The Medtronic CoreValve™ Evolut R™ FORWARD Study
Conditions: Aortic Valve Stenosis
Sponsor: Medtronic Cardiovascular

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The Medtronic CoreValve™ Evolut R™ FORWARD Study 
 
Clinical Investigational Plan 
 
Version: 1.0 
Effective Date: 18 August 2015 
 
 
Sponsors 
Global Sponsor  
Medtronic Plc., Coronary and Structural Heart Clinical 
8200 Coral Sea St NE, MVS 66, Mounds View, MN 55112, United States 
Local Sponsors 
Europe 
Medtronic Bakken Research Center BV 
Coronary and Structural Heart Disease Management Department  
Endepolsdomein 5, 6229 GW Maastricht, The Netherlands 
Australia 
Medtronic Australasia Pty Ltd 
97 Waterloo Road, North Ryde, NSW 2113, Australia 
Canada 
Medtronic of Canada Ltd. 
99 Hereford St., Brampton, ON, L6Y 0R3, Canada 
Latin America 
Medtronic Latin America Plc 
3750 NW 87th Avenue, Miami, Florida 33178, United States 
 
CONFIDENTAL and PROPRIETARY 
This document contains confidential information and is solely the property of Medtronic, Plc.  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of this document constitutes an agreement by the recipient that no unpublished information contained 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, Plc.  This document 
may be disclosed to the appropriate Ethics Committee (EC) or Institutional Review Board (IRB) with the 
stipulation that the EC/IRB treats the information contained herein as the confidential property of 
Medtronic, Plc. 

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Change History record 
 
CIP Change History 
Version 
Summary of Changes 
Author 
1.0 
Initial Release 
Rijk de Jong 
 

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TABLE OF CONTENTS 
1 
GENERAL INFORMATION ....................................................................................................................................... 10 
1.1 
Introduction..................................................................................................................................... 10 
1.2 
Medtronic CoreValve™ Evolut R™ System  ..................................................................................... 11 
1.2.1 CoreValve™ Evolut™ R Transcatheter Aortic Valve (TAV) .................................................... 11 
1.2.2 CoreValve™ EnVeo™ R Delivery Catheter System (DCS) with EnVeo™ R InLine Sheath ...... 11 
1.2.3 CoreValve™ EnVeo R Loading System (LS) ........................................................................... 12 
1.2.4 Intended Use ........................................................................................................................ 13 
2 
STUDY PLAN ........................................................................................................................................................... 14 
2.1 
Study objectives .............................................................................................................................. 14 
2.2 
Clinical endpoints ............................................................................................................................ 14 
2.2.1 Primary endpoint ................................................................................................................. 14 
2.2.2 Secondary Efficacy Endpoints .............................................................................................. 14 
2.2.3 Secondary Safety Endpoints ................................................................................................. 14 
2.2.4 Rationale for Selection of Study Endpoints .......................................................................... 15 
2.3 
Study population ............................................................................................................................. 15 
2.4 
Study design .................................................................................................................................... 15 
2.5 
Number of investigation sites and study duration .......................................................................... 16 
2.6 
Randomization and blinding ............................................................................................................ 16 
2.7 
Statistical Methods and Analysis ..................................................................................................... 16 
2.7.1 Primary Hypothesis .............................................................................................................. 17 
2.7.2 Rationale for Choice of Hypothesis ...................................................................................... 17 
2.7.3 Sample Size Calculation and Methods ................................................................................. 18 
2.7.4 Analysis of Clinical Data ....................................................................................................... 18 
3 
SUBJECT SELECTION ............................................................................................................................................... 20 
3.1 
Inclusion criteria .............................................................................................................................. 20 
3.2 
Exclusion criteria ............................................................................................................................. 20 
4 
STUDY PREPARATION PROCEDURES ...................................................................................................................... 21 
4.1 
Investigator/Investigation site selection ......................................................................................... 21 
4.1.1 Investigator selection criteria .............................................................................................. 21 
4.1.2 Investigation site selection criteria ...................................................................................... 21 

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4.1.3 Clinical Investigation Agreement ......................................................................................... 21 
4.1.4 Curriculum Vitae .................................................................................................................. 22 
4.2 
Ethics ............................................................................................................................................... 22 
4.2.1 EC/IRB approval ................................................................................................................... 22 
4.2.2 Informed consent process ................................................................................................... 22 
4.2.3 Revisions in Patient Informed Consent and Data Release Form .......................................... 24 
4.2.4 Regulatory submission ......................................................................................................... 24 
4.3 
Regulatory compliance .................................................................................................................... 24 
4.4 
Training requirements ..................................................................................................................... 25 
4.5 
Study Center Investigative Team Members .................................................................................... 25 
4.5.1 Principal Investigator ........................................................................................................... 25 
4.5.2 Heart Team .......................................................................................................................... 25 
4.5.3 Cardiologist / Echocardiographer ........................................................................................ 26 
4.5.4 Other Trial Support Staff ...................................................................................................... 26 
4.6 
Clinical study materials and clinical study-specific equipment ....................................................... 26 
4.7 
CoreValve Evolut R system traceability ........................................................................................... 26 
5 
STUDY METHODS ................................................................................................................................................... 28 
5.1 
Screening and Enrollment ............................................................................................................... 28 
5.2 
Procedures for Trial Conduct........................................................................................................... 29 
5.2.1 Study Visit Requirements Matrix ......................................................................................... 30 
5.2.2 Baseline Procedures ............................................................................................................. 31 
5.2.3 Implant Procedure ............................................................................................................... 31 
5.2.4 Discharge .............................................................................................................................. 32 
5.2.5 Follow-up Visits .................................................................................................................... 32 
5.2.6 30 days ................................................................................................................................. 32 
5.2.7 One Year ............................................................................................................................... 32 
5.2.8 Two Years ............................................................................................................................. 33 
5.2.9 Three Years  ......................................................................................................................... 33 
5.2.10 Four and Five Years .............................................................................................................. 33 
5.2.11 Other Evaluations ................................................................................................................. 33 
5.3 
Trial Assessments ............................................................................................................................ 34 
5.3.1 Relevant Medications .......................................................................................................... 34 
5.3.2 Risk Scores ............................................................................................................................ 34 

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5.3.3 Heart Team Assessment....................................................................................................... 34 
5.3.4 Katz ADL ............................................................................................................................... 34 
5.3.5 Multi-slice Computed Tomography ..................................................................................... 35 
5.3.6 Echocardiography ................................................................................................................ 35 
5.3.7 12-Lead ECG ......................................................................................................................... 35 
5.3.8 NYHA Functional Classification ............................................................................................ 35 
5.3.9 Neurologic Assessment ........................................................................................................ 36 
5.3.10 Vital Status ........................................................................................................................... 36 
5.4 
Subject Accountability ..................................................................................................................... 37 
5.4.1 Missed Follow-up Visit ......................................................................................................... 37 
5.4.2 Lost To Follow-Up ................................................................................................................ 37 
5.4.3 Subject Withdrawal .............................................................................................................. 37 
5.4.4 Subject Disposition ............................................................................................................... 38 
5.5 
Role of the sponsor’s representatives ............................................................................................. 38 
5.6 
Source documents ........................................................................................................................... 39 
5.7 
Adverse events and Device Deficiencies ......................................................................................... 39 
5.7.1 Definition/classification ....................................................................................................... 39 
5.7.2 Recording and reporting of Adverse Events ........................................................................ 41 
5.7.3 Classification of Causal Relationships .................................................................................. 42 
5.7.4 Recording and reporting of Device Deficiencies .................................................................. 43 
5.7.5 Adverse Event and Device Deficiency Reporting Requirement ........................................... 43 
5.7.6 Emergency Contact for Reporting Events and Device Deficiencies ..................................... 46 
5.7.7 Clinical Events Committee ................................................................................................... 46 
5.8 
Study deviations and CIP changes ................................................................................................... 46 
5.8.1 Request for approval of study deviations ............................................................................ 47 
5.8.2 Reporting requirements for study deviations ...................................................................... 47 
5.8.3 Amendments to the Clinical Investigation Plan ................................................................... 48 
6 
QUALITY CONTROL PROCEDURES .......................................................................................................................... 49 
6.1 
Procedures for database management ........................................................................................... 49 
6.1.1 Data collection ..................................................................................................................... 49 
6.1.2 Time windows for completion and submission of Case Report Forms ................................ 49 
6.1.3 Data review and processing ................................................................................................. 49 
6.2 
Monitoring procedures ................................................................................................................... 50 

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6.2.1 Accessibility of investigation site staff and study materials ................................................. 50 
6.2.2 Audits and investigation site inspections ............................................................................. 50 
6.3 
Study suspension or early termination ........................................................................................... 51 
6.3.1 Early study suspension or termination ................................................................................ 51 
6.3.2 Early investigation site suspension or termination .............................................................. 51 
6.3.3 Subject follow-up in case of termination ............................................................................. 51 
6.4 
Study close out ................................................................................................................................ 51 
7 
PUBLICATION POLICY ............................................................................................................................................. 52 
8 
STUDY MANAGEMENT ........................................................................................................................................... 53 
8.1 
Study staff ....................................................................................................................................... 53 
8.2 
Advisory committees ....................................................................................................................... 53 
8.2.1 Principal Coordinating Investigators .................................................................................... 53 
8.2.2 Steering Committee ............................................................................................................. 53 
8.2.3 Clinical Events Committee ................................................................................................... 53 
8.2.4 Publication Committee ........................................................................................................ 53 
8.3 
Records and reports ........................................................................................................................ 54 
8.3.1 Investigator records ............................................................................................................. 54 
8.3.2 Investigator reporting responsibilities ................................................................................. 54 
8.3.3 Sponsor records ................................................................................................................... 55 
8.3.4 Sponsor reporting responsibilities ....................................................................................... 56 
8.3.5 Record retention and inspection ......................................................................................... 56 
8.4 
Miscellaneous .................................................................................................................................. 57 
8.4.1 Insurance .............................................................................................................................. 57 
8.4.2 Study reimbursement and indemnification ......................................................................... 57 
8.4.3 Subject confidentiality ......................................................................................................... 57 
9 
RISKS AND BENEFITS .............................................................................................................................................. 58 
9.1 
Anticipated Clinical Benefits ............................................................................................................ 58 
9.2 
Risks ................................................................................................................................................. 58 
9.3 
Risk-to-benefit rationale ................................................................................................................. 58 
10 
APPENDICES ........................................................................................................................................................... 59 
11 
REFERENCES ........................................................................................................................................................... 93 

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LIST OF APPENDICES 
APPENDIX A. ABBREVIATIONS 
APPENDIX B. RECOMMENDED ECHOCARDIOGRAPHY PROCEDURES 
APPENDIX C. RECOMMENDED MSCT PROCEDURES  
APPENDIX D. DEFINITIONS: RISK SCORES AND OTHER CO-MORBIDITIES 
APPENDIX E. DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS 
APPENDIX F. RESHEATH AND RECAPTURE DEFINITIONS 
APPENDIX G. EVENT CODE LIST 
 
 

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SYNOPSIS 
Title 
Medtronic CoreValve™ Evolut R™ FORWARD Study 
Purpose 
The study objective is to document the clinical and device performance outcomes of 
the Evolut R system used in routine hospital practice in a large patient cohort for the 
treatment of symptomatic native aortic valve stenosis or a stenosed, insufficient, or 
combined surgical bioprosthetic valve failure necessitating valve replacement. 
Design 
Prospective, single arm, multi-center, observational, post market study. In Australia 
and Canada it is a prospective, single arm, multi-center pre-market study. 
Product Name 
Medtronic CoreValve™ Evolut R™ System  
Objectives 
Document safety and clinical performance in a large patient cohort in a routine 
hospital setting 
Endpoints 
Primary Endpoint:  All-cause mortality at 30 days post implant 
Secondary Endpoints: VARC-2 safety and efficacy endpoints as well as hemodynamic 
performance metrics (incl. mean gradient, effective orifice area and prosthetic 
regurgitation) 
Study Sites 
Up to 60 centers worldwide. Geographies may include Europe, Australia, Middle East 
and Africa, Latin America and Canada. 
Sample Size 
Approximately 1000 implanted subjects, consented for follow-up through three years.  
Subject Evaluation 
For each subject, data will be collected preoperatively, intra-operatively, at 
hospital discharge, 30 days, 1, 2 and 3 years.   
Inclusion Criteria 
Patients must meet ALL of the following inclusion criteria: 
• 
Symptomatic native aortic valve stenosis or a stenosed, insufficient, or 
combined surgical bioprosthetic valve failure necessitating valve 
replacement 
• 
Acceptable candidate for elective treatment with the Evolut R System and 
in conformity with the local regulatory and medico economic context 
• 
Age ≥80 years OR considered to be at high or greater risk for surgical 
aortic valve replacement (AVR) where high risk is defined as: 
o Society of Thoracic Surgeons (STS) predicted risk of mortality ≥8%  
OR  
o Documented heart team agreement of risk for AVR due to frailty 
or comorbidities. 
• 
Geographically stable and willing to return to the implanting site for all 
follow-up visits 
• 
Of legal age to provide informed consent (patient Informed Consent or 
Data Release Form) in the country where they enroll in the trial 
• 
The patient has been informed of the nature of the study, is able and 
willing to provide consent without assistance from a legal representative 
and has consented to participate, and has authorized the collection and 
release of his/her medical information by signing a Patient Informed 
Consent or Data Release Form. 

