TAVR Low 
indication; therefore, the estimated total duration of the trial (first subject enrolled to last subject 
completing his/her last follow-up exam) is estimated to be 12 years.  
5.2.  Rationale  
This trial will evaluate the safety and effectiveness of the Medtronic Transcatheter Aortic Valve 
Replacement system (Evolut R and Evolut PRO systems) in patients with aortic stenosis who are at low 
predicted risk for mortality at 30 days with SAVR. Data from this trial will be used to additionally support 
regulatory reports for the TAVR in Low Risk Patients Trial. 
6. Product Description  
6.1 Trial Materials 
Medtronic will control the supply of investigational devices and trial materials (eg, Investigator Site File, 
eCRF access). Investigational devices will not be sent to the site until the site is activated. Commercial 
product may be used in situations where investigational is not available. 
Medtronic will not provide any trial-specific equipment to the sites. Equipment used for assessing study 
variables (eg, echocardiographic systems) should be maintained per the site’s standard procedures. 
6.2 Device Accountability 
The Evolut R and Evolut PRO systems are not approved for use in low risk patients, and therefore are 
considered investigational devices. As such, they should be stored as labeled and in a secure location. 
The method of storage should prevent the use of these investigational devices for applications other 
than mentioned in this CIP. The investigator shall maintain adequate records of the receipt and 
disposition of all investigational devices. 
Centers are required to maintain investigational device records that contain the following information: 
• 
Investigational device name 
• 
TAV serial number 

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• 
Lot number (for delivery catheter system and loading system only) 
• 
Date of receipt of device 
• 
Name of person receiving the device 
• 
Name of person using the device 
• 
Date of implant or use 
• 
ID number of subject receiving or using the device 
• 
Disposition (implanted, disposed of, or returned to Medtronic) 
For devices that are returned to Medtronic or disposed of, centers are required to document the 
following information: 
• 
TAV serial numbers 
• 
Lot numbers (for delivery catheter system and loading system only) 
• 
The quantity and reason for the device being returned to Medtronic or disposed of 
• 
Name of the person who returned or disposed of each device 
• 
Date of shipment back to Medtronic 
At the trial closeout visit, the investigator must return to Medtronic any unused devices and a copy of 
the completed device inventory. The investigator’s copy of the device reconciliation records must 
document any unused devices that have been returned to Medtronic as well as all product usage 
including opened but non-implanted devices.  
6.3.  Device Malfunction or Explant 
In the event of a device malfunction of the Medtronic TAVR system prior to implant, or in the event a 
TAV or surgical bioprosthesis is explanted after implant (due to reintervention or autopsy), the TAV or 
surgical bioprosthesis, and/or affected components Medtronic TAVR system should be sent to 
Medtronic at the following address: 
Medtronic  
Attn: Explant Lab [PE#] 
1851 E. Deere Avenue 
Santa Ana, CA 92705-5720 
Additional details surrounding the device return process are contained within the Medtronic explant kit 
that will be provided upon notification of a device malfunction or explant. 
This trial will utilize the CV Pathology Explant Core Lab for any explants performed during the duration 
of the trial. 

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7. Selection of Subjects 
7.1. Study Population 
The population includes males and females with severe aortic stenosis with a clinical indication for 
surgical aortic valve replacement with a bioprosthesis who are at low predicted risk of mortality at 30 
days for surgical aortic valve replacement. 
7.2. Subject Enrollment 
Subjects are considered enrolled at time of consent.  
7.3. Inclusion Criteria 
Prospective subjects must meet all following inclusion criteria to be eligible for the trial: 
1. Severe aortic stenosis, defined as follows: 
a) For symptomatic patients: 
Aortic valve area ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), OR mean gradient ≥40 
mmHg, OR Maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography at rest 
b) For asymptomatic patients: 
- 
Very severe aortic stenosis with an aortic valve area of ≤1.0 cm2 (or aortic valve area index 
of ≤0.6 cm2/m2), AND maximal aortic velocity ≥5.0 m/sec , or mean gradient ≥60 mmHg by 
transthoracic echocardiography at rest, OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND a mean 
gradient ≥40 mmHg or maximal aortic valve velocity ≥4.0 m/sec by transthoracic 
echocardiography at rest, AND an exercise tolerance test that demonstrates a limited 
exercise capacity, abnormal BP response, or arrhythmia OR 
- 
Aortic valve area of ≤1.0 cm2 (or aortic valve area index of ≤0.6 cm2/m2), AND mean gradient 
≥40 mmHg, or maximal aortic valve velocity ≥4.0 m/sec by transthoracic echocardiography 
at rest, AND a left ventricular ejection fraction <50%. 
2. Patient is considered low risk for SAVR, where low risk is defined as predicted risk of mortality for 
SAVR <3% at 30 days per multidisciplinary local heart team assessment. 
3. The subject and the treating physician agree that the subject will return for all post-procedure 
follow-up visits. 
7.4. Exclusion Criteria 
If any of the following exclusion criteria are present, the prospective subject is not eligible for 
implantation: 