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Exclusion Criteria 
Patients are NOT eligible for study participation if they meet ANY of the following 
exclusion criteria: 
• 
Known hypersensitivity or contraindication to aspirin, heparin (HIT/HITTS) 
and bivalirudin, ticlopidine, clopidogrel, Nitinol (Titanium or Nickel), or 
sensitivity to contrast media, which cannot be adequately premedicated 
• 
Preexisting mechanical heart valve in aortic position 
• 
Ongoing sepsis, including active endocarditis 
• 
Anatomically not suitable for the Evolut R system 
• 
Estimated life expectancy of less than 1 year  
• 
Participating in another trial that may influence the outcome of this trial  
• 
Need for emergency surgery for any reason 
Professional 
Services 
Echo Core Laboratory, Clinical Events Committee, CRO for monitoring in Australia 
Global Sponsor  
Medtronic Plc., Coronary and Structural Heart Clinical 
8200 Coral Sea St NE, MVS 66, Mounds View, MN 55112, United States 
Local Sponsors 
Europe 
Medtronic Bakken Research Center BV 
Coronary and Structural Heart Disease Management Department  
Endepolsdomein 5, 6229 GW Maastricht, The Netherlands 
Australia 
Medtronic Australasia Pty Ltd 
97 Waterloo Road, North Ryde, NSW 2113, Australia 
Canada 
Medtronic of Canada Ltd. 
99 Hereford St., Brampton, ON, L6Y 0R3, Canada 
Latin America 
Medtronic Latin America Plc 
3750 NW 87th Avenue, Miami, Florida 33178, United States 
Coordinating 
Principal 
Investigators 
Prof. Eberhard Grube 
Medizinische  Klinik u. Poliklinik II 
Universitätsklinikum Bonn 
53105 Bonn, Germany 
 
Prof. Stephan Windecker  
Bern University Hospital 
Department of Invasive Cardiology 
3010 Bern, Switzerland 

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1 GENERAL INFORMATION 
1.1 Introduction 
Transcatheter aortic valve implantation (TAVI) has become a routine treatment option at specialized 
heart centers treating patients with severe aortic stenosis who are at high risk for surgical aortic valve 
replacement (SAVR). Growing clinical evidence from observational and now randomized controlled 
studies demonstrates that TAVI provides good hemodynamic outcomes and is an effective and useful 
treatment for high and extreme risk patients with severe aortic stenosis.1,2,3,4,5,6,7 
Currently, two different TAVI device systems have been widely used: the balloon expandable Edwards 
Sapien™ valve (Edwards Lifesciences, Irvine CA, USA), and the self-expanding Medtronic CoreValve 
System (Medtronic, Santa Ana, CA, USA). The 18 French (Fr) Medtronic CoreValve system (hereafter, 
“CoreValve”) was CE Marked in 2007, and to date, more than 65,000 devices have been sold in more 
than 70 countries.  There is extensive published experience demonstrating the CoreValve system is 
fulfilling its intended role with a favorable risk/benefit ratio,8,9,10,11and large clinical trials in the United 
States have further demonstrated its safety and effectiveness in patients at extreme6 and high risk for 
SAVR.7 
The CoreValve system is approved for implantation via the transfemoral, subclavian, and direct aortic 
approaches, and is commercially available in four valve sizes (23 mm, 26 mm, 29 mm, and 31 mm) to 
accommodate a wide range of patient anatomies. In June 2013, the CoreValve system was also CE 
approved for use in failed surgical bioprostheses, where the approved indication was expanded to 
include patients with stenotic or regurgitant surgical aortic bioprostheses. 
While there have been significant improvements in TAVI outcomes due to better patient selection, 
increasing operator experience, and iterations in device technology, important issues remain.  Clinical 
challenges where further advances would be desirable include the occurrence of major procedural 
complications,12,13,14 stroke,15,16,17 paravalvular leak,18,19 vascular complications,20,21 and need for new 
pacemaker insertion.22,23,24,25 
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 the bioprosthesis if the 
initial implant positioning is sub-optimal (too high or too low). This feature is desirable in that it 
facilitates accurate and precise final positioning and may mitigate risks associated with sub-optimal 
positioning such as paravalvular leak,26,27 acute migration,14 and AV-conduction disturbance related to 
implant depth.22 
The 23 mm size Evolut R system was issued the CE mark on 12 August, 2014 on the basis of the 
established CoreValve clinical data and supportive data from the literature on competitive recapturable 
technology and represents the first commercial approval of the Evolut R recapture technology.  

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In October 2013, Medtronic initiated a 60 subject multi-center clinical study in Europe, Australia, and 
New Zealand to confirm that changes incorporated into the 26 and 29 mm size Evolut R systems have not 
adversely impacted the established safety and clinical performance of the Medtronic CoreValve System. 
Taken together, these data demonstrated the Evolut R system is safe, performs as intended, and that the 
benefits outweigh the risks for use in the intended patient population, resulting in CE marking on 30 
January 2015.  
1.2 Medtronic CoreValve™ Evolut R™ System  
The Evolut R system (manufactured by Medtronic, Plc.) is a recapturable transcatheter aortic valve 
implantation system, which includes the Evolut R transcatheter aortic valve, the EnVeo™ R delivery 
catheter system, and the EnVeo™ R loading system.A detailed description of the system components is 
provided in sections 1.2.1 through 1.2.3. 
Additional information on the description of each important component, ingredient, property and 
principle of operation of the device system/product, including any materials in contact with tissues or 
body fluids, details of any medicinal products, human and/or animal tissues or their derivatives or other 
biologically active substances, are on file at Medtronic and can be provided upon request. For Australia, 
this information can be found in the Investigator’s Brochure. 
1.2.1 CoreValve™ Evolut™ R Transcatheter Aortic Valve (TAV) 
The Evolut R TAV (Figure 2, A) is currently available in three sizes (23 mm, 26 mm and 29 mm), covering 
an aortic annulus diameter of 18 to 26 mm (Table 1). The Evolut R 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. Consistent with the approved CoreValve TAV, the Evolut R TAV is 
processed with the same anti-mineralization treatment of alpha-amino oleic acid (AOA), a compound 
derived from oleic acid, a naturally occurring long-chain fatty acid frame. 
Table 1. Patient Anatomical Diameters 
Bioprosthesis Model 
Bioprosthesis Size 
Aortic Annulus Diameter 
EVOLUTR-23 
23 mm 
18 mm–20 mm 
EVOLUTR-26 
26 mm 
20 mm–23 mm 
EVOLUTR-29 
29 mm 
23 mm–26 mm 
1.2.2 CoreValve™ EnVeo™ R Delivery Catheter System (DCS) with EnVeo™ R InLine Sheath 
The EnVeo R delivery catheter system facilitates the placement of the TAV within the annulus of the 
aortic valve (Figure 2, B). The catheter assembly is flexible and compatible with a 0.889 mm (0.035-inch) 
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 

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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, which effectively reduces the access site size by approximately 4 Fr (the additional 
diameter of an external introducer sheath) to the capsule diameter (18 Fr), Figure 1. The EnVeo R 
delivery catheter system is also compatible with an external 18 Fr introducer. 
Figure 1. Illustration of the reduction of the access site size with the Enveo R InLine Sheath (Fr = French; OD 
= Outer Diameter) 
The catheter packaging contains an integrated loading bath and a removable tray with three 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. 
1.2.3 CoreValve™ EnVeo R Loading System (LS) 
The EnVeo R loading system facilitates manual loading of the TAV into the deployment sheath capsule of 
the delivery catheter system by gradually reducing the diameter of the bioprosthesis radially to an 
optimal diameter (Figure 2, C). 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 delivery catheter system in cold sterile saline. 

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Figure 2 A) Evolut R 26 mm and 29 mm TAVs (left) and representative top view (right), B) EnVeo R delivery 
catheter system with the EnVeo R InLine sheath, C) EnVeo R loading system 
For more detailed information on intended use of the device, indications and contraindications, as well 
as a complete list of warnings, precautions and potential adverse effects, please refer to the IFU (and/or 
IB for Australia) of device, which is provided with the product and available in the appropriate local 
language. 
Any future CE-Mark approved CoreValve Evolut R models (including TAV, DCS and LS systems) may be 
used in all participating countries (excluding Australia and Canada) in the study as well. 
1.2.4 Intended Use 
The Evolut R System is intended for relief of aortic stenosis in patients with symptomatic heart disease 
due to severe native calcific aortic stenosis who are judged by a heart team, to be at high or extreme risk 
for open heart surgery.  The Evolut R TAV treats 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.28,29,30,31  Its intended performance is to 
relieve aortic valve stenosis without inducing significant regurgitation, thereby restoring effective aortic 
valve function. A detailed description of the Evolut R System, including a complete list of indications and 
contraindications, is provided in the Instructions for Use and Investigator’s Brochure (IB). 
The intended purpose of the Evolut R System in this clinical study is in line with the intended purpose in 
the Instruction for Use and IB. The Evolut R system is an investigational device in Australia and Canada 
and is market approved in all other participating countries; labelling for all devices will be done in 
compliance with local regulatory requirements.  
For necessary training and experience needed to use the Evolut R system – regardless whether the 
device is investigational or not at the site – refer to section 4.1.1. 

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2 STUDY PLAN 
2.1 Study objectives 
The study objective is to document the clinical and device performance outcomes of the Evolut R system 
used in routine hospital practice in a large patient cohort for the treatment of symptomatic native aortic 
valve stenosis or a stenosed, insufficient, or combined surgical bioprosthetic valve failure necessitating 
valve replacement. 
2.2 Clinical endpoints 
The endpoints used to evaluate the study objective are defined in this section. 
2.2.1 Primary endpoint 
1. All-cause mortality rate at 30 days post procedure 
2.2.2 Secondary Efficacy Endpoints 
2. Device success rate at 24 hours to 7 daysi, defined according to the Valve Academic Research 
Consortium-2 (VARC-2) guidelines as:32  
• 
Absence of procedural mortality, AND 
• 
Correct positioning of a single prosthetic heart valve into the proper anatomical location, 
AND  
• 
Intended performance of the prosthetic heart valve, defined as the absence of patient-
prosthesis mismatch and mean gradient < 20 mmHg (or peak velocity < 3 m/sec), AND No 
moderate or severe prosthetic valve regurgitation. 
3. Hemodynamic performance at 24 hours to 7 days (discharge) and 1 year post procedure, 
including the following hemodynamic metrics as measured by transthoracic echocardiography 
(TTE) and assessed by an independent core laboratory: 
• 
Mean prosthetic valve gradient 
• 
Effective orifice area 
• 
Degree of prosthetic valve regurgitation (transvalvular, paravalvular, and total) 
2.2.3 Secondary Safety Endpoints 
4. Early Safety composite endpoint at 30 days post procedure, defined according to the VARC-2 
guidelines32, defined as any of the following components:  
• 
All-cause mortality 
• 
All stroke (disabling and non-disabling) 
                                                          
 
i Time window for Echo assessment 

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• 
Life-threatening bleeding 
• 
Acute kidney injury: stage 2 or 3 (including renal replacement therapy) 
• 
Coronary artery obstruction requiring intervention 
• 
Major vascular complication 
• 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
5. Event rates of the individual components of the VARC-2 composite Early Safety endpoint32 at 30 
days post procedure 
6. Rate of new permanent pacemaker implant at 30 days post procedure 
2.2.4 Rationale for Selection of Study Endpoints 
The basis for the selection of these endpoints includes the following considerations: 
• 
They are clinically relevant and address important safety and efficacy aspects of the Evolut 
R System. 
• 
They are objectively defined and measurable in the majority of subjects.ii 
• 
They are consistent with current recommendations for endpoints in TAVI clinical studies.34 
2.3 Study population 
The study population includes patients with symptomatic native aortic valve stenosis or a stenosed, 
insufficient, or combined surgical bioprosthetic valve failure necessitating valve replacement who are 
scheduled for an elective transcatheter aortic valve implantation. Patients who will undergo an 
emergency procedure should not be included in this study. 
2.4 Study design 
This is a prospective, single arm, multi-center, observational, post market study. In Australia and Canada 
it is a prospective, single arm, multi-center pre-market study.    
Approximately 1000 subjects implanted with the Evolut R system will be included. Subjects will be 
followed at 1 month, 1, 2 and 3 years after the procedure. Based on clinical assessments during the 
course of the study, follow up may be extended to up to 5 years post procedure. 
Enrollment parameters are included in the study to avoid introduction of bias to the trial results due to 
disproportionate enrollment. Enrollment shall not exceed 7.5% (75 patients) of the total implanted 
patients at any individual site. In addition, enrollment shall not exceed 40% (400 patients) of the total 
implanted patients at any individual country.  
Enrollment will be competitive across sites. The per-site and per-country enrollment cap may be 
increased upon Sponsor approval. There is no set minimum number of patients to be enrolled per site; 
however there is an expected minimum enrollment of 15 subjects per site. 
                                                          
 
ii In some cases, transthoracic echocardiography can be technically difficult, and image quality may be sub-optimal for assessment of prosthetic 
regurgitation or hemodynamic performance variables. 

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At the time when the study-wide enrollment cap of 1000 implanted subjects has been reached, further 
enrollment into the study will cease regardless of whether individual sites have reached their per-site 
cap. 
The study methods include the following measures to minimize potential sources of bias: 
• 
An external, independent Clinical Events Committee (CEC) will review and adjudicate, at 
minimum, all deaths and safety 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 study endpoint 
results will be based on Core Lab assessments. 
• 
Study sites should follow their institutional procedures for maintenance of 
echocardiography and laboratory equipment used for assessing the study variables. 
• 
Study monitors will verify patients’ data and ensure compliance with the Clinical 
Investigational Plan and other study requirements. 
2.5 Number of investigation sites and study duration 
The study will be a multicenter, multinational study conducted at up to 60 investigational sites. These 
centers may be located in Europe, Middle East and Africa, Latin America, Australia and Canada. Other 
regions may be added depending on the regulatory status of the device. At the time this Clinical 
Investigation Plan was finalized not all participating investigation sites were identified. A list of 
participating investigation sites which includes the name and title of the investigator(s) who is (are) 
responsible for conducting the trial, and the address and telephone number(s) of the trial site(s). They 
will be submitted under a separate cover and will be available in the Investigator Site File. 
It is anticipated that enrollment will take approximately 18 months.  As each implanted subject is to be 
followed for three years, the estimated study duration is approximately 54 months, excluding the time 
required for preparing the final report. If each subject will be followed for 5 years, the estimated study 
duration is approximately 78 months. 
2.6 Randomization and blinding 
The study is a non-randomized trial and does not require blinding techniques. 
2.7 Statistical Methods and Analysis 
Any deviations from this section and/or the Statistical Analysis Plan will be described and justified in the 
Final Clinical Study Report, as appropriate. 
 
 
 

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2.7.1 Primary Hypothesis 
The primary endpoint of the study is the all-cause mortality at 30 days post procedure, which will be 
compared to a performance goal of 10.0%. Therefore the study hypotheses are: 
H0: π ≥ 10.0% 
HA: π < 10.0% 
Where π denotes the binary rate of all-cause mortality rate at 30 days post procedure. This one-sided 
test will be carried out at the 0.05 significance level using the exact test. 
 