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1. Subject has refused surgical aortic valve replacement (SAVR) as a treatment option – Not Applicable 
for Continued Access 
2. Any condition considered a contraindication for placement of a bioprosthetic valve (eg, subject is 
indicated for mechanical prosthetic valve). 
3. A known hypersensitivity or contraindication to any of the following that cannot be adequately pre-
medicated: 
a. aspirin or heparin (HIT/HITTS) and bivalirudin 
b. ticlopidine and clopidogrel 
c. Nitinol (titanium or nickel) 
d. contrast media 
4. Blood dyscrasias as defined: leukopenia (WBC <1000 mm3), thrombocytopenia (platelet count 
<50,000 cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states. 
5. Ongoing sepsis, including active endocarditis. 
6. Any percutaneous coronary or peripheral interventional procedure with a bare metal stent within 30 
days prior to Heart Team approval, or drug eluting stent performed within 180 days prior to Heart 
Team approval.  
7. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left main coronary 
artery. 
8. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 
10 weeks of Heart Team assessment. 
9. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support. 
10. Recent (within 2 months of Heart Team assessment) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA). 
11. Gastrointestinal (GI) bleeding that would preclude anticoagulation. 
12. Subject refuses a blood transfusion. 
13. Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, 
prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate 
rehabilitation from the procedure or compliance with follow-up visits). 
14. Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid 
conditions. 
15. Other medical, social, or psychological conditions that in the opinion of the investigator precludes 
the subject from appropriate consent or adherence to the protocol follow-up exams. 
16. Currently participating in an investigational drug or another device trial (excluding registries). 
17. Evidence of an acute myocardial infarction ≤30 days before the trial procedure due to unstable 
coronary artery disease (WHO criteria). 
18. Need for emergency surgery for any reason. 
19. Subject is pregnant or breast feeding. 

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20. Subject is less than legal age of consent, legally incompetent, or otherwise vulnerable 
Anatomical exclusion criteria: 
21. Pre-existing prosthetic heart valve in any position. 
22. Severe mitral regurgitation amenable to surgical replacement or repair. 
23. Severe tricuspid regurgitation amenable to surgical replacement or repair. 
24. Moderate or severe mitral stenosis amenable to surgical replacement or repair. 
25. Hypertrophic obstructive cardiomyopathy with left ventricular outflow gradient. 
26. Bicuspid aortic valve verified by echocardiography, MDCT, or MRI.  
27. Prohibitive left ventricular outflow tract calcification. 
28. Sinus of Valsalva diameter unsuitable for placement of the self-expanding bioprosthesis. 
29. Aortic annulus diameter of <18 or >30 mm. 
30. Significant aortopathy requiring ascending aortic replacement. 
For transfemoral or transaxillary (subclavian) access: 
31. Access vessel mean diameter <5.0 mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean 
diameter <5.5 mm for Evolut 34R mm or TAVR PRO TAV. However, for transaxillary (subclavian) 
access in patients with a patent LIMA, access vessel mean diameter <5.5mm for Evolut 23R, 26R, or 
29R mm TAV, or access vessel mean diameter <6.0 mm for the Evolut 34R or TAVR PRO TAVi. 
                                                          
iFor subjects with a patent LIMA undergoing tranaxillary (subclavian) access, the minimal access vessel mean diameter is 5.5 mm for the Evolut 
23R, 26R, and 29R TAV, and 6.0 mm for the Evolut 34R and TAVR PRO TAV. 

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8. Study Procedures  
Trial procedures will continue to be followed as outlined in the primary TAVR in Low Risk Patients 
protocol, unless otherwise noted below.  
8.1. Schedule of Events 
Follow-up protocol evaluations should be performed at the trial site. The protocol recommended 
evaluations for each trial interval are listed as follows. 
Baseline/Pre-implant (within 12 weeks prior to submission to the Heart Team; except for MDCT and 
coronary arteriography) ii 
Baseline data will be collected for subjects prior to procedure to capture data points included in the TVT-
R data collection forms including: 
• 
Subject demographics 
• 
History and Risk Factors, including cardiac history and other history and risk factorsiii 
• 
Pre-Procedure Status, including NYHA class, cardiac medications  
• 
5 Meter Walk Test 
• 
KCCQ-12 
• 
STS Risk Factor 
• 
Labs 
• 
Coronary Arteriography 
• 
TTE 
• 
MDCT 
• 
Heart Team Assessment 
 
 
                                                          
ii Pre-implant MDCT and Coronary arteriography should be performed within 365 days of Heart Team approval. 
iii Definitions of STS risk factors and other co-morbidities are provided in Appendix I. 

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Peri- and Post- Procedure 
The following peri- and post-procedure data will be collected for subjects to capture data points 
included in the TVT-R data collection forms, including: 
• 
Procedure information 
• 
Device information 
• 
Hemodynamics (pre-implant and post-implant) 
• 
Post Procedure Labs 
• 
12-lead ECG 
• 
Echocardiogram 
• 
Adverse events, interventions and surgical procedure assessment  
Discharge (7 days post procedure or discharge, whichever comes first) 
The following data will be collected for subjects prior to discharge to capture data points included in the 
TVT-R data collection forms, including: 
• 
RBC/whole blood transfusion 
• 
Number of hours in ICU 
• 
Discharge date and status 
• 
Discharge medications 
• 
Adverse event assessment  
30 days (between 30 to 45 days post implant) 
The following data will be collected for subjects at 30 days to capture data points included in the TVT-R 
data collection forms including: 
• 
Clinical Assessment 
• 
Five meter walk 
• 
KCCQ-12 
• 
12-lead ECG 
• 
Echocardiogram 
• 
Medications 
• 
NYHA Classification 
• 
Adverse event assessment  
 
 

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One Year (between 335 and 395 days post implant) 
The following data will be collected for subjects at 1 year to capture data points included in the TVT-R 
data collection forms including: 
• 
Clinical Assessment 
• 
Five meter walk 
• 
KCCQ-12 
• 
12-lead ECG 
• 
Echocardiogram 
• 
Medications 
• 
NYHA Classification 
• 
Adverse event assessment  
Evaluations 2 - through 10 - years 
Subject evaluations will occur via standard of care treatment. Data collected through CMS claims data 
will be reported to the sponsor out to 10 years post implant. These clinical summaries will report long 
term follow-up and monitor adverse events [all-cause mortality, all stroke, and repeat procedure for 
valve-related dysfunction (surgical or interventional therapy)].  
8.1.1 Echocardiography 
Transthoracic echocardiography (TTE) will be performed at the following intervals: pre-implant, peri- 
and post- procedure, 30 days, and 1 year. Exams will not be sent to an Echo Core Lab for central 
assessment. 
8.2. Subject Consent 
Prior to enrolling in the trial, patients are required to be fully informed of the details of trial participation 
as required by applicable regulations, the site’s IRB and by Medtronic. Informed consent must be 
obtained from each patient prior to conducting any protocol-induced activities beyond standard of care, 
by using the informed consent form (ICF) approved by that site’s IRB and by Medtronic. The ICF must be 
signed and dated by the patient and by the person obtaining the consent. Any additional persons 
required by the site’s IRB to sign the informed consent form must also comply. 
 

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8.3. Subject Screening  
The process of patient screening and subject enrollment is as follows: 
• 
Patients identified by or presented to the trial site with aortic stenosis will be screened by the 
investigative team for the criteria described in 7.3 and 7.4, Inclusion and Exclusion Criteria, using 
available medical records, including relevant imaging studies previously performed for diagnostic 
purposes. 
• 
If the patient is deemed a potential candidate for the trial, the investigational status of the 
Medtronic TAVR System and all aspects of the trial will be explained to the patient. The patient will 
then be invited to participate in the Low Risk Continued Access Trial. 
• 
If the patient agrees to participate, written informed consent will be obtained. This will be 
considered the point of enrollment and the subject will be assigned a Subject ID number. 
• 
The subject will undergo transthoracic echocardiography (TTE) to assess his/her degree of aortic 
stenosis. 
• 
Subjects who meet the criteria for aortic stenosisiv will undergo:  
• 
Multi-Detector Computed Tomography (MDCT) of their peripheral vasculature and aortic 
annulus to assess anatomic suitability for the Medtronic TAVR, and 
• 
Local Heart Team assessment to determine his/her operative risk profile for SAVR. 
• 
All study-specific screening assessments will be indicated on the provided consent eCRF in Oracle 
RDC. 
• 
Subjects confirmed eligible for implantation by the local Heart Team will be assigned to TAVR with 
the Medtronic TAVR system.  
• 
In case of required coronary revascularization, concomitant percutaneous coronary intervention 
(PCI)v and TAVR is encouraged; however, staging is left to the discretion of the operator.  
• 
Implantation should occur within 90 days of local Heart Team approval. 
• 
All Attempted Implant and Implanted subject’s baseline, implant, and follow-up information will be 
entered in to TVT-R. 
 
Patients should give written consent before undergoing any protocol testing. However, if any of 
protocol baseline/screening evaluations (eg, echocardiography, MDCT, coronary arteriography, lab 
work) have been performed for clinical diagnostic purposes prior to consenting, they can be used as 
the Protocol exams, provided they were obtained within the protocol time windows and contain the 
necessary information. 
 
                                                          
ivIf a subject has balloon aortic valvuloplasty after their qualifying TTE, they must have repeat TTE to confirm he/she meets criteria for severe 
aortic stenosis as described in Section 3.3.5.1 prior to Heart Team approval of the subject. 
v Index PCI should be performed at the TAVR implanting center; index PCI operators will be considered investigators. 

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8.4. Subject Disposition 
Sites will maintain electronic records in Oracle RDC of subjects consented (point of subject enrollment) 
where Subject’s ID number will be assigned to each patient. Electronic records in Oracle RDC will also 
include, date of heart team approval, date attempted and implanted, the name of the implanters and 
information identifying the devices used. Subjects who are consented but are not taken to the 
procedure room for implantation will be exited from the trial and will not be followed beyond the date 
of trial exit. Subjects with an attempted implant who do not receive a TAV for any reason will be 
followed for the trial duration. Subjects that have their TAV explanted will be followed for the trial 
duration.  
8.5. Assessment of Safety 
Adverse events (as identified on the TVT-R data collection forms) will be captured on the AE section of 
the TVT-R data collection forms through the 12-month follow-up visit and via CMS claims data through 
10 years. Due to the limitations of the TVT-R database, this study will not follow ISO14155:2011, 
MEDDEV 2.7/3, or 21 CFR 812 regarding pre-market safety compliance requirements.  
It is the responsibility of the physician(s) to assess the subject for adverse events and capture the 
required adverse event information on the AE section of the TVT-R data collection form, to ensure site 
specific safety reporting requirements are met, and follow Medical Device Reporting requirements. 
Upon data received from the TVT-R or CMS, Medtronic will ensure all device-related adverse events, 
AEs, SAEs, and Deaths are reviewed and reported upon.  
A CRO contracted by ACC/STS will adjudicate Stroke, TIA, and Aortic Valve Reintervention AEs. If 
necessary, the CRO may request source documentation for an adverse event identified on the TVT-R 
data collection form for further information. 
8.6. Recording Data 
Trial sites will assign a unique ID number that is obtained from Oracle RDC to each subject. Records of 
the subject/subject ID relationship will be maintained by the trial site. Individual subject medical 
information obtained as a result of this trial will be considered confidential.  
This trial will utilize an Oracle RDC system for subject tracking that is the property of Medtronic. This 
trial will also utilize the TVT-R database system for data collection through 12 months follow up for all 
attempted implant and implanted subjects.  
Trial personnel will be delegated for eCRF completion Delegated Tasks List (DTL) in the TVT-R and RDC 
system.   The Data Collection Forms and eCRFs must be completed and/or updated to reflect the latest 
observations on the subjects participating in the trial.  For Oracle RDC, username and password will be 