2.7.2 Rationale for Choice of Hypothesis 
The performance goal for all-cause mortality at 30 days was established through the following data 
sources: 
1. Data from the CoreValve IDE clinical study 
2. Review of the published literature on the Medtronic CoreValve System current through April 
2013   
Criteria for selection of the articles included the following: 
• 
Study was published in peer reviewed journal 
• 
Study was multi-center 
• 
Results were representative of high risk population 
• 
Results for all-cause mortality were reported by device type 
• 
Study was not a first in man, feasibility, or confined to early Medtronic CoreValve experience 
Of the literature reviewed, 4 articles were selected. Information on the historical data is presented in 
Table 2. 
Table 2. Information on control data sources for all-cause mortality at 30 days 
Author 
Study Name 
Number 
of 
CoreValve 
Patients 
Age 
(years) 
Mean ± SD 
Logistic 
Euroscore 
(%) 
Mean ± SD 
STS Score 
(%) 
Mean ± SD 
All-Cause 
Mortality at 30 
days 
(%) 
US CoreValve IDE study: Extreme Risk Cohort1 
639 
83 ± 8 
23 ± 17 
10 ± 6 
9.1 
US CoreValve IDE study: High Risk Cohort1 
390 
83 ± 7 
18 ± 13 
7 ± 3 
3.3 
Bosmans33 
Belgian Registry 
141 
82 ± 6 
25 ± 15 
Not reported 
11.0 
Gilard34 
FRANCE 2 Registry 
1043 
82 ± 7 
21 ± 14 
14 ± 11 
9.4 
Chieffo35 
PRAGMATIC 
453 
81 ± 7 
21 ± 13 
8 ± 6 
7.5 
Moat36 
UK TAVI Registry 
452 
81 ± 7 
18 (11-28) 
Not reported 
5.8 
Random effects meta-analytic rate 
7.3 
(95% CI 5.4 - 10.0) 
1. 
Data include all access routes.   
 
The random effect meta-analysis showed that the all-cause mortality rate at 30 days post procedure for 

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CoreValve was 7.3% with a 95% C.I. of 5.4% to 10.0%. We expect EVOLUT R TAV will have a similar rate as 
CoreValve, which is 7.3% at 30 days. And the all-cause mortality rate for EVOLUT R will not be higher 
than the upper bond of the 95% C.I. for CoreValve. Therefore the performance goal was set to 10.0%. 
2.7.3 Sample Size Calculation and Methods   
The following are assumptions for the sample size estimate: 
One-sided alpha = 0.05 
π0 = 10.0% 
π = 7.3% 
Power = 90% 
In the above expressions, π0 and π denote the Performance Goal (null hypothesis proportion) and true 
proportion, respectively, for all-cause mortality rate at 30 days. Using an exact binomial test, Power 
Analysis and Sample Size (PASS) software calculates that a total of 934 evaluable subjects is required to 
attain 90% power in a one-sided test at the 0.05 level of significance. The final sample size is increased to 
1000 evaluable subjects to account for 7% attrition rate.  
2.7.4 Analysis of Clinical Data 
Subjects who are taken to the procedure room for implantation will comprise the study population 
evaluated for the study objectives and associated endpoints.   
The analysis sets are further defined as follows:  
1. Safety Set. The safety set includes all subjects who are brought into the procedure room for 
implantation.  
2. Device Success/ Hemodynamic Performance Set. The device success/ hemodynamic performance 
set includes all subjects who are implanted with the Evolut R TAV, defined as the Evolut R TAV is 
placed in the aortic annulus and completely released from the EnVeo R catheter delivery system. 
The Final Report will be prepared when all patients have completed their follow-up evaluations or exited 
the study. All analyses will be described in a Statistical Analysis Plan (SAP) which will be completed prior 
to analysis. No interim analysis is planned.  
Every effort will be undertaken to minimize missing data. A minimal amount of missing data is 
anticipated for the primary endpoint. However, if outcome data are missing, the primary analysis will be 
based on the complete case. And the Kaplan-Meier rate at 30 days and its standard error, as a secondary 
analysis, will be used in the calculation of the test statistic. To assess the potential impact of these 
missing data, a sensitivity analysis will be conducted which will include a complete case, a best case 
(assume missing subjects are alive), a worst-case (assume missing subjects have died), and a tipping 
point analysis. 
Descriptive statistics will be provided for baseline demographic and clinical variables, as well as for the 
secondary endpoints. For categorical variables the numbers and percentages will be displayed. For 

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continuous variables the means, medians, standard deviations, and ranges will be presented. For time to 
event variables, Kaplan-Meier event rates and confidence intervals will be calculated. 
No statistical techniques will be used to impute missing data for continuous or categorical outcomes. If a 
subject’s data are missing for any reason, that subject will not be included in that portion of the analysis. 
The number of subjects included in each analysis will be reported so that the reader can assess the 
potential impact of missing data. 
Additional (annual) reports providing only descriptive statistics will only be written upon request of the 
EC/IRB and/or Regulatory Authority, as applicable. 
 

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3 SUBJECT SELECTION 
Subject selection criteria are based on the Instructions for Use of the Evolut R System. 
3.1 Inclusion criteria 
Patients must meet ALL of the following inclusion criteria: 
• 
Symptomatic native aortic valve stenosis or a stenosed, insufficient, or combined surgical 
bioprosthetic valve failure necessitating valve replacement 
• 
Acceptable candidate for elective treatment with the Evolut R System and in conformity with 
the local regulatory and medico economic context 
• 
Age ≥80 years OR considered to be at high or greater risk for surgical aortic valve 
replacement (AVR) where high risk is defined as: 
o Society of Thoracic Surgeons (STS) predicted risk of mortality ≥8%  
OR  
o Documented heart team agreement of risk for AVR due to frailty or comorbidities. 
• 
Geographically stable and willing to return to the implanting site for all follow-up visits 
• 
Of legal age to provide informed consent (patient Informed Consent or Data Release Form) 
in the country where they enroll in the trial 
• 
The patient has been informed of the nature of the study, is able and willing to provide 
consent without assistance from a legal representative and has consented to participate, and 
has authorized the collection and release of his/her medical information by signing a Patient 
Informed Consent or Data Release Form. 
3.2 Exclusion criteria 
Patients are NOT eligible for study participation if they meet ANY of the following exclusion criteria: 
• 
Known hypersensitivity or contraindication to aspirin, heparin (HIT/HITTS) and bivalirudin, 
ticlopidine, clopidogrel, Nitinol (Titanium or Nickel), or sensitivity to contrast media, which 
cannot be adequately premedicated 
• 
Preexisting mechanical heart valve in aortic position 
• 
Ongoing sepsis, including active endocarditis 
• 
Anatomically not suitable for the Evolut R system 
• 
Estimated life expectancy of less than 1 year  
• 
Participating in another trial that may influence the outcome of this trial  
• 
Need for emergency surgery for any reason  

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4 STUDY PREPARATION PROCEDURES 
4.1 Investigator/Investigation site selection 
4.1.1 Investigator selection criteria 
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
study as well as ensure data integrity and the rights, safety and well-being of the subjects involved in the 
clinical study. 
An investigator may be included in the clinical study if compliant with the following requirements:  
• 
Is appropriately qualified practitioner legally entitled to practice, and experienced in the 
diagnosis and treatment of patients requiring an aortic valve treatment with a TAVI;   
• 
Prior to their first implant under this study protocol, each participating implanter must have 
performed - either as first or second implanter - at least 50 cumulative CoreValve implants, of 
which at least 10 were Evolut R implants; 
• 
The Principal Investigator has demonstrated experience with conducting clinical (device) trials 
that comply with applicable regulatory standards;  
• 
Principal Investigator, co-investigators, and study staff must be willing to provide their 
Curriculum Vitae and training evidence; 
4.1.2 Investigation site selection criteria 
An investigation site may be selected for participation in the clinical study if compliant with the following 
requirements:  
• 
Site must have sufficient patient population to meet enrollment expectations 
• 
Site must have the presence of an active multi-disciplinary heart team for patient evaluation 
(refer to section 4.5.2 for more information) 
• 
Site must use Multi Slice Computed Tomography (MSCT) routinely for screening patients 
• 
Site is willing to participate in follow-up of patients for 60 months; 
• 
Site should have adequate staff that is accessible and has time to manage the study for 7 days 
per week, 24 hours per day; 
• 
Site must be willing to sign and comply with the protocol-specific Clinical Trial Agreement; 
• 
Site must be willing to comply with the Clinical Investigation Plan and data collection 
requirements, including Adverse Event reporting; 
• 
Site must be willing to comply with all requirements of the relative regulatory agencies, Ethics 
Committees and Institutional Review Boards. 
• 
Site must have an internet connection with sufficient speed of data transfer. 
4.1.3 Clinical Investigation Agreement 
A Clinical Investigation Agreement shall be in place, signed by the participating investigation site and/or 
principal investigator of each investigation site, as per the local legal requirements, and returned to 
Medtronic prior to the commencement of any clinical study activities. The investigator is indicating 

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approval of the Clinical Investigation Plan and subsequent amendments, by a fully executed agreement. 
Amendments to this Clinical Investigation Plan shall be agreed upon between Medtronic and 
investigator(s) and be recorded with a justification for the amendments.  
4.1.4 Curriculum Vitae  
An up to date signed and dated Curriculum Vitae from all key members of the investigation site team  
participating in this clinical study as listed on the Delegated task List shall be obtained, evidencing the 
required qualifications, including the year and where obtained, and including their current position at the 
investigation site. The signature on the CV must be dated within 3 years prior to the date of activation of 
the investigation site.  
4.2 Ethics 
4.2.1 EC/IRB approval 
Prior to enrolling subjects in this clinical study, each investigation site’s EC/IRB will be required to 
approve the current Clinical Investigation Plan, the Patient Informed Consent form or Patient Data 
Release Form, including any other written information to be provided to the subjects. EC/IRB approval of 
the clinical study must be received in the form of a letter and provided to Medtronic before 
commencement of the clinical study at an investigation site. The approval letter must contain enough 
information to identify the version or date of the documents approved. If this information is not 
contained in the approval letter, it must be retrievable from the corresponding submission letter. In 
addition, the approval letter needs to be accompanied by an EC/IRB roster or letter of compliance, to 
allow verification that the investigator, other investigation site personnel, and/or Medtronic personnel 
are not members of the EC/IRB. If they are members of the EC/IRB, written documentation is required 
stating that he/she did not participate in the approval process. If the EC/IRB imposes any additional 
requirements (e.g. safety reports, progress reports etc.), Medtronic will prepare the required documents 
and send them to the investigator for reporting to the EC/IRB. Investigators must inform Medtronic of 
any change in status of EC/IRB approval once the investigation site has started enrolment. If any action is 
taken by an EC/IRB with respect to the investigation, that information will be forwarded to Medtronic by 
the respective investigator. 
4.2.2 Informed consent process 
Patient Informed Consent 
The investigator or authorized designee must obtain written informed consent before any clinical study 
related activity takes place.   
Well in advance of the consent discussion, the patient should receive the EC/IRB approved Patient 
Informed Consent Form. During the consent discussion the investigator or his/her authorized designee 
must fully inform the patient of all aspects of the clinical study that are relevant to the patient’s decision 
to participate in the clinical study. If a patient is illiterate, an impartial witness must be present during 
the entire informed consent discussion. All items addressed in the Patient Informed Consent Form must 

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be explained. The language used shall be as non-technical as possible and must be understandable to the 
patient and the impartial witness, where applicable.  
The patient must have ample time and opportunity to read and understand the Patient Information and 
the Informed Consent Form, to inquire about details of the clinical study, and to decide whether or not 
to participate in the clinical study. All questions about the clinical study should be answered to the 
satisfaction of the patient. 
Neither the investigator, nor the investigation site staff shall coerce or unduly influence a patient to 
participate or to continue to participate in the clinical study. The informed consent process shall not 
waive or appear to waive the patient’s rights. 
When the patient decides to participate in the clinical study, the Informed Consent Form must be signed 
and personally dated by the patient and investigator or authorized designee. If applicable, the witness 
shall also sign and personally date the consent form to attest that the information in the Patient 
Information and Informed Consent Form was accurately explained and clearly understood by the patient, 
and that informed consent was freely given. 
After all persons have signed and dated the Informed Consent Form, the investigator must provide the 
patient with a copy of the Patient Information and the signed and dated Informed Consent Form.  
The study data can only be submitted to Medtronic upon fully execution of the Patient Informed Consent 
Form. 
Patient Data Release 
The investigator must obtain written Data Release Consent prior to releasing personal information of the 
subject. 
During the consent discussion the investigator or his/her designee must fully inform the subject of the 
study in a non-technical wording understandable for the subject. If a patient is illiterate, an impartial 
witness must be present during the entire informed consent discussion. 
The subject must have ample time and opportunity to inquire about details of the study, and to decide 
whether or not to participate in the clinical study. All questions about the study should be answered to 
the satisfaction of the subject.  
When the subject decides to participate in the clinical study, the written Data Release Consent form 
must be signed and personally dated by the subject and the investigator. If applicable, the witness shall 
also sign and personally date the Data Release Consent form to attest that the information in the Data 
Release Consent Form was accurately explained and clearly understood by the patient, and that 
informed consent was freely given. 
After all persons have signed and dated the Data Release Consent Form the investigator must provide 
the subject with a copy of the signed and dated Data Release Consent form.  
The study data can only be submitted to Medtronic upon fully execution of the Data Release Consent 
Form.  

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4.2.3 Revisions in Patient Informed Consent and Data Release Form  
Medtronic will inform the investigators whenever information becomes available that may be relevant to 
the subject’s confirmed participation in the clinical study. The investigator or his/her authorized designee 
should inform the subject in a timely manner.  
Medtronic will revise the written Patient Informed Consent and Data Release Forms whenever new 
information becomes available that may be relevant to the subject’s confirmed participation in the 
clinical study. The revised information will be sent to the investigator for approval by the EC/IRB. After 
approval by the EC/IRB, a copy of this information must be provided to the participating subjects, and 
the informed consent process as described above needs to be repeated.  
4.2.4 Regulatory submission 
In countries where submission to the regulatory authority is required per local law, no patients will be 
enrolled in the clinical study until the particular regulatory authority has approved the current Clinical 
Investigation Plan of the clinical study and other documents as required according to the local 
requirements. 
If the regulatory authority imposes any additional requirements (e.g. safety reports, progress reports 
etc.), Medtronic will prepare the required documents and send them to the respective authority, either 
directly or through the investigational site. 
Other documents that are referred to in this Clinical Investigation Plan are listed below and will be made 
available upon request: 
• 
Patient Informed Consent Form / Patient Data Release Form 
• 
Instructions for Use 
• 
Investigator’s Brochure 
• 
Case Report Forms 
• 
Monitoring Plan 
• 
Data Management Plan 
• 
Statistical Analysis Plan 
4.3 Regulatory compliance 
This clinical study will be conducted in compliance with the latest version of the Declaration of Helsinki 
(2013), the international standard ISO 14155: 2011 (except for full device accountability and Adverse 
Event reporting), laws and regulations of the countries in which the clinical study is conducted, including 
data protection laws, the Clinical Investigation Agreement and the Clinical Investigation Plan. Only in the 
countries where this is a pre-market study (Australia and Canada), full device accountability will be done. 
All principles of the Declaration of Helsinki (2013) have been implemented in this clinical study by means 
of the informed consent process, EC/IRB approval, study training, clinical trial registration, preclinical 
testing, risk benefit assessment and publication policy. Pediatric, legally incompetent, or otherwise 
vulnerable patients are not eligible for the study. Further, the Evolut R system will not be used as an 
emergency treatment. 

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The sponsor will avoid improper influence on, or inducement of the subject, monitor, and investigator(s) 
or other parties participating in, or contributing to, the clinical study by implementing the informed 
consent process, Clinical Investigation Agreements and EC/IRB approval. 
4.4 Training requirements 
Prior to investigation site activation or subsequent involvement in clinical study activities, Medtronic or 
designated local CRO will provide clinical study training relevant and pertinent to the involvement of 
personnel conducting clinical study activities, including, investigator responsibilities, ISO 14155:2011, the 
CIP, PIC, use of data collection tools and applicable local regulations.  
All study personnel should be trained in accordance to their responsibilities (as documented in the 
Delegated Task List) and no specific study activities should be performed before training is done.  
Training may be conducted via site (initiation) visits, investigator meetings, and/or other media sessions. 
4.5 Study Center Investigative Team Members 
The following is a description of the key personnel who typically forms the investigative team at each 
study center. 
4.5.1 Principal Investigator 
Each center will have at least one Principal Investigator (PI), who is an interventional cardiologist or a 
cardiothoracic surgeon.  The PI has overall responsibility for the conduct of the study at the center, 
including protecting the rights, safety, and welfare of the study subjects at their center, for the integrity 
of the study data generated by their center, and for ensuring the study is conducted in compliance with 
the CIP and their local regulatory and EC/IRB requirements. 
4.5.2 Heart Team 
A Heart Team will assess individual patient risks as well as the technical suitability of TAVI, including 
determinations regarding eligibility of the prospective subject for the study as detailed in section 5.1.  
Typically the local Heart Team comprises of the following members: 
1) A cardiothoracic surgeon 
2) An interventional cardiologist 
3) An echocardiographer  
The PI or delegated Investigator(s) may serve as one of the members of the Heart Team. The PI or 
delegated Investigator(s) (as documented on the Delegated Task List) is/are responsible for 
documentation of the Heart Team assessment decision. 
Heart Team members who – apart from their involvement in patient evaluation and assessment - do not 
perform any study specific activity do not need to be trained or delegated on the study. 
 
 

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4.5.3 Cardiologist / Echocardiographer 
Each center typically has a designated cardiologist whose responsibility includes the assessment of 
echocardiograms. Please refer to Appendix B for recommended echocardiogram acquisition guidelines 
and images. 
4.5.4 Other Trial Support Staff 
The PI will ensure that the investigative site has the appropriate support staff to maintain the trial.   
Additional staff may include co-investigators, research coordinators, and other specialized health care 
professionals.  The PI will document authorization of delegated tasks using the Delegation of Tasks Log 
provided by Medtronic. 
4.6 Clinical study materials and clinical study-specific equipment 
Medtronic will control the supply of the latest version of the Clinical Investigation Plan and all other 
materials required to conduct the clinical investigation.  
Medtronic will provide the Investigator Site File and e-CRF access to the center upon receipt or 
completion of the following: 
• 
A signed Clinical Investigation Agreement; 
• 
A copy of the Ethics Committee approval letter, including a membership list or a statement 
that no Ethics Committee approval is necessary; 
• 
The Ethics Committee and Medtronic approved Patient Informed Consent or Patient Data 
Release Form 
• 
Regulatory Authority approval/notification, if applicable; 
• 
Delegated Task List (DTL); the Principal Investigator can delegate tasks to the study staff. 
These tasks must be documented on the Delegated Task List and the study team must have 
been trained to perform these tasks as documented in the Study Training Form.  
• 
Curriculum Vitae of the Principal Investigator and study staff signed and dated within 3 years 
prior to center activation date; 
• 
Study team training documentation; 
No study-specific equipment will be provided by the sponsor; all exams are performed with hospital 
equipment and used within standard of care. Maintenance and calibration of study-specific equipment is 
the responsibility of the investigation site and will be performed per hospital procedures. 
4.7 CoreValve Evolut R system traceability 
In countries where the Evolut R system is CE-marked and commercially available, the Evolut R system will 
be obtained by the sites according to standard hospital procedures for commercial products. Existing 
approved procedures for commercial product regarding distribution, shipment, storage, handling, and 
return of these devices will be followed. The devices should be used within the intended approved 
indication. Serial number of implanted Evolut R TAV and LOT number for the Evolut R DCS will be 
captured in the e-CRF. Additional device traceability is not applicable and a full device tracking as 

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required by ISO 14155 will not be performed due to the post-market nature of the study (use of the 
device within its intended labeling). 
 
In countries where the Evolut R system is not approved for commercial use and is considered 
investigational, the Evolut R system should be stored as labeled and in a secure location.  The method of 
storage should prevent the use of these investigational devices for other applications than mentioned in 
this CIP.  
Medtronic will only allow shipment of investigational devices to the investigation site or investigator, 
after the Clinical Study Manager has declared the investigation site ready to start the clinical study. 
Medtronic registers the number of used investigational devices and will only ship additional 
investigational devices to the investigation site in case a substantial number of the previously shipped 
devices have been used and the CRFs have been received. 
Centers are required to maintain investigational device records that contain the following information: 
• 
Investigational device name 
• 
Serial number 
• 
Lot number (for delivery and loading systems 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 Investigational devices that are returned to Medtronic or disposed of, centers are required to 
document the following information: 
• 
The device serial numbers 
• 
Lot numbers (for delivery systems 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 end of the trial enrollment period, all remaining investigational devices must be returned to 
Medtronic. 
  

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5 STUDY METHODS 
5.1 Screening and Enrollment 
The process of patient screening and subject enrollment is as follows (Figure 3): 
1. 
Patients identified by the study center to have aortic stenosis will be screened by the investigative 
team for the criteria described in Section 3 using available medical records, including relevant 
imaging studies that have been previously performed for diagnostic purposes. 
• 
A recentiii Multi-Slice Computed Tomography (MSCT) of the patient’s peripheral vasculature 
and aortic annulus must be available to assess anatomic suitability for Evolut R TAV 
implantationiv. If no recentiii MSCT is available or is planned per standard care, the patient 
should not be considered for any further for participation in this study.  
2. 
Evaluate risk profile of the patient based on age and STS score. Patients with age <80 years and a 
STS predicted risk of mortality of <8% must be evaluated by a heart team to confirm and document 
the patient is at high or greater risk for AVR due to frailty or comorbidities.  
3. 
If, based on the review of available information, the patient is deemed to be a potential candidate 
for the Evolut R system and the study, all aspects of the study will be explained to the patient. The 
patient will then be invited to participate in the study. 
4. If the patient agrees to participate, written informed consent (patient Informed Consent or Data 
Release Form) will be obtained. This will be considered the point of enrollment, and the subject will 
be assigned a Subject ID number. The site should document in the patient’s medical record that the 
subject gave informed consent (patient Informed Consent or Data Release Form). Furthermore, the 
subject shall be provided with a copy of the signed Patient Informed Consent or Patient Data Release 
Form. 
 
Centers will maintain a log of patients consented, procedure-attempted, and implanted, as well as the 
Subject ID numbers assigned to each subject.   
                                                          
 
iii MSCT should be within 365 days of index procedure 
iv Recommended multi-slice computed tomography acquisition guidelines are provided in Appendix C 

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* MSCT should be within 365 days of index procedure 
** If diagnostic MSCT acquisition is planned per standard care, refer to recommended MSCT acquisition guidelines provided in Appendix C.  
 
Figure 3. Flow diagram of the study entry process 
5.2 Procedures for Trial Conduct 
An overview of all data collection requirements is given in Table 3. All exams are typical for TAVI and are 
considered standard of care exams in the participating hospitals. 
 
 
 
 
Yes
шϴй
Age (years) 
 
STS 
predicted 
risk of 
mortality
Documented 
Heart Team 
agreement 
patient is high 
or greater risk 
for AVR
Obtain informed consent (either patient Informed Consent or Data Release Form)
<80
шϴϬ
<8%
Yes
Yes
Diagnostic 
MSCT 
acquisition 
planned?** 
Screen for eligibility 
 
Diagnostic 
MSCT 
available?* 
No
No
No

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5.2.1 Study Visit Requirements Matrix 
The following table indicates the parameters expected to be routinely evaluated by investigational sites. 
Table 3: Schedule of assessments 
Data Collection Requirement 
Assessment Intervals 
 
Baseline5 
Implant 
Discharge 
30 Days5 
1 Year5 
2 & 3 
Years5 
Study Exit 
Heart Team Assessment1 
X 
 
 
 
 
 
 
Informed Consent (either patient 
Informed Consent or Data 
Release Form) 
X 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
X 
X 
X 
 
NYHA Classification 
X 
 
 
X 
X 
X 
 
Risk scores (STS risk score, Log. 
EuroSCORE and EuroSCORE II) 
X 
 
 
 
 
 
 
Katz ADL 
X 
 
 
 
 
 
 
Relevant Medications 
X 
 
X 
X 
X 
X 
 
MSCT 
X2 
 
 
 
 
 
 
Transthoracic Echo (TTE) 
X 
 
X3 
 
X 
 
 
12-lead ECG 
X 
 
X 
X 
X 
X 
 
Operative Information 
 
X 
 
 
 
 
 
Modified Rankin Score4 
X 
 
X 
X 
X 
X 
 
Adverse Events/ 
Device Deficiency 
X 
X 
X 
X 
X 
X 
 
Vital Status 
 
 
 
 
 
 
X 
Notes 
1. 
Heart Team assessment documentation required for enrolled subjects who are <80 years of age and have a STS 
predicted risk of mortality of <8%. 
2. 
Pre-implant MSCT should be within 365 days of index procedure.  
3. 
It is recommended to perform TTE for device success within 24 hours to 7 days post-procedure 
4. 
Modified Rankin Score to be performed at 90 days following any stroke as well. 
5. 
Patients are followed per standard of care, therefore there are no mandatory visit windows defined in this study, 
however the visit windows defined below are provided as recommendation and guidance.  
 
Baseline 
Within 10 weeks prior to index procedure (except for TTE and MSCT) 
 
30 Days 
Between 30 and 60 days post procedure 
 
1 Year 
Between 365 and 425 days post procedure 
 
2 Years 
Between 730 and 790 days post procedure 
 
3 Years 
Between 1095 and 1155 days post procedure 
 
 
 
 
 
 

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5.2.2 Baseline Procedures 
There are no mandatory visit windows defined in this study, however it is recommended that baseline 
assessments should occur within 10 weeks prior to the index procedure; except for MSCTv. 
• 
Heart Team assessment for enrolled subjects who are <80 years of age and have a STS predicted 
risk of mortality of <8%. The Heart Team’s assessment must be documented on the Heart Team 
Assessment form. 
• 
Informed Consent (patient Informed Consent or Data Release Form) 
• 
Demographics and Medical History  
• 
Physical Examination 
• 
NYHA functional classification  
• 
Risk Scoresvi, including 
o Logistic EuroSCORE 
o EuroSCORE II 
o Society of Thoracic Surgeons Score for predicted risk of mortality 
• 
Katz ADL score 
• 
Trans-Thoracic Echocardiogram (TTE) 
o Please refer to the Appendix B for recommended TTE acquisition guidelines and images. 
• 
MSCT (peripheral vasculature and aortic annulus) 
o Please refer to Appendix C for recommended MSCT acquisition guidelines. 
• 
12-lead Electrocardiogram (ECG) 
• 
Relevant medications 
• 
Modified Rankin Score (mRS) 
• 
Review of relevant adverse events and device deficiencies (see section 5.7  for requirements) 
5.2.3 Implant Procedure 
The implantation procedure is performed according to the standard procedures of the implanting 
physicians. Procedural aspects specific to the Evolut R System should be performed according to the 
Instructions for Use (and/or IB for Australia). 
Per VARC 2, up to 72 hours continuous rhythm monitoring is recommended in order to maximize 
detection of arrhythmias. 
The following implant data will be collected and recorded on the implant e-CRF: 
• 
Operative information 
• 
Serial number, valve size and disposition of implanted valve or opened valve packages 
• 
Documentation of device failure or malfunction (as applicable) 
• 
Review of relevant adverse events and device deficiencies (see section  5.7  for requirements) 
 
 
 
                                                          
 
v Pre-implant MSCT and TTE must be performed within 365 days of index procedure 
vi Definitions of EuroSCORE, STS, and other co-morbidities are provided in Appendix D 

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Attempted procedure 
An attempted procedure is one where the trial subject has entered the procedure room for implantation, 
but did not receive an Evolut R TAV for any reason.  
If a procedure was attempted, and the Evolut R TAV is not implanted, the subject will be followed for 
safety reporting for 30 days post-attempted implant, and then exited from the trial. AE data should be 
collected on the AE e-CRF, and trial exit data on the Trial Exit e-CRF. 
5.2.4 Discharge 
Prior to hospital discharge, the following data will be collected. 
• 
12-lead ECG 
• 
Modified Rankin Score (mRS) 
• 
Physical Examination 
• 
Trans-Thoracic Echocardiogram (for device success)  
o Per the VARC 2 definition for Device Success, the recommended time window for the TTE 
is 24 hours to 7 days Post Procedure; 
o Please refer to the Appendix B for recommended TTE acquisition guidelines and images. 
• 
Relevant medication use. 
• 
Review of relevant adverse events and device deficiencies (see section  5.7 for requirements) 
5.2.5 Follow-up Visits  
Patients are followed per standard of care. Information from visits performed at the implanting hospital 
should preferably be used for the follow-up visits. If the patient did not return to the implanting hospital, 
but was followed at a local hospital, this information can be used as an alternative. If no hospital visit 
occurred, a telephone follow-up visit can be performed.  
5.2.6 30 days  
There are no mandatory visit windows defined in this study; however it is recommended that the 30-day 
follow up visit should occur between 30 and 60 days post procedure. 
• 
NYHA functional classification  
• 
12-lead ECG 
• 
Physical Examination 
• 
Relevant medication use. 
• 
Modified Rankin Score (mRS) 
• 
Review of relevant adverse events and device deficiencies (see section 5.7 for requirements) 
5.2.7 One Year  
There are no mandatory visit windows defined in this study; however it is recommended that the 1-year 
follow up visit should occur between 365 and 425 days post procedure. 
• 
NYHA functional classification  
• 
Trans-Thoracic Echocardiogram (TTE) 
o Please refer to the Appendix B for detailed instructions, guidelines and required images. 
• 
12-lead ECG 