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provided to trial personnel trained and delegated to eCRF completion and / or approval per the DTL.  
The investigator (or approved sub-investigator) will electronically sign the appropriate pages of each 
eCRF in Oracle RDC. 
After all one year follow-up is complete, sites will no longer enter subject data in the TVT-R database.  
Standard of care clinical data available through claims data submitted to CMS will be provided for 2- 
through 10-year follow-up.  ACC/STS will link CMS claims data with subject records in TVT-R.  The CMS 
and TVT-R linked data is provided to Medtronic with adverse event tables for 2- through 10-year follow-
up reporting requirements.  
Any clinical data entered in to the databases must have a corresponding source document. 
All trial-related documents must be retained until notified by Medtronic that retention is no longer 
required. Medtronic will inform the investigator/institution when these documents are no longer 
required to be retained. 
No trial document or image should be destroyed without prior written agreement between Medtronic 
and the investigator. Should the investigator wish to assign the trial records to another party or move 
them to another location, advance written notice must be given to Medtronic. 
8.7. Time Windows for Completion and Submission of eCRFs and 
Data Collection Forms 
The TVT-R Data Collection Forms and Oracle RDC electronic case report forms (eCRFs) should be 
completed as soon as possible and recommended to be completed within 2 weeks of the applicable 
follow-up visit. 
8.8. Deviation Handling 
The investigator shall not deviate from the protocol. Protocol deviations will not be required to be 
reported for the continued access trial to Medtronic and Medtronic will not be held responsible for 
reviewing protocol deviations. Investigators are required to adhere to local IRB/EC procedures for 
reporting deviations.  
Medtronic will not be responsible for submitting a report of patients to the FDA that were implanted 
before obtaining informed consent. Medtronic will also not be responsible for securing or tracking 
compliance in instances that the investigator is not complying with the signed agreement, the 
investigational plan, the requirements of this part or other applicable FDA regulations, or any conditions 
of approval imposed by the reviewing IRB or FDA. 

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8.9. Subject Withdrawal or Discontinuation  
All subjects will be encouraged to remain in the trial through the last follow-up visit at 10 years. Subjects 
who discontinue participation prematurely will be included in the analysis of results (as appropriate) and 
will not be replaced in the enrollment of total trial subjects. If a subject is discontinued from the trial 
early, the reason for discontinuation should be documented in the subject file and a Trial Exit eCRF must 
be completed. 
The study trial site will make every effort to have all subjects complete the follow up visit schedule. A 
subject will not be considered lost to follow-up unless all efforts to obtain compliance are unsuccessful. 
At a minimum, the effort to obtain follow-up information must include 3 attempts to make contact via 
telephone and if contact via phone is not successful, a traceable letter from the investigator should be 
sent to the subject’s last known address. Should both telephone and mail efforts to contact the subject 
be unsuccessful, the subject’s primary physician should be contacted. Subjects will then be deemed lost 
to follow up. All contact efforts to obtain follow-up must be documented in both the subject’s medical 
records and on the Trial Exit eCRF. 
If a subject discontinues the trial at any time, is withdrawn from the trial early, or completes all protocol 
required follow-up a Trial Exit eCRF must be completed and they should continue to be followed by the 
implanting site according to their routine clinical practice for aortic valve patients. If, for any reason, this 
is not possible for a particular subject, or if a subject needs to change their follow-up site at any time 
point after conclusion of the trial, investigators should refer subjects to a local site with appropriate 
training and experience in managing patients with implanted aortic valves. 
9. Data Review Committees  
A Clinical Events Committee (CEC) will not provide independent medical review and adjudication of 
adverse event data for the continued access trial. 
A Data Safety Monitoring Board (DSMB) will not assess interim trial data and provide recommendations 
to Medtronic regarding trial conduct for the continued access trial.  
10. Risks and Benefits 
The risks and benefits of the continued access trial are identical to the risks and benefits outlined in the 
TAVR in Low Risk Patients protocol. 

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11. Statistical Design and Methods 
The statistical analyses will be performed by Medtronic employed statisticians. The study will provide 
descriptive results only as there are no statistical hypotheses associated with this study. 
11.1 Analysis Populations 
11.1.1 Approved Population 
If the subject signs informed consent, meets all inclusion and none of the exclusion criteria, and the 
Heart Team determines the subject is suitable for the trial, the subject is assigned TAVR and then added 
to the approved population. Within the approved population the following analysis sets are 
distinguished: 
• 
The attempted implant set: The attempted implant set consists of all Heart Team approved subjects 
with an attempted implant procedure, defined as when the subject is brought into the procedure 
room and any of the following have occurred: anesthesia administered, vascular line placed, TEE 
placed, or any monitoring line placed.  
• 
The implanted set: The Implanted set consists of all the attempted implant subjects who are 
implanted with the TAV device. 
The primary analysis for the primary objective, secondary safety objectives and secondary effectiveness 
objectives (except device success) will use the attempted implant set. Device success will use the 
implanted set. 
11.2 Description of Baseline Variables 
Baseline demographic and clinical variables will be summarized. All continuous variables will be 
summarized as means, medians, standard deviations, interquartile ranges, minima and maxima, and 
categorical variables will be summarized as frequencies and percentages. 
11.3 Sample Size  
The sample size of the continued access phase of the TAVR in Low Risk Patients Trial will be determined 
based on FDA approval. The sample size is not expected to exceed 3660 attempted implant subjects at 
up to 61 hospitals in the United States. 
11.4 Subject Accountability 
Follow-up visits at 30-days and one year are conducted by the sites with data collected through TVT-R. 
The distribution of follow- up visits and visit compliance by one year will be summarized, which include 
number expected, visit completed, missed visit, deaths, withdrawal, lost to follow-up and visit pending. 