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• 
Physical Examination 
• 
Relevant medication use. 
• 
Modified Rankin Score (mRS) 
• 
Review of relevant adverse events and device deficiencies (see section 5.7 for requirements) 
5.2.8 Two Years  
There are no mandatory visit windows defined in this study; however it is recommended that the 2-year 
follow up visit should occur between 730 and 790 days post procedure. 
• 
NYHA functional classification  
• 
12-lead ECG 
• 
Physical Examination 
• 
Relevant medication use. 
• 
Modified Rankin Score (mRS) 
• 
Review of relevant adverse events and device deficiencies (see section  5.7 for requirements) 
5.2.9 Three Years  
There are no mandatory visit windows defined in this study; however it is recommended that the 3-year 
follow up visit should occur between 1095 and 1155 days post procedure. 
• 
NYHA functional classification  
• 
12-lead ECG 
• 
Physical Examination 
• 
Relevant medication use. 
• 
Modified Rankin Score (mRS) 
• 
Review of relevant adverse events and device deficiencies (see section  5.7 for requirements) 
5.2.10 Four and Five Years 
If, based on clinical assessments during the course of the study, follow up is extended to up to 5 years 
post procedure, the follow up visits are recommended to occur between 1460 and 1520 days for the 4-
year follow up visit and between 1825 and 1885 days for the 5-year follow up visit. 
• 
NYHA functional classification  
• 
12-lead ECG 
• 
Physical Examination 
• 
Relevant medication use. 
• 
Modified Rankin Score (mRS) 
• 
Review of relevant adverse events and device deficiencies (see section  5.7 for requirements) 
5.2.11 Other Evaluations 
• 
A mRS assessment should be performed at baseline, all scheduled visits and at 90 days after the 
onset of any stroke. 
 
 
 
 
 
 

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5.3 Trial Assessments 
5.3.1 Relevant Medications 
Use of the following medications will be collected at baseline and at each postoperative interval and 
recorded on the appropriate e-CRF: 
• 
Anticoagulants 
• 
Antiplatelets 
• 
Aspirin (including Carbasalate calcium) 
The Investigator’s standard clinical practice will determine the appropriate anti-thrombotic medication 
use for each subject. 
5.3.2 Risk Scores 
The Logistic EuroSCORE, EuroSCORE II and Society of Thoracic Surgeons’ (STS) risk models predict the risk 
of operative mortality after adult cardiac surgery on the basis of patient demographic and clinical 
variables.   
The risk scores should be calculated at baseline for each subject using the online calculator:  
• 
Logistic EuroSCORE: http://euroscore.org/calcold.html 
• 
EuroSCORE II: http://euroscore.org/calc.html 
• 
STS Risk Score: http://riskcalc.sts.org/stswebriskcalc/#/ 
The online calculator provides additional guidance and definitions for each of the parameters used to 
calculate the scores. The predicted risks of mortality should be recorded on the Baseline e-CRF. The Risk 
Scores should be printed from the online calculators and filed as source documentation for trial subjects. 
5.3.3 Heart Team Assessment 
Patients with age <80 years and a STS predicted risk of mortality of <8% must be evaluated by a heart 
team to confirm the patient is at high or greater risk for AVR due to frailty or comorbidities. 
The Heart Team’s assessment must be documented on the Heart Team Assessment form and signed by 
the PI or delegated Investigator(s) (as documented on the Delegated Task List) (see section 4.5.2).  
5.3.4 Katz ADL 
Katz Index of Independence in Activities of Daily Living: the Katz Index of Independence in Activities of 
Daily Living, in short, the Katz ADL, is a questionnaire to assess functional status as a measurement of the 
patient’s ability to perform activities of daily living independently. The index ranks adequacy of 
performance in six functions. Patients are scored yes or no for independence in each of the six functions. 
A score of six indicates full function and 2 or less indicates severe functional impairment. 
Detailed information about the Katz ADL including guidelines to perform them can be found in the 
Investigator Site File. The site will record frailty assessment data on the appropriate e-CRF. 
 

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5.3.5 Multi-slice Computed Tomography 
All subjects enrolled in this study must have a routine cardiac Multi-slice Computed Tomography (MSCT) 
recording available at baseline for evaluation of the aortic valve anatomy, determination of aortic root 
dimensions for device sizing, and for evaluation of peripheral vessel dimensions and anatomy.  
MSCT’s are performed per standard care in all investigational sites (see section 4.1.2.). Please refer to 
Appendix C for recommended MSCT acquisition guidelines. If no recentvii MSCT image is available or 
planned per standard care, the patient should not be enrolled in this study (see section 5.1). 
Data to be recorded from the MSCT recording on the appropriate e-CRF include the following: 
• 
Aortic valve annulus perimeter  
• 
Mean Sinus of Valsalva diameter 
• 
Mean Sinus of Valsalva height 
• 
Calcification of Aorta and LVOT 
• 
Access vessel tortuosity and calcification 
5.3.6 Echocardiography 
Transthoracic echocardiography (TTE) exams, performed per standard care, are collected at the following 
intervals: baseline (pre-implant), 24 hours to 7 days (for device success) and 1 year.  
These TTE exams will be sent to the Echo Core Lab for central assessment. Please refer to Appendix B for 
recommended TTE acquisition guidelines and images. 
Sites should make every effort to utilize the same echo machine for all patients at the above mentioned 
intervals. Additionally, sites should perform regular maintenance and calibration of echo machines per 
local standards and ensure proper documentation is available for audit, as applicable. 
5.3.7 12-Lead ECG 
The standard 12-lead ECG will be utilized as a diagnostic and prognostic tool. All ECGs are analyzed 
utilizing both qualitative and quantitative methodology, to assess cardiac rhythm, noting any cardiac 
arrhythmias and indications for pacing.  The site will record ECG data on the appropriate e-CRF. 
5.3.8 NYHA Functional Classification 
The New York Heart Association (NYHA) Functional Classification is a system for defining cardiac disease 
and related functional limitations into four broad categorizations as defined in Table 4. 
 
                                                          
 
vii Pre-implant MSCT must be performed within 365 days of index procedure 

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Table 4. New York Heart Association (NYHA) Functional Classification 
Classification 
Description 
Class I 
Subject with cardiac disease but without resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
Class II 
Subjects with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
Class III 
Subjects with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is 
increased. 
NYHA classification will be assessed at baseline, 30 days, 1, 2 and 3 years, and the results recorded on 
the appropriate e-CRF. 
5.3.9 Neurologic Assessment 
The incidence of new clinically detectable neurological events or deficits, or any comparative change in 
indices of higher cognitive function following implantation of the Evolut R system in the treatment of 
patients with symptomatic severe aortic stenosis is an important clinical endpoint. Per the VARC-2 
guidelines, it is recommended to complete mRS assessments at baseline, all scheduled visits and at 90 
days after onset of any confirmed or suspected neurological event (see Table 3). The mRS will be used to 
classify non-disabling versus disabling stroke in accordance with the VARC-2 definitions. In addition, it is 
recommended to use neuroimaging to assess the ethiology of the stroke. 
Confirmed or suspected strokes (disabling and non-disabling) meeting the VARC-2 criteria should be 
reported as Serious Adverse Events (SAEs) according to the requirement in section 5.7. 
5.3.10 Vital Status 
A vital status (alive or deceased) should be confirmed for trial subjects at trial exit and recorded on the 
appropriate e-CRF.   
 
 
 
 

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5.4 Subject Accountability 
5.4.1 Missed Follow-up Visit 
The Investigator should make every effort to contact the subject preferably within the visit window, to 
collect the subject’s vital status as well as information related to potential adverse events, safety data, 
and hospitalizations. 
As only standard of care data are being collected, subjects cannot miss study-specific visits. In case no 
standard of care visit has taken place in the pre-specified follow-up interval period, sites should conduct 
a telephone follow-up visit just prior to the closure of the visit window. Up to 3 attempts and any 
information received during a telephone follow-up should be filed as source documentation by the sites. 
If the subject cannot be reached by phone, the visit should be considered missed and, if applicable a 
protocol deviation must be completed, as outlined in section 5.8. 
5.4.2 Lost To Follow-Up 
The subject may only be considered lost to follow-up after all efforts to obtain compliance are 
exhausted.  At a minimum, four attempts must be made to contact the subject and documented in the 
subject’s trial records: 
• 
3 telephone attempts to the subject’s last known phone number, and if unsuccessful,  
• 
1 certified letter from the PI to the subject’s last known address  
If the site is unable to reach the subject after the documented attempts, the site should make every 
attempt to verify the subject’s vital status (alive or deceased).   
5.4.3 Subject Withdrawal 
All subjects will be encouraged to remain in the study through the last follow-up visit at three years and 
up to 5 years, if the study is extended based on clinical assessments during the course of the study. 
Subjects who discontinue participation prematurely will be included in the analysis of results (as 
appropriate) but they will not be replaced in the enrollment of total study subjects. If a study subject is 
discontinued from the study early, the reason for discontinuation should be documented in the subject 
file and a Study Exit e-CRF must be completed. If discontinuation is because of safety or lack of 
effectiveness, the patient shall be asked to be followed for collecting safety data outside the clinical 
study. 
Once a subject has been enrolled in the study (i.e. written Informed Consent has been obtained) he/she 
may withdraw his/her consent to participate in the study at any time without prejudice. Participation in 
this study is entirely voluntary. 
If a subject discontinues the study at any time, is withdrawn from the study early, or completes all 
follow-up visits they should continue to be followed-by the implanting center according to their standard 
clinical practice for transcatheter aortic valve patients.  

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5.4.4 Subject Disposition 
The Investigation site will maintain a log of all subjects enrolled in the clinical study, assigning an 
identification code linked to their names, alternative subject identification or contact information.  
 
There are several scenarios in which a subject may exit the trial.  Table 5 below details how the data will 
be handled for each scenario. 
Table5. Trial Exit Scenarios 
Scenario 
Follow-up Required 
e-CRFs Required 
Subject enrolled, but no implant 
attempted (i.e. not taken to the 
procedure room for implantation) 
None 
 
Inclusion/Exclusion e-CRF 
 
Baseline e-CRF (as applicable)  
 
AE e-CRF (as applicable) 
 
Trial Exit e-CRF 
Subject enrolled, implant attempted 
(i.e. taken to the procedure room), 
but the subject does not receive the 
Evolut R TAV 
30 days post-attempted 
implant for safety only 
 
Inclusion/Exclusion e-CRF 
 
Baseline e-CRF (including TTE) 
 
Implant e-CRF 
 
Discharge e-CRF  
 
30 Day e-CRF 
 
AE e-CRF (as applicable) 
 
Trial Exit e-CRF 
Subject enrolled, implanted with 
Evolut R TAV, and has his/her valve 
explanted 
Discharge following explant 
hospitalization or 30 days 
post implant (whichever 
comes later). 
 
All required e-CRFs through last visit 
completed 
 
Surgical Reintervention e-CRF 
 
AE e-CRF (as applicable) 
 
Trial Exit e-CRF 
Subject enrolled, implanted with 
Evolut R TAV, and exits the trial early 
due to any of the following: 
 
Lost to Follow-up 
 
Death 
 
Withdrawal 
Through point of death, 
withdrawal, or last visit 
completed 
 
All required e-CRFs through last visit 
completed 
 
AE e-CRF (as applicable) 
 
Trial Exit e-CRF 
Subject enrolled, implanted and 
completes the trial requirements 
Through 3 year follow-up 
 
All required e-CRFs 
 
AE e-CRF (as appropriate) 
 
Trial Exit e-CRF 
5.5 Role of the sponsor’s representatives 
Representatives from Medtronic may provide technical support during the implant procedures to the 
implanting physicians and study center staff relative to the use of the Evolut R system. This activity will 
be performed under supervision of the Principal Investigator and will not bias the data integrity in any 

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way. The sponsor representatives providing technical support shall be listed on the Sponsor Technical 
Support List. 
5.6 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 study data collection or 
adverse event reporting. 
The e-CRFs may not serve as source documents. Source documentation for data elements not routinely 
captured in medical records (e.g. echocardiography variables, Modified Rankin Score, risk score 
calculators) may vary from center to center: the site may use technical worksheets if identified as source 
documents. Worksheets need to be signed and dated by the Principal Investigator or a delegated 
Investigator. 
Data reported on the e-CRFs should be traceable to source documents. Source documents must be 
available for review by Medtronic personnel and/or applicable regulatory agencies or EC/IRB and will be 
used for verification of the data reported on the e-CRFs and adjudication of AEs. 
Where copies of the original source document as well as print outs of original electronic source 
documents are retained, these shall be signed and dated by a member of the investigation site team with 
a statement that it is a true reproduction of the original source document. 
The Investigator must ensure the availability of source documents from which the information on the e-
CRFs was derived. In addition, the medical records of study subjects should be marked or flagged in such 
a way to indicate their participation in the study. For Investigational sites in Sweden, the investigator 
should also provide a short explanation on the clinical study in the patient medical files. 
5.7 Adverse events and Device Deficiencies 
5.7.1 Definition/classification  
For the purposes of the clinical report, Medtronic will classify each adverse event according to ISO 
14155:2011 (Table 6). 
Where the definition indicates “device”, it refers to any component of the Evolut R system used in the 
study.  
Table 6. Adverse Event Definitions 
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 persons, whether or not 
related to the investigational medical device 
NOTE 1:  This definition includes events related to the investigational medical device or the comparator. 

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NOTE 2:  This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational medical devices. 
Adverse Device Effect (ADE): (ISO14155:2011 3.1) 
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device 
Serious Adverse Event (SAE): (ISO 14155:2011 3.37) 
An adverse event that  
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in  
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or  
4. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect.   
 
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. 
Serious Adverse Device Effect (SADE): (ISO 14155:2011 3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event.   
Unanticipated Serious Adverse Device Effect (USADE): (ISO 14155:2011 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 
 
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: (ISO 14155:2011 3.15) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety 
or performance 
 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labelling. 
An event is not considered an AE if it has been identified as a pre-existing condition, unless there is a 
change in nature, severity or degree of incidence of the event.  
 

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5.7.2 Recording and reporting of Adverse Events 
Investigators are required to report all serious adverse events (SAE) and all VARC 2 Adverse Events (AE) 
regardless of seriousness observed in the study subjects from their point of enrollment until completion 
of follow-up. The list of VARC 2 Adverse Events is provided in table 7. The event definitions and event 
code list can be found in Appendix E and G, respectively. 
Table 7. List of VARC 2 Adverse Events 
Event Type 
All-cause Mortality 
Myocardial Infarction 
Stroke and TIA 
Thrombo-embolic events (eg, stroke) 
Bleeding 
Vascular Access Site and Access-Related Complications 
Acute Kidney Injury 
New and/or worsened conduction disturbances 
Repeat procedure (BAV, TAVI, or SAVR) 
Hospitalizations for valve-related symptoms or worsening congestive heart failure 
TAV iin TAV deployment 
Conversion to open surgery 
Unplanned use of cardiopulmonary bypass (CPB) 
Coronary artery obstruction 
Ventricular septal perforation 
Mitral valve apparatus damage or dysfunction 
Cardiac tamponade 
Prosthetic valve endocarditis 
Prosthetic valve thrombosis 
Valve migration 
Valve embolization 
Ectopic valve deployment 
Stent fracture 
 
The VARC-2 document provides standardization of endpoint definitions for studies evaluating the use of 
TAVI. This study follows VARC-2 to allow for improved comparability and interpretability of study results. 
Due to the nature and regulatory strategy of this study, the scope of Adverse Event reporting in this 
study has been limited to reporting of all SAE’s and all VARC 2 Adverse Events (AE) regardless of 
seriousness. This is a deviation from ISO14155:2011. 
These Adverse Events, documented in the subject’s medical record will be reported to Medtronic on an 
Adverse Event e-CRF as described in this section. 

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For all reportable AEs, investigators should assess and document the following information on the 
Adverse Event e-CRF: 
• 
Date of onset or first observation 
• 
Date site became aware of the event 
• 
AE code number 
• 
Description of the event 
• 
Seriousness of the event 
• 
Causal relationship of the event to the Evolut R™ TAV 
• 
Causal relationship of the event to the Enveo R™ DCS 
• 
Causal relationship of the event to the implant procedure 
• 
Treatment required 
• 
Outcome or status of the event 
Refer to section 5.7.6 for emergency contact details for reporting events and device deficiencies, 
especially for immediate reporting. 
5.7.3 Classification of Causal Relationships 
For each reported AE, the causal relationship between the AE and the trial devices and implant 
procedure will be classified as related, not related or unknown.  The causal relationships are defined in 
table 8. 
The following definitions are intended as guidelines for classifying causal relationships between the 
event and the Evolut R valve, the EnVeo R catheter delivery system and the implant procedure 
 
Table 8. Adverse Event Causal Relationship Definitions 
Related to the Evolut R 
valve 
The event is associated with the Evolut R valve by the chronology and physiology 
and was caused by the Evolut R valve. 
Not related to the Evolut R 
valve 
The event is not related to the Evolut R valve. 
Unknown relation to the 
Evolut R valve 
There is not enough evidence to confirm or deny the relation to the Evolut R valve. 
Related to the EnVeo R 
delivery system 
The event is associated with the EnVeo R delivery system by the chronology and 
physiology and was caused by the EnVeo R delivery system. 
Not related to the EnVeo R 
delivery system 
The event is not related to the EnVeo R delivery system. 
Unknown relation to the 
EnVeo R delivery system 
There is not enough evidence to confirm or deny the relation to the EnVeo R 
delivery system. 
Related to the implant 
procedure1 
The event is associated with the implant procedure by the chronology or physiology 
and was caused by the implant procedure. 
Not related to the implant 
procedure1 
The event is not related to the implant procedure. 
Unknown relation to the 
implant procedure1 
There is not enough evidence to confirm or deny relation to the implant procedure. 
1 Timeframe for assessing implant procedure relationships begin when subject is being prepared for the implant (or re-implant) 
procedure.   

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5.7.4 Recording 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 e-CRF only.   
Device deficiencies that did not lead to an AE should be reported on a Device Deficiency e-CRF (one for 
each device deficiency). 
Device deficiencies that did not lead to an adverse event but might have led to a SADE if a) a suitable 
action had not been taken, or b) an intervention had not been made, or c) circumstances had been less 
fortunate, should be reported to Medtronic immediately of the site’s first learning of the event on a 
Device Deficiency e-CRF (see table 9). 
Refer to section 5.7.6 for emergency contact details for reporting events and device deficiencies, 
especially for immediate reporting. 
5.7.5 Adverse Event and Device Deficiency Reporting Requirement 
Adverse events and device deficiencies that occur during and are recorded in this trial are required to be 
reported to Medtronic via the AE or device deficiency e-CRF, as per the timeframes listed in Table 9 (for 
countries where the device is investigational) and 10 (for countries where the device is commercially 
available) or per local requirements, whichever is more stringent. 
Table 9. Investigator Reporting Requirements to Medtronic in countries where the device is investigational 
Event Type 
Investigator Timeframe for Reporting to Medtronic 
Canada 
Serious Adverse Event (SAE) 
Immediately, but no later than 5 calendar days 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 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Serious Adverse Device Effect 
(SADE) 
Immediately, but within 72 hours of the investigator’s / site’s first 
knowledge of the event 
Unanticipated Adverse Device Effect 
(UADE) 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Unanticipated Serious Adverse 
Device Effect (USADE) 
Immediately, but within 72 hours of the investigator’s / site’s first 
knowledge of the event 
Endpoint Adverse Event (AE) 
No later than 15 calendar days of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency 
Immediately, but within 72 hours of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency that might have 
led to an SADE 
Immediately, but within 72 hours of the investigator’s / site’s first 
knowledge of the event 
Australia 
Serious Adverse Event (SAE) 
Immediately, but within 24 hours  of the investigator’s / site’s first 
knowledge of the event 

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Adverse Device Effect (ADE) or 
Device Related Adverse Event 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Serious Adverse Device Effect 
(SADE) 
Immediately, but within 24 hours  of the investigator’s / site’s first 
knowledge of the event 
Unanticipated Adverse Device Effect 
(UADE) 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Unanticipated Serious Adverse 
Device Effect (USADE) 
Immediately, but within 24 hours  of the investigator’s / site’s first 
knowledge of the event 
Endpoint Adverse Event (AE) 
No later than 15 calendar days of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency 
No later than 15 calendar days of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency that might have 
led to an SADE 
Immediately, but within 24 hours  of the investigator’s / site’s first 
knowledge of the event 
 
Table 10. Investigator Reporting Requirements to Medtronic in countries where the device is commercially 
available 
Event Type 
Investigator Timeframe for Reporting to Medtronic 
Serious Adverse Event (SAE) 
Immediately, but no later than 5 calendar days 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 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Serious Adverse Device Effect (SADE) 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Unanticipated Adverse Device Effect 
(UADE) 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Unanticipated Serious Adverse 
Device Effect (USADE) 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
Endpoint Adverse Event (AE) 
No later than 15 calendar days of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency 
No later than 15 calendar days of the investigator’s / site’s first 
knowledge of the event 
Device Deficiency that might have 
led to an SADE 
Immediately, but no later than 5 calendar days of the investigator’s / 
site’s first knowledge of the event 
 
In addition, Investigators are obligated to report adverse events in accordance with the requirements of 
their reviewing Ethics Board, Regulatory Authority and local regulations. Table 11 provides a list of 
reporting requirements for Australian sites. 
 

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Table 11: Investigator responsibility for adverse event reporting to HREC 
Report 
Submit to 
Description/Constraints 
USADE 
HREC 
The investigator should comply with the applicable regulatory 
requirement(s) related to the reporting of USADE to the HREC. 
(The Australian Clinical Trial Handbook section 4.11.1) 
USADEs 
HREC 
At least six-monthly,  the investigator must provide to HREC responsible 
for trial; 
• listing of all USADEs, Australian and international  
a report which includes sponsor and investigator comment as to whether 
action is planned for the trial  
(NHMRC Safety Monitoring Position Statement May 2009 section 2.3) 
Annual Safety 
Report/ updated IB/ 
approved PI 
HREC 
At least annually, the investigator must provide to HREC responsible for 
trial; 
• an updated Investigator Brochure, or 
• an EU Annual Safety Report (or similar format report), or 
• current, approved Product Information (PI), if appropriate (eg in a 
study for a product approved in Australia or where an Investigator 
Brochure is no longer maintained) 
• other reports consistent with section 5.5.5 of the National Statement1 
and Good Clinical Practice (GCP) as adopted by the Therapeutic Goods 
Administration (TGA) 
(NHMRC Safety Monitoring Position Statement May 2009 section 2.4)  
Death 
Sponsor of 
trial, HREC 
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). 
(The Australian Clinical Trial Handbook section 4.11.3) 
Other information 
in a prompt manner 
HREC 
For each trial, the investigator must also provide:  
• information which materially impacts the continued ethical 
acceptability of the trial or 
• information that requires, or indicates the need for, a change to the 
protocol, including changed safety monitoring in the view of the 
investigator or sponsor 
(NHMRC Safety Monitoring Position Statement May 2009 section 2.2) 
The Sponsor is obligated to report adverse events and device deficiencies that occur during this trial to 
the Regulatory Authorities and Ethics Board as per local requirements. The applicable timeframes are 
described in the Evolut R FORWARD Safety Plan.  
A list of anticipated adverse events that are expected in nature can be found in the Instructions for Use 
of the Evolut R system (and/or IB for Australia). 
 
 

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5.7.6 Emergency Contact for Reporting Events and Device Deficiencies 
Investigators should contact their responsible field monitor if they have any questions regarding 
reportable AE’s and/or Device Deficiencies. Sponsor contact information (including name, title, address, 
and telephone number(s)) is subject to change and will be maintained in a document separate from the 
protocol and provided to sites. 
For Adverse Events or Device Deficiencies that require immediate reporting (see table 9 and 10), initial 
reporting shall be done by completing the appropriate e-CRF. If the e-CRF is not available, the Adverse 
Event or Device Deficiency Form in the Investigator Site File must be completed and submitted to the 
rs.evolutr.emergency@medtronic.com email box and/or to the responsible field monitor (contact 
information is provided in a document separate from the protocol and provided to sites).  In due time, 
the Adverse Event or Device Deficiency needs to be entered in the e-CRF as well. 
5.7.7 Clinical Events Committee 
A Clinical Events Committee (CEC) will provide independent medical review and adjudication of adverse 
event data.  The CEC will adjudicate at least all deaths and safety endpoint events reported by the 
investigators. Further adverse events could be reviewed and adjudicated upon request of the Sponsor. 
The CEC will follow the recommendations of VARC-234 for classifying adverse events that relate to clinical 
safety endpoints 
The CEC members will be free from bias towards the study and will be independent from both the study 
and investigators and Medtronic. The committee will consist of at least 3 independent experts (non-
Medtronic employed physicians) with expertise relevant to the study. This may include experience in the 
areas of: 
• 
Cardiac surgery 
• 
Interventional cardiology 
• 
Neurology 
• 
Electrophysiology 
A CEC charter will be developed and approved by Medtronic.  
5.8 Study deviations and CIP changes 
A study deviation is an event where the investigator or investigation site personnel did not conduct the 
clinical study according to the Clinical Investigation Plan or Clinical Investigation Agreement.  
The investigator is not allowed to deviate from the above mentioned documents except with prior 
approval. All deviations shall be documented and explained, regardless the reason for the deviation. 
Examples of protocol deviations include but are not limited to the following: 
• 
Failure to obtain informed consent (either signed patient Informed Consent or Data Release 
Form) prior to participation 
• 
Incorrect version of the Patient Informed Consent or Patient Data Release Form used 
• 
Failure to obtain EC/IRB approval before the start of the study 
• 
Implanted subject did not meet inclusion/exclusion criteria  

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• 
Follow-up visit not done 
• 
Adverse events not reported in the required time frame as required by regulation or as specified 
in the CIP 
• 
Source data permanently lost 
• 
Enrollment of patients during lapse of EC/IRB approval 
5.8.1 Request for approval of study deviations 
The investigator shall obtain documented approval from Medtronic, before implementation, for any 
change in- or deviation from the Clinical Investigation Plan. In case of study deviations that can affect the 
subject’s rights, safety and well-being or the scientific integrity of the clinical study, approval from the 
EC/IRB and regulatory authority (if applicable) must also be obtained before implementation. The 
investigator shall timely contact the Clinical Study Manager for review of the proposed change/deviation. 
Prior approval is not always realistic in situations where unforeseen circumstances are beyond the 
investigator’s control. However, also in these cases, the event is considered a deviation, and shall be 
reported.  
In any emergency situation the investigator shall exercise his/her judgment to safeguard the subject’s 
interest. Such deviations from the Clinical Investigation Plan do not require the prior approval of 
Medtronic. The investigator shall report the deviation as soon as possible to Medtronic and the 
reviewing EC/IRB, if applicable. Medtronic will inform the regulatory authorities, if required. 
5.8.2 Reporting requirements for study deviations 
Study deviations should be reported to Medtronic via the Study Deviation e-CRF (one e-CRF for each 
protocol deviation).  Relevant information for each deviation will be documented on a deviation form 
completed by site personnel and reviewed by the Investigator. 
Investigators should report the following deviations to Medtronic and their reviewing EC/IRB:  
• 
Failure to obtain written informed consent (either patient Informed Consent or Data Release 
Form) 
• 
Deviations to protect the life or physical well-being of a subject in an emergency 
In addition, Investigators are required to adhere to local EC/IRB 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, in 
accordance with Medtronic SOPs. 
Medtronic will provide investigation site-specific reports to the investigators on a periodic basis 
summarizing information on deviations that occurred at the investigation site. 
 