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When TVT-R data is merged with CMS data, acquired data for longer-term follow-up (2 through 10 
years) subjects that are matched between the databases will be included in subject accountability and 
analysis. CMS data does not have specified follow-up visits. The number of subjects matched between 
TVT-R and CMS will be provided, with the number of subjects at risk in the cohort for each specified 
timepoint (1 year, 2 year, 3 year, 4 year, 5 year, 6 year, 7 year, 8 year, 9 year and 10 year).  
11.5 Analysis of Endpoints 
The endpoints are descriptive and no statistical hypothesis test will be performed. Device success will 
be summarized using frequencies and percentages. Kaplan-Meier estimates at 30 days will be provided 
for composite of death, all stroke, life-threatening bleed or major vascular complication and new permanent 
pacemaker implantation. Kaplan-Meier estimates at 1 year will be provided for prosthetic valve endocarditis, 
prosthetic valve thrombosis and life-threatening bleeding. In addition, Kaplan-Meier estimates will be 
provided for all-cause mortality, all stroke and aortic valve dysfunction requiring repeat procedure at 1 
year and annually up to 10 years. KCCQ at baseline and 1 year, and KCCQ change from baseline to 1 
year will be summarized as means, medians, standard deviations, interquartile ranges, minima, 
maxima and 95% confidence intervals. 
12. Ethics 
12.1. Statement(s) of Compliance  
The trial will be conducted in compliance with the protocol, and 21 CFR Parts 36, 43, 47, 50, 54, and 56. 
In addition, the trial will be conducted in compliance with 21 CFR Part 11 and in accordance with the 
Declaration of Helsinki. The principles of the Declaration of Helsinki are implemented in this trial by 
means of the Patient Informed Consent (IC) process, Ethics Board approval, trial training, clinical trial 
registration, pre-clinical testing, risk benefit assessment, and publication policy. 
The trial will follow 21 CFR Part 812 except where noted in the clinical investigation plan and FDA 
approval documentation.  
Regulatory authority notification/approval to conduct the trial is required. Investigational sites will be 
not be activated, nor begin enrolling subjects until the required approval/favorable opinion from the 
respective regulatory agency has been obtained (as appropriate). Additionally, any requirements 
imposed by a local regulatory agency or Ethics Board shall be followed, as appropriate.  

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13. Study Administration 
13.1. Study Training 
Prior to involvement in the continued access trial activities, Medtronic and ACC/STS will provide training 
to the investigative team on the trial methods, procedures, data entry, and requirements. Medtronic 
will maintain documentation of these training sessions. 
13.2. Monitoring  
No source data verification will occur, and subject records will not be reviewed by Medtronic. If 
necessary, source documents may be requested for safety event analysis.  
Measures to ensure data cleanliness and integrity in the TVT-R database will be consistent with TVT-R 
processes and procedures. 
13.3. Data Management 
For data stored in Oracle RDC, Medtronic will be responsible for the processing and quality control of 
the data. Centralized data review, database cleaning and issuing and resolving data queries will be done 
according to Medtronic internal SOPs and the Data Management Plan for this trial. The trial database 
will be developed and validated per the Data Management Plan for this trial. The Oracle RDC database 
will maintain an audit trail of all changes made to the eCRFs. 
For data stored in TVT-R, ACC/STS will be responsible for data quality review and processing. Data 
review will be conducted by programmatic quality checks throughout the data entry and submission 
process. 
13.4. Confidentiality 
All information and data sent to parties involved in trial conduct concerning subjects or their 
participation in this trial will be considered confidential. Trial sites will assign a unique subject ID number 
(SID) to each subject. Records of the subject/SID relationship will be maintained by the trial site. The SID 
is to be recorded on all trial documents to link them to the subject’s medical records at the site. To 
maintain confidentiality, the subjects’ name or any other personal identifiers should not be recorded on 
any trial document other than the informed consent form. In the event a subject’s name is included for 
any reason, it will be masked as applicable. In the event of inability to mask the identification (eg, digital 
media), it will be handled in a confidential manner by the authorized personnel. 

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13.5. Liability 
Medtronic (including all wholly owned subsidiaries) maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with applicable law and 
custom concerning specific insurance coverage. If required, a Clinical Trial Insurance 
statement/certificate will be provided to the IRB/EC if required.  
13.6. CIP Amendments 
Medtronic will submit any significant amendment to the CIP, including a justification for the 
amendment, to the FDA and to the investigators to obtain approval from their IRB/EC. The investigator 
will only implement the amendment after approval of the IRB/EC, regulatory agencies, and Medtronic. 
Administrative amendments to the CIP will be submitted to the IRB/EC for notification. 
13.7. Record Retention 
The investigator must retain the Investigator Site File, source documents, and any other data collection 
records, until informed by Medtronic they no longer need to be retained. At a minimum, the 
investigator must retain records for at least 2 years (or for 15 years if required by local law) after the last 
approval of a marketing application and until there are no pending or contemplated marketing 
applications. The investigator should take measures to prevent accidental or early destruction of the 
trial related materials. 
13.8. Publication and Use of Information 
Medtronic and the Low Risk Publications Committee can utilize the data from the continued access trial 
as desired for publications or other use of information. The principal results from any single site 
experience within the trial is not allowed until both the preparation and publication of the multisite 
results, and then only with written permission from Medtronic. 
13.9. Suspension or Early Termination 
Medtronic may decide to suspend or prematurely terminate the trial. If the trial is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators and regulatory 
authorities of the termination or suspension and the reason(s) for this. The investigator shall then 
promptly inform the reviewing IRB. Medtronic will, as soon as possible, provide a written statement to 
the investigators to enable prompt notification of the IRBs. If trial enrollment is terminated early, follow-
up visits will continue for all enrolled subjects. 

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Medtronic may decide to suspend or prematurely terminate an investigation site. If an investigation site 
is suspended or prematurely terminated, Medtronic shall promptly inform the investigator(s) of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform the 
reviewing IRB. 
 If any action is taken by an EC/IRB with respect to the investigation, that information will be forwarded 
to the sponsor. 
 
 

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14 Appendices  
APPENDIX I: DEFINITIONS OF STS FACTORS AND OTHER CO-
MORBIDITIES 
1.0 STS Factors 
The STS Risk Calculator can be found at www.sts.org 
Factor 
Definition 
Heart Failure 
Physician documentation or report that the patient has been in a state of heart failure 
within the past 2 weeks. Heart failure is defined as physician documentation or report of 
any of the following clinical symptoms of heart failure described as unusual dyspnea on 
light exertion, recurrent dyspnea occurring in the supine position, fluid retention; or the 
description of rales, jugular venous 
Distension, pulmonary edema on physical exam, or pulmonary edema on chest x-ray 
presumed to be cardiac dysfunction. A low ejection fraction alone, without clinical 
evidence of heart failure does not qualify as heart failure. An elevated BNP without other 
supporting documentation should not be coded as CHF. 
Diabetes 
History of diabetes diagnosed and/or treated by a healthcare provider. The American 
Diabetes Association criteria include documentation of the following: 
1. Hemoglobin A1c ≥6.5%; or 
2. Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L); or 
3. 2-h Plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or 
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L) 
This does not include gestational diabetes. 
Dialysis 
Subject currently (prior to surgery) undergoing dialysis 
 
 

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1.0 STS Factors (continued) 
Factor 
Definition 
Hypertension 
Any of the following: 
• 
documented history of hypertension diagnosed and treated with 
medication, diet and/or exercise, 
• 
prior documentation of blood pressure >140 mmHg systolic or 90 mmHg 
diastolic for patients without diabetes or chronic kidney disease, or prior 
documentation of blood pressure >130 mmHg systolic or 80 mmHg diastolic 
on at least 2 occasions for patients with diabetes or chronic kidney disease 
• 
currently on pharmacologic therapy to control hypertension 
Immunocompromise 
Indicate whether immunocompromise is present due to immunosuppressive medication 
therapy within 30 days preceding the operative procedure or existing medical condition. 
This includes, but is not limited to systemic steroid therapy, anti-rejection medications 
and chemotherapy. This does not include topical steroid applications, one time systemic 
therapy, inhaled steroid therapy or preprocedure protocol. 
Arrhythmia 
• 
History or preoperative arrhythmia (sustained ventricular tachycardia, 
ventricular fibrillation, atrial fibrillation, atrial flutter, third degree heart 
block, second degree heart block, sick sinus syndrome) that has been treated 
with any of the following modalities: 
• 
ablation therapy 
• 
AICD 
• 
pacemaker 
• 
pharmacologic treatment 
• 
electrocardioversion, defibrillation 
Atrial fibrillation/atrial 
flutter 
Presence of atrial fibrillation or flutter within 30 days of the procedure 
Myocardial infarction 
History of at least one documented myocardial infarction at any time prior this surgery 
 
 

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1.0 STS Factors (continued) 
Factor 
Definition 
Endocarditis 
Indicate whether the patient has a history of endocarditis. Endocarditis must meet at 
least 1 of the following criteria: 
1. Patient has organisms cultured from valve or vegetation. 
2. Patient has 2 or more of the following signs or symptoms: fever (>38°C or >100.4°F), 
new or changing murmur*, embolic phenomena*, skin manifestations* (ie, petechiae, 
splinter hemorrhages, painful subcutaneous nodules), congestive heart failure*, or 
cardiac conduction abnormality. 
*with no other recognized cause and at least 1 of the following: 
a. organisms cultured from 2 or more blood cultures 
b. organisms seen on Gram’s stain of valve when culture is 
negative or not done 
c. valvular vegetation seen during an invasive procedure or 
autopsy 
d. positive laboratory test on blood or urine (eg, antigen tests for H 
mmunocom, S mmunocom, N mmunocompro, or Group B 
Streptococcus) 
evidence of new vegetation seen on echocardiogram and if diagnosis is made 
antemortem, physician institutes appropriate antimicrobial therapy. 
Chronic lung disease 
Presence of lung disease and severity level as follows: 
None 
Mild: FEV1 60% to 75% of predicted, and/or on chronic inhaled or oral bronchodilator 
therapy. 
Moderate: FEV1 50% to 59% of predicted, and/or on chronic steroid therapy aimed at 
lung disease. 
Severe: FEV1 <60 or Room Air pCO2 >50. 
CLD present, severity not documented 
Unknown 
A history of chronic inhalation reactive disease (asbestosis, mesothelioma, black lung 
disease or pneumoconiosis) may qualify as chronic lung disease. Radiation induced 
pneumonitis or radiation fibrosis also qualifies as chronic lung disease. (if above criteria 
is met) A history of atelectasis is a transient condition and does not qualify. Chronic lung 
disease can include patients with chronic obstructive pulmonary disease, chronic 
bronchitis, or emphysema. It can also include a patient who is currently being chronically 
treated with inhaled or oral pharmacological therapy (eg, beta-adrenergic agonist, anti-
inflammatory agent, leukotriene receptor antagonist, or steroid). Patients with asthma 
or seasonal allergies are not 
considered to have chronic lung disease. 