 

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5.8.3 Amendments to the Clinical Investigation Plan 
The investigator will propose any appropriate modification(s) of the Clinical Investigation Plan or product 
use. Medtronic will review this proposal and decide whether the modification(s) will be implemented.  
Medtronic will submit any significant amendment to the Clinical Investigation Plan, including a 
justification for this amendment, to the appropriate regulatory authorities, EC/IRB’s and to the 
investigators. The investigator will only implement the amendment after approval of the EC/IRB, 
regulatory authority (if applicable) and sponsor. Furthermore investigators shall sign any approved 
amendment for agreement.  

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6 QUALITY CONTROL PROCEDURES 
6.1 Procedures for database management 
6.1.1 Data collection 
This study will utilize an Oracle Clinical Remote Data Capture (RDC) system that is the property of 
Medtronic. Each enrolled subject will be assigned to a unique study ID number, which is pre-configured 
in Oracle Clinical. Records of the subject/subject ID relationship will be maintained by the study site. 
Individual subject medical information obtained as a result of this study will be considered confidential. 
Required data will be recorded on electronic case report forms (e-CRFs) by authorized site personnel as 
indicated on the Delegation Task List (DTL), which can be found in the Investigator Site File.  Study 
personnel delegated for e-CRF 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 e-CRFs 
must be completed and/or updated to reflect the latest observations on the subjects participating in the 
study.  The investigator (or approved sub-investigator) will electronically sign the appropriate pages of 
each e-CRF. 
Data from the core lab will be entered into the Oracle Clinical RDC system by core lab personnel per their 
procedures established for the study. The core lab cardiologist will approve core lab e-CRFs. 
The Oracle Clinical RDC system maintains an audit trail of entries, changes, and corrections in e-CRFs. If a 
person only authorized to complete e-CRFs makes changes to an already signed e-CRF, the investigator 
shall re-approve this e-CRF. 
The investigator must ensure accuracy, completeness, legibility and timeliness of the data reported in 
the e-CRFs and in all other required reports. Data reported on the e-CRFs which are derived from source 
documents must be consistent with the source documents or the discrepancies need to be justified in a 
documented rationale, signed and dated by an Investigator and filed in the patient medical file. 
6.1.2 Time windows for completion and submission of Case Report Forms 
It is the intention to complete the e-CRF no later than 20 working days after the procedure or follow-up 
visit took place, except for e-CRFs documenting AEs or Device Deficiencies that require immediate 
reporting.  
6.1.3 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 study. The study database will employ validation programs (e.g. 
range and logic checks) on entered data to identify possible data entry errors and to facilitate data 
validation.  
 

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6.2 Monitoring procedures 
Monitoring visits will be conducted at the start, during and at the closure of the clinical study in 
accordance with Medtronic SOPs and the Monitoring Plan.  
Periodic monitoring visits will be conducted at the start, during and at the closure of the clinical study. 
Monitoring visits will occur based on implant rate and volume, duration of the study, study compliance 
at each center, and any suspected inconsistency in data that require investigation. At a minimum, there 
will be one visit per year at each investigation site that has enrolled subjects.  
Regulatory documents, Informed Consents or Data Release Forms, Investigator Site File and CRFs will be 
reviewed for each study center. Over time, 100% of the Informed Consent or Data Release forms will be 
reviewed for accurate completion. Moreover, CRF data related to the primary and secondary endpoints 
as well as study-specific adverse events will be verified against the patient’s medical records. 
Site personnel will complete e-CRFs following each subject visit. Study data submitted will be reviewed 
against patient charts and other sources containing original records of patient data. Source document 
verification will occur in accordance to the Monitoring Plan. 
The progress of the study will be monitored by: 
• 
On-site review, as deemed appropriate by Medtronic 
• 
Telephone communications between the site personnel (e.g., investigator, study coordinator) 
and study monitors 
• 
Review of e-CRFs and the associated clinical records 
• 
Review of regulatory documents 
Monitoring and monitoring oversight will be provided by Medtronic. Representatives of Medtronic (i.e. 
contractors and designees) may also act as study monitors.   
6.2.1 Accessibility of investigation site staff and study materials 
The principal investigator(s), his/her delegate(s) and the study coordinator(s) shall be accessible to 
Medtronic field personnel and the Clinical Study Manager. This accessibility is of particular importance 
for reviewing data in the Case Report Form (CRF). Direct access to patient medical files for source data 
verification will need to be granted and prepared prior to any monitoring visits.  
6.2.2 Audits and investigation site inspections  
In addition to regular monitoring visits, Medtronic may conduct audits at participating investigation sites. 
The purpose of an audit is to verify the adequate performance of the clinical study related activities. 
Independent of the employees involved in the clinical study. Regulatory bodies may also perform 
inspections at participating investigation sites. Any regulatory authority inspection announcements shall 
be forwarded immediately to the Clinical Study Manager. 
The investigator and/or institution shall permit Medtronic and regulatory bodies direct access to source 
data and documents, taking into account any restrictions due to local law, to perform clinical study-
related monitoring, audits, EC/IRB review, and regulatory inspections. 

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6.3 Study suspension or early termination 
6.3.1 Early study suspension or termination 
Medtronic or Regulatory Authority may decide to suspend or prematurely terminate the clinical study. If 
the clinical study is terminated prematurely or suspended, Medtronic shall promptly inform the 
investigators and regulatory authorities ( if applicable) of the termination or suspension and the 
reason(s) for this. The investigator shall then promptly inform the reviewing EC/IRB and the study 
subjects.  
6.3.2 Early investigation site suspension or termination 
Medtronic, EC/IRB or Regulatory Authority 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 EC/IRB and the study subjects.  
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definite 
outcomes, investigators must assess whether to continue, modify or immediately stop the clinical study 
in the respective investigation site and immediately inform the sponsor and EC/IRB, if applicable. 
6.3.3 Subject follow-up in case of termination 
In case of early termination, all subjects should be followed by their physicians per their standard 
hospital practice and no further patient data will be collected under this Clinical Investigation Plan. 
6.4 Study close out 
A study closeout visit can be performed either in person or by phone. Study closeout visits may be 
performed to ensure that study data are correctly entered on the e-CRFs and all patients are exited from 
the study. In addition, all open queries should be resolved and closed. During these visits, the monitors 
will also ensure that the Investigator Site File is up to date and complete and that any outstanding action 
items from previous visits have been resolved. 
After study close-out, all patients will be followed accordingly to the hospitals standard of care practices. 
Medtronic and/or its designees will notify the site in writing of the intention to close the study and if 
required will notify/report to EC/IRB and Regulatory Authority. 

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7 PUBLICATION POLICY 
Medtronic is committed to the widespread dissemination of all primary and secondary endpoint results. 
Publications and presentations referring to the Medtronic CoreValve™ Evolut R™ FORWARD Study will be 
coordinated by a Publication Committee to allow the use of all available data. The Publication Committee 
will consist of the Steering Committee and Medtronic representatives.  
Medtronic intends to publish the results of the study in a reputable peer reviewed scientific journal and 
present the data at major congresses. 
Following analysis and presentation of the endpoint results, active participation of all participating 
investigators, CEC 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 study 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. 

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8 STUDY MANAGEMENT 
8.1 Study staff 
A list of sponsor personnel (including, study management, monitors and safety representatives) and their 
contact details will be maintained in the Investigator Site File and provided to the study centers. 
8.2 Advisory committees 
8.2.1 Principal Coordinating Investigators 
Two Principal coordinating Investigators will take responsibility for the scientific validity of the clinical 
investigation plan, assessment of the study quality and conduct as well as for the scientific quality of the 
final study report. The Principal Coordinating Investigators are: 
 
Prof. Eberhard Grube 
MED. Klinik u. Poliklinik II 
Universitätsklinikum Bonn 
53105 Bonn, Germany 
 
 
Prof. Stephan Windecker  
Bern University Hospital 
Department of Invasive Cardiology 
3010 Bern, Switzerland 
8.2.2 Steering Committee 
The Steering Committee will take responsibility for the scientific validity of the clinical investigation plan, 
assessment of the study quality and conduct as well as for the scientific quality of the final study report. 
This committee will meet periodically to monitor patient enrollment, clinical site progress, and protocol 
compliance. A detailed description of their activities can be found in the Steering Committee charter. 
8.2.3 Clinical Events Committee 
A Clinical Event Committee (CEC) will be installed. See section 5.7.7 for more details.  
8.2.4 Publication Committee 
A Publication Committee will review and approve publication of ideas and facilitate submissions, 
including abstracts and manuscripts. The Publication Committee will be responsible for: 
• 
Defining and refining the publication strategy 
• 
Overseeing the development of manuscripts, abstracts, and presentations 
• 
Identifying and appointing the manuscript/abstract first author(s)/writer(s)/presenters(s) 
• 
Reviewing the publication 
See section 7 for more details. 
 

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8.3 Records and reports 
8.3.1 Investigator records 
At a minimum, the following records must be kept by the investigator:  
• 
Clinical Investigation Plan and, if applicable, any amendments 
• 
Instructions for Use (and/or IB for Australia)) 
• 
EC notification, approval and correspondence, and EC voting list  
• 
Medtronic and EC/IRB approved Patient Informed Consent or Patient Data Release Form 
• 
Regulatory Authority approval or notification if applicable 
• 
Fully signed Clinical Investigation Agreement and confidentiality agreement (if not included in 
the Clinical Investigation Agreement) 
• 
Insurance certificates, where applicable 
• 
Completed Delegated Task List and Curriculum Vitae of all investigation site personnel 
• 
Training documentation of all investigation site personnel 
• 
Relevant communications 
• 
Subject screening log, enrollment log and/or subject identification log  
• 
Signed, dated and fully executed Patient Informed Consent or Patient Data Release Form. 
• 
Medical records of each enrolled subject, including, for example, progress notes of the 
physicians, the subject’s hospital chart(s) and the nurses’ notes 
• 
All adverse event/device deficiency information 
• 
Device accountability Records (for Australia and Canada only) 
• 
Financial Disclosure Information, if requested by the local EC/IRB or regulatory authority 
8.3.2 Investigator reporting responsibilities 
Table 12. Investigator reporting responsibilities 
Report 
Submitted to 
Description 
Adverse Events 
Sponsor, EC/IRB, and 
local regulatory 
authority, where 
applicable 
Refer to section 5.7 for reporting requirements. 
Withdrawal of EC/IRB 
approval 
Sponsor 
Investigator must inform Medtronic in case 
EC/IRB approval is withdrawn within 5 working 
days. 
Final Clinical Study 
Report 
EC/IRB 
A copy of the Final Clinical Study Report will be 
provided to the EC/IRB. 
 
 
 
 
 

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Report 
Submitted to 
Description 
Deviations from Investigational Plan 
Planned deviation 
Sponsor, EC/IRB 
Prior approval from Medtronic must always be 
obtained. If the deviation affects scientific 
soundness of the clinical study or the rights, 
safety, or welfare of the subject and is not an 
emergency, prior approval must be obtained 
from the reviewing EC/IRB if required. 
Other Deviations 
Sponsor 
Deviations that are beyond the control of the 
investigator (such as subject who fails to return 
to follow-up visit) or deviations that do not affect 
the scientific soundness of the clinical study or 
the rights, safety, or welfare of the subject and 
are not an emergency, should be submitted as 
they are identified by the investigation site or 
Medtronic staff. 
 
8.3.3 Sponsor records 
At a minimum, the sponsor will keep the following records: 
• 
All essential study documents and correspondence that pertains to the clinical study 
• 
CIP and, if applicable, any amendments 
• 
Instructions for Use (and/or IB for Australia) 
• 
Curriculum Vitae of investigators and investigation site personnel 
• 
Delegated Task Lists and training records of investigators and investigation site personnel 
• 
EC/IRB approvals/notifications  
• 
Signed Clinical Investigation Agreements and signed agreements with third parties 
• 
Insurance certificates 
• 
Medtronic and EC/IRC approved Patient Informed Consent or Patient Data Release Form 
• 
Site selection reports, site initiation reports and monitoring visit letters and reports 
• 
Adverse event and Device Deficiency reports 
• 
Fully executed e-CRFs and corrections 
• 
Regulatory Authority approval or notification if applicable 
• 
Financial Disclosure Information, if requested by the local EC/IRB or regulatory authority 
• 
Shipping records for investigational devices and clinical-investigation related documents and 
materials 
• 
Sample of labeling attached to the investigational device 
 
 
 
 
 

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8.3.4 Sponsor reporting responsibilities 
Table 13. Sponsor reporting responsibilities 
Report 
Submit to 
Description 
Adverse Events 
EC/IRB, 
Investigators, and 
regulatory 
authorities, where 
applicable 
Medtronic will report adverse events as 
required and in compliance with local 
regulatory requirements, as applicable. 
Withdrawal of EC/IRB 
approval 
EC/IRB, 
Investigators, and 
regulatory 
authorities, where 
applicable 
In case of withdrawal of EC/IRB approval 
Medtronic will suspend the clinical study as 
described below. 
Premature termination or 
suspension of study 
EC/IRB, 
Investigators, and 
regulatory 
authorities, where 
applicable 
Medtronic will provide prompt written 
notification of termination or suspension 
and reason(s) to investigator and where 
required to EC/IRB and regulatory 
authorities. 
Emergency Deviations from 
Investigational Plan 
Regulatory 
authorities, where 
applicable 
If required, Medtronic will inform regulatory 
authorities as soon as possible about any 
emergency deviations that affect scientific 
soundness of the clinical study or the rights, 
safety, or welfare of the subject. 
Final Report 
Investigators, and 
regulatory 
authorities, where 
applicable 
Medtronic will provide all investigators with 
a copy of the Final Clinical Study Report of 
the clinical study.  
EC/IRBs and regulatory authorities will be 
informed when required. 
8.3.5 Record retention and inspection 
Medtronic records and reports will be stored at Medtronic during the course of the study. After the 
closure of the study, all records and reports will be archived by Medtronic permanently. 
The investigator must be willing to give access to study monitors, auditors, MEC/IRB members and 
inspectors, and have appropriate facilities to retain relevant study documents. 
The investigator must retain the Investigator Site File, patient data sources and e-CRFs for a minimum of 
two years after study closure or longer if required by local law and regulations. 
The investigator and sponsor must take measures to prevent accidental or early destruction of the study 
related materials.  
 