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1.0 STS Factors (continued) 
Factor 
Definition 
Peripheral vascular 
disease 
History of peripheral arterial disease (includes upper and lower extremity, renal, 
mesenteric, and abdominal aortic systems). This can include: 
• 
claudication , either with exertion or at rest 
• 
amputation for arterial vascular insufficiency 
• 
vascular reconstruction, bypass surgery, or percutaneous intervention to the 
extremities (excluding dialysis fistulas and vein stripping) 
• 
documented aortic aneurysm with or without repair 
• 
positive noninvasive test (eg, ankle brachial index ≤0.9, ultrasound, magnetic 
resonance or computed tomography imaging of >50% diameter stenosis in 
any peripheral artery, ie, renal, subclavian, femoral, iliac), or angiographic 
imaging 
*Excludes disease in the carotid cerebrovascular arteries, or thoracic aorta. PVD does not 
include deep vein thrombosis 
Cerebrovascular 
disease 
Indicate whether the patient has a current or previous history of any of the following: 
a. Stroke: Stroke is an acute episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or retinal vascular 
injury as a result of hemorrhage or infarction, where the 
neurological dysfunction lasts for greater than 24 hours. 
b. TIA: is defined as a transient episode of focal neurological 
dysfunction caused by brain, spinal cord, or retinal ischemia, 
without acute infarction, where the neurological dysfunction 
resolves within 24 hours. 
c. Noninvasive or invasive arterial imaging test demonstrating 
≥50% stenosis of any of the major extracranial or intracranial 
vessels to the brain 
d. Previous cervical or cerebral artery revascularization surgery or 
percutaneous intervention. This does not include chronic 
(nonvascular) neurological diseases or other acute neurological 
insults such as metabolic and anoxic ischemic encephalopathy. 
Cerebrovascular 
accident 
History of stroke. Stroke is an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction, where the neurological dysfunction lasts for greater than 24 hours. 
Previous cardiac 
interventions 
Any previous cardiovascular intervention, either surgical or non-surgical, which may 
include those done during the current admission. 
 
 

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1.0 STS Factors (continued) 
Factor 
Definition 
Number of diseased 
vessels 
The number of diseased major native coronary vessel systems: LAD system, Circumflex 
system, and/or Right system with ≥50% narrowing of any vessel preoperatively. 
NOTE: Left main disease (≥50%) is counted as TWO vessels (LAD and Circumflex, which 
may include a Ramus Intermedius). For example, left main and RCA would count as three 
total. A vessel that has ever been considered diseased, should always be considered 
diseased. 
Inotropes 
Subject received IV inotropic agents within 48 hours preceding surgery. 
Cardiogenic shock 
A sustained (>30 min) episode of hypoperfusion evidenced by systolic blood pressure 
<90 mm Hg and/or, if available, cardiac index <2.2 L/min per square meter determined 
to be secondary to cardiac dysfunction and/or the requirement for parenteral inotropic 
or vasopressor agents or mechanical support (eg, IABP, extracorporeal circulation, VADs) 
to maintain blood pressure and cardiac index above those specified levels. Note: 
Transient episodes of hypotension reversed with IV fluid or atropine do not constitute 
cardiogenic shock. The hemodynamic compromise (with or without extraordinary 
supportive therapy) must persist for at least 30 min. 
Resuscitation  
Patient required cardiopulmonary resuscitation before the start of the operative 
procedure which includes the institution of anesthetic management. Capture 
resuscitation timeframe: within 1 hour or 1-24 hours pre-op 
Incidence 
Indicate if this is the patient's: 
• 
first surgery 
• 
first re-op surgery 
• 
second re-op surgery 
• 
third re-op surgery 
• 
fourth or more re-op surgery. 
Surgery is defined as cardiothoracic operations (heart or great vessels) surgical 
procedures performed with or without cardiopulmonary bypass (CPB). Also include lung 
procedures utilizing CPB or tracheal procedures utilizing CPB. Reoperation increases risk 
due to the presence of scar tissue and adhesions. 
 
 

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1.0 STS Factors (continued) 
Factor 
Definition 
Cardiac presentation 
on admission 
Indicate the patient’s cardiac symptoms at the time of this admission. 
No Symptoms: No Symptoms, no angina. 
Stable Angina: Angina without a change in frequency or pattern for the prior 6 weeks. 
Angina is controlled by rest and/or oral or transcutaneous medications. 
Unstable Angina: There are three principal presentations of unstable angina: 1. Rest 
angina (occurring at rest and prolonged, usually >20 minutes); 2. New-onset angina 
(within the past 2 months, of at least Canadian Cardiovascular Society Class III severity); 
or 3. Increasing angina (previously diagnosed angina that has become distinctly more 
frequent, longer in duration, or increased by 1 or more Canadian Cardiovascular Society 
class to at least CCS III severity). 
–Non-ST Elevation MI (Non- STEMI): The patient was hospitalized for a non-ST elevation 
myocardial infarction (STEMI) as documented in the medical record. Non-STEMIs are 
characterized by the presence of both criteria: 
a. Cardiac biomarkers (creatinine kinase-myocardial band, 
Troponin T or I) exceed the upper limit of normal according to 
the individual hospital’s laboratory parameters with a clinical 
presentation which is consistent or suggestive of ischemia. ECG 
changes and/or ischemic symptoms may or may not be present. 
b. Absence of ECG changes diagnostic of a STEMI  
–ST Elevation MI (STEMI): The patient ’presented with a ST elevation myocardial 
infarction (STEMI) or its equivalent as documented in the medical record. STEMIs are 
characterized by the presence of both criteria: 

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a. ECG evidence of STEMI: New or presumed new ST segment 
elevation or new left bundle branch block not documented to be 
resolved within 20 minutes. ST segment elevation is defined by 
new or presumed new sustained ST-segment elevation at the J-
point in two contiguous electrocardiogram (ECG) leads with the 
cutoff points: ≥0.2 mV in men or ≥0.15mV in women in leads V2-
V3 and/or ≥0.1 mV in other leads and lasting greater than or 
equal to 20 minutes. If no exact ST-elevation measurement is 
recorded in the medical chart, physician’s written 
documentation of ST elevation or Q waves is acceptable. If only 
one ECG is performed, then the assumption that the ST 
elevation persisted at least the required 20 minutes is 
acceptable. Left bundle branch block (LBBB) refers to new or 
presumed new LBBB on the initial ECG. 
b. Cardiac biomarkers (creatinine kinase-myocardial band, 
Troponin T or I) exceed the upper limit of normal according to 
the individual hospital’s laboratory parameters a clinical 
presentation which is consistent or suggestive of ischemia. 
Angina equivalent 
Other: Presentation/symptom not listed above. 
 
 

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1.0 STS Factors (continued) 
Factor 
Definition 
Status of the procedure 
Elective: The patient's cardiac function has been stable in the days or weeks prior to the 
operation. The procedure could be deferred without increased risk of compromised 
cardiac outcome.  
Urgent: Procedure required during same hospitalization in order to minimize chance of 
further clinical deterioration. Examples include but are not limited to: Worsening, 
sudden chest pain, CHF, acute myocardial infarction (AMI), anatomy, IABP, unstable 
angina (USA) with intravenous (IV) nitroglycerin (NTG) or rest angina.  
Emergent: Patients requiring emergency operations will have ongoing, refractory 
(difficult, complicated, and/or unmanageable) unrelenting cardiac compromise, with or 
without hemodynamic instability, and not responsive to any form of therapy except 
cardiac surgery. An emergency procedure is one in which there should be no delay in 
providing operative intervention. The patient’s clinical status includes any of the 
following: a. Ischemic dysfunction (any of the following): (1) Ongoing ischemia including 
rest angina despite maximal medical therapy (medical and/or IABP)); (2) Acute Evolving 
Myocardial Infarction within 24 hours before surgery; or (3) pulmonary edema requiring 
intubation. b. Mechanical dysfunction (either of the following): (1) shock with circulatory 
support; or (2) shock without circulatory support. 
Emergent Salvage: The patient is undergoing CPR en route to the OR or prior to 
anesthesia induction or has ongoing ECMO to maintain life. 
 
 

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1.0 STS Factors (continued) 
Co-morbidity 
Definition/Criteria 
Porcelain aorta or 
severely 
atherosclerotic aorta 
Heavy circumferential calcification or severe atheromatous plaques of the entire 
ascending aorta extending to the arch such that aortic cross-clamping is not feasible. 
Frailty 
Slowness, weakness, exhaustion, wasting and malnutrition, poor endurance and 
inactivity, loss of independence 
Criteria:  
• 
5 meter walking time 
• 
Grip strength  
• 
BMI <20 kg/m2 and/or weight loss 5 kg/yr  
• 
Serum albumin <3.5 g/dL  
• 
Cognitive impairment or dementia  
Sever liver 
disease/cirrhosis 
Any of the following: 
• 
Child-Pugh class C  
• 
MELD score ≥10  
• 
Portal-caval, spleno-renal, or transjugular intrahepatic portal shunt  
• 
Biopsy proven cirrhosis with portal hypertension or hepatocellular 
dysfunction  
Hostile chest 
Any of the following or other reasons that make redo operation through sternotomy 
or right anterior thoracotomy prohibitively hazardous:  
• 
Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease)  
• 
Complications from prior surgery  
• 
Evidence of severe radiation damage (eg, skin burns, bone destruction, muscle 
loss, lung fibrosis or esophageal stricture)  
• 
History of multiple recurrent pleural effusions causing internal adhesions  
IMA or other critical 
conduit(s) crossing 
midline and/or 
adherent to posterior 
table of sternum  
 
A patent IMA graft that is adherent to the sternum such that injuring it during re-
operation is likely. A patient may be considered extreme risk if any of the following 
are present:  
• 
The conduit(s) are radiographically indistinguishable from the posterior table of 
the sternum.  
• 
The conduit(s) are radiographically distinguishable from the posterior table of the 
sternum but lie within 2-3 mm of the posterior table. 
Severe pulmonary 
hypertension  
Severe right 
ventricular 
dysfunction  
Primary or secondary pulmonary hypertension with PA systolic pressures greater than 
2/3 of systemic pressure  
Criteria as defined by the guidelines (eg, TAPSE <15mm, RV end-systolic area >20 cm2) 
 

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APPENDIX II: TVT-R DATA COLLECTION FORM IDENTIFED 
ADVERSE EVENTS 
2.0 Adverse Events 
• 
Myocardial Infarction 
• 
Coronary Compression or Obstruction 
• 
Endocarditis 
• 
Conduction/Native Pacer Disturbance 
Requiring Pacer 
• 
Conduction/Native Pacer Disturbance 
Requiring ICD 
• 
Cardiac Arrest 
• 
Atrial Fibrillation 
• 
Annular Dissection 
• 
Aortic Dissection 
• 
Perforation with or without Tamponade 
• 
Bleeding at Access Site 
• 
Hematoma at Access Site 
• 
Retroperitoneal Bleeding 
• 
GI Bleed 
• 
GU Bleed 
• 
Other Bleed 
• 
Device Migration 
• 
Device Embolization Left Ventricle 
• 
Device Embolization Aorta 
• 
Device Recapture or Retrieval Transient 
Ischemic Attack 
• 
Ischemic Stroke 
• 
Hemorrhagic Stroke 
• 
Undetermined Stroke 
• 
Device Fracture 
• 
Device Thrombosis 
• 
Other Device Related Event 
• 
New Requirement for Dialysis 
• 
Aortic Valve Re-intervention 
• 
Unplanned Other Cardiac Surgery or 
Intervention 
• 
Unplanned Vascular Surgery or 
Intervention 
• 
Percutaneous Coronary Intervention 
• 
Valve Related Readmission 
• 
Non-Valve Related Readmission 
• 
Major Vascular Complication 
• 
Minor Vascular Complication 
• 
Transapical Related Event 
• 
Major Bleeding Event 
• 
Life Threatening Bleeding 
 
15 Version History 
Version 
Summary of Changes 
Author(s)/Title 
1A 
Initial Release 
Morgan Lillehei /Senior Clinical 
Research Specialist