 

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8.4 Miscellaneous 
8.4.1 Insurance 
The global sponsor Medtronic Plc., and the local sponsors: Medtronic Bakken Research Center BV, 
Medtronic of Canada Ltd. and Medtronic Australasia, maintain appropriate clinical study liability 
insurance coverage if required under applicable laws and regulations and will comply with applicable law 
and custom concerning specific insurance coverage.   
8.4.2 Study reimbursement and indemnification 
Study reimbursement is outlined in the Clinical Study Agreement. Indemnification will be done according 
to local laws. 
8.4.3 Subject confidentiality 
All information and data sent to parties involved in study conduct concerning patients or their 
participation in this study will be considered confidential.  Each enrolled subject will be assigned to a 
unique study ID number, which is pre-configured in Oracle Clinical.  Records of the subject/study ID 
number relationship will be maintained by the study center.  The study ID number is to be recorded on 
all study 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 study document 
other than the Patient Informed Consent or Patient Data Release Form.  In the event a subject’s name is 
included for any reason, it will be blinded as applicable.  In the event of inability to blind the 
identification (e.g., digital media), it will be handled in a confidential manner by the authorized 
personnel. 
Confidentiality of data will be observed by all parties involved at all times throughout the clinical 
investigation.  All data shall be secured against unauthorized access.  The privacy of each subject and 
confidentiality of his/her information shall be preserved in reports and when publishing any data. 
 
 

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9 RISKS AND BENEFITS 
9.1 Anticipated Clinical Benefits 
Participation in this clinical study will not result in any direct benefit to the patient. Trial subjects 
implanted with an Evolut R TAV receive the same medical treatment as if they were not participating in 
this post-market study. Participation contributes to expansion the knowledge base with respect to the 
use of the Evolut R system in a routine hospital setting.  
9.2 Risks 
There are possible risks and side effects connected to the Evolut R TAV implant but the risks are similar 
to those for an implant of the Evolut R TAV without participation in this study.  
Risks and events will be continuously monitored, assessed and documented by the investigator. Refer to 
the Instructions for Use (and/or IB for Australia) for the list of anticipated adverse events which may be 
associated with the use of the Evolut R System. 
9.3 Risk-to-benefit rationale 
Appropriate risk management activities have been performed for the Evolut R System resulting in a 
positive risk-to-benefit rationale as confirmed by CE mark. Risks and potential benefits are similar for 
subjects being implanted as part of this study protocol compared to subjects implanted while not 
participating in this study. 

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10 APPENDICES 
 
APPENDIX A. ABBREVIATIONS 
APPENDIX B. RECOMMENDED ECHOCARDIOGRAPHY PROCEDURES 
APPENDIX C. RECOMMENDED MSCT PROCEDURES  
APPENDIX D. DEFINITIONS: RISK SCORES AND OTHER CO-MORBIDITIES 
APPENDIX E. DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS 
APPENDIX F. RESHEATH AND RECAPTURE DEFINITIONS 
APPENDIX G. EVENT CODE LIST 
 
The following information will be kept separate from the CIP and independently provided to the 
investigators. The sponsor will maintain updated lists. 
- List of names and addresses of the investigation sites in which the clinical study will be 
conducted 
- Initial list of names, addresses, and professional positions of clinical investigators, principal 
clinical investigators and coordinating clinical investigators 
- List of names and addresses of other institutions involved in the clinical study 
- Case Report Forms. CRFs shall be developed to capture the data for each enrolled subject as 
required by the CIP. The CRFs shall include information on the condition of each subject upon 
entering, and during the course of, the clinical study, exposure to the investigational 
device/product and any other therapies 
- 
Instructions For Use 
- 
Investigators Brochure

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APPENDIX A. ABBREVIATIONS 
Abbreviation 
Term 
2D 
Two Dimensional 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
AF 
Atrial Fibrillation 
AR 
Aortic Regurgitation 
AS 
Aortic Stenosis 
AVR 
Aortic Valve Replacement 
BAV 
Balloon Aortic Valvuloplasty 
CE 
European Conformity 
CEC 
Clinical Events Committee 
CIP 
Clinical Investigation Plan 
CLS 
Compression Loading System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CVA 
Cerebrovascular Accident 
DCS 
Delivery Catheter System 
ECG 
Electrocardiogram 
e-CRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
EuroSCORE 
European System for Cardiac Operative Risk Evaluation 
Fr 
French 
GCP 
Good Clinical Practice 
HVD 
Heart Valve Dysfunction 
HR 
Heart Rate 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IRB/EC 
Institutional Review Board/Ethics Committee  
IFU 
Instructions for use 
ITT 
Intent-to-treat 
LA 
Left Atrial/Atrium 
LBBB 
Left Bundle Branch Block 

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Abbreviation 
Term 
LVEF 
Left Ventricular Ejection Fraction 
LVOT 
Left Ventricular Outflow Tract 
MACCE 
Major Adverse Cardiovascular and Cerebrovascular Event 
MCS 
Medtronic CoreValve® System 
MEC 
Medical Ethics Committee 
MI 
Myocardial Infarction 
mRS 
Modified Rankin Score 
NYHA 
New York Heart Association 
PAV 
Percutaneous Aortic Valve 
PCI 
Percutaneous Coronary Intervention 
TAVI 
Transcatheter aortic valve implant 
QoL 
Quality of Life 
RBBB 
Right Bundle Branch Block 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAVR 
Surgical Aortic Valve Replacement 
SOP 
Standard Operating Procedures 
STS 
Society of Thoracic Surgeons 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiography 
U(S)ADE 
Unanticipated (Serious) Adverse Device Effect 

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APPENDIX B. RECOMMENDED ECHOCARDIOGRAPHY PROCEDURES 
B.1 
Required Exams 
Transthoracic echocardiography is required at the following intervals: 
Interval 
Time Window 
Baseline (Pre-implant) 
Within 10 weeks prior to index procedure 
Device Success 
Between 24 hours and 7 days post-procedure 
1 year 
Between 365 and 395 days post procedure 
 
B.2 
General Imaging and Recording Procedures 
• 
A list of recommended images is provided in Section B.3, 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 (e.g. 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. Note: This may be done only after the subject has provided Informed Consent by 
signing the Patient Informed Consent or Data Release Form!  
• 
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 should be DICOM files in a true or pure DICOM format. 
• 
The following information should be documented on CD-R disks sent to the Echo Core Lab: 
- Study site ID number 
- Subject ID number 
- Exam date 
- Study interval 
 
 
 
 
 

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B.3 
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 (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. 2D grayscale-guided M-mode at LV minor axis (LV dimensions, avoid papillary muscles) 
11. Frozen image of measured LV dimensions (without measurements) 
12. Frozen image of LV m-mode with measurements 
13. 2D grayscale LV at apical level 
14. 2D grayscale aortic valve level (post TAVI the native annulus is usually identified by maximal calcification) 
15. 2D grayscale-guided M-mode of left atrial & aortic dimensions  
16. 2D color Doppler of AR: post-TAVI 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 
17. 2D grayscale ZOOM & focused on RV outflow tract (RVOT) – pulmonic valve should be visible 
18. Frozen image of measured RVOT diameter 
19. PW Doppler of RVOT velocity (within 0.5 -1 cm below the pulmonic valve) (frozen image without 
measurements) 
20. Frozen image of RVOT velocity with measured VTI 
Parasternal long-axis view (RV inflow) 
21. 2D color Doppler of tricuspid regurgitation (TR) 
22. If TR is present, CW Doppler of TR jet (frozen image without measurements) 
23. Frozen image of TR jet velocity with measurements 
Apical 4-Chamber window 
24. 2D grayscale standard view  
25. 2D color Doppler of MR  
26. If MR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
27. If MR is present, CW Doppler of MR jet (frozen image) 
28. 2D color Doppler of TR 
29. If TR is present, CW Doppler of TR jet (frozen image without measurement) 
30. Frozen image of TR jet velocity with measurements 
31. 2D grayscale focussed on LV with decreased depth 
32. PW Doppler of transmitral flow at mitral valve tips (frozen image) 
33. Tissue Doppler of the septal mitral annulus (frozen image) 

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

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B.4 
Acquisition of Key Variables 
B.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 4A and B).37,38 
Following implantation of the Evolut R, LVOT diameter is measured from the parasternal long-axis view, 
immediately proximal to the inflow aspect of the stent, and in mid systole (Figure 4C and D).37,38 ,39 
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-
implantation, LVOT diameter measurement is from outer edge to outer edge of the inflow aspect of the 
stent. 
 

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B.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”). 
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 5A).37   The 
recommended procedure is to initially place the sample volume within the aortic valve leaflets, and then 
gradually move it apically until a clear spectral waveform is observed with a well-defined peak and 
minimal spectral broadening (Figure 5B).34 
Post implantation, the sample volume should be placed proximal to the inflow aspect of the stent.40  Full-
screen imaging of the Evolut R should be used to verify positioning of the sample volume below the stent 
before switching to spectral Doppler mode (Figure 5C and D). 40,41 
The LVOT VTI is measured by tracing the modal velocity (middle of the dense signal) for use in the 
continuity equation.37 

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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 stent; (D) Full-screen imaging of stent to ensure positioning of sample volume 
below the stent. 
B.4.3 Aortic Valve Velocities 
The 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 (Figure6).37 

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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. 
B.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 just below 
the skirt and frame to assess paravalvular regurgitation, and at the coaptation point of the leaflets for 
transvalvular (central) regurgitation.42 
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.  In addition, the right ventricular outflow tract diameter (RVOT) and RVOT 
velocity time integral (VTI) should be measured to allow derivation of regurgitant volume and fraction. 
The degree of transvalvular, paravalvular, and total (transvalvular plus paravalvular) AR will be graded as 
none, trace, mild, moderate, and severe based on the synthesis of the Doppler parameters shown in 
Table 14.36,37   The category of “trace” should be used in cases where regurgitation is barely detectable by 
color Doppler.36  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 14. Parameters for evaluation of the severity of aortic regurgitation 
Parameter 
Mild 
Moderate 
Severe 
Jet width in central jets (% LVOT diameter): 
color1 
Narrow (≤25%) 
Intermediate 
(26% - 64%) 
Large (≥65%) 
Jet density: CW Doppler 
Incomplete or faint 
Dense 
Dense 
Jet deceleration rate (PHT, ms): CW Doppler2 
Slow (>500) 
Variable (200 – 500) 
Steep (<200) 
LVOT flow vs pulmonary flow: PW Doppler 
Slightly increased 
Intermediate 
Greatly increased 
Diastolic flow reversal in descending aorta: 
PW 
Absent or brief early 
diastolic 
Intermediate 
Prominent, 
holodiastolic 
Circumferential extent of prosthetic 
paravalvular regurgitation (%) 
<10 
10 – 19 
≥20 
Quantitative Parameters 
   Regurgitant volume (ml/beat) 
<30 
30 – 59 
≥60 
   Regurgitant fraction (%) 
<30 
30 – 49 
≥50 
PHT = pressure half-time 
B.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 15.43 
Table 15. 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 
B.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. 

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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 16.43  
Table 16. 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 
B.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 7).  Left ventricular 
chamber dimensions, septal thickness, and posterior wall thickness are measured using the American 
Society of Echocardiography (ASE) measurement convention44 (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 7. Measurements of the left ventricle (A) and left atrium (B) using 2-D guided m-mode 
B.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 
A 
B 

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Figure 8).  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: 
x
Mitral inflow “A” velocity 
x
Mitral inflow “E” velocity 
x
Mitral inflow E-wave deceleration time 
 
 
 
Figure 8. 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: 
ͻ 
Mitral annular tissue Doppler systolic velocity (septal and lateral) 
ͻ 
Mitral annular tissue Doppler early diastolic velocity (septal and lateral) 
ͻ 
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.45 
 
 

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B.5 
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 study. Qualitative assessment of valvular regurgitation will be performed using the 
criteria described in Sections B.4.4 through B.4.6. 
The Echo Core Lab will report the following variables: 
• 
Heart rate 
• 
Aortic annulus diameter (pre-implant only) 
• 
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 
• 
Right ventricular outflow tract (RVOT) diameter(post-implant; if aortic regurgitation > mild by visual 
estimate) 
• 
RVOT VTI (post-implant; if aortic regurgitation > mild by visual estimate) 
• 
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 by the Echo Core Lab: 
• 
Peak Pressure Gradient (Peak ∆ P) Across the Aortic Valve in mmHg 
Peak ∆ P = 4 x (V2
2) 
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 
 

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• 
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 m2viii 
• 
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 
• 
LVOT/aortic valve velocity time integral ratio (Velocity Ratio) 
Velocity Ratio = 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 
• 
Fractional Shortening (FS) in % 
FS = [(LVIDD - LVIDS)/LVIDD] x 100 
Where: LVIDD is left ventricular internal dimension at end diastole in cm, and LVIDS is left ventricular internal 
dimension at end systole in cm  
• 
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 
• 
Aortic Regurgitant Volume (RV) in ml/beat 
RV = SVLVOT – SVRVOT 
Where: SVLVOT = LVOT diameter2 x 0.785 x LVOT VTI, and SVRVOT = RVOT diameter2 x 0.785 x RVOTVTI 
• 
Aortic Regurgitant Fraction (RF) in % 
RF = RV/SVLVOT 
• 
Body Surface Area (BSA) in m2 
BSA = 0.007184 x (height in cm0.725 x weight in kg0.425) 
                                                          
 
viii BSA derived from height and weight reported on the site e-CRF 

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APPENDIX C. RECOMMENDED MSCT PROCEDURES 
C.1 
Introduction 
Multi-slice Computed Tomography (Cardiac MSCT) 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 recommended guidelines for acquiring the images for assessing 
anatomical suitability for implantation. 
C.2 
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) 
C.3 
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 17. 
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). 
C.4 
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 17. Recommended scan parameters 
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. 
 
C.5 
Required Aortic Root Measurements 
The following measurements of the aortic root are obtained for assessing anatomical suitability: 
• 
Aortic valve annulus perimeter (measured at systole if retrospective gating is used) 
• 
Mean sinus of Valsalva diameter (measured at diastole) 
• 
Mean sinus of Valsalva heights (measured at diastole) 
 
C.6 
Reformatting of Images46 
• 
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 9, upper left panel). 
• 
In the sagittal window, the horizontal line is rotated clockwise or counter-clockwise to align with 
virtual basal plane (Figure 9, 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 10).  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. 

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• 
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 9. 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 10. 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). 
C.7 
Aortic Annulus Measurements 
• 
Choose the cleanest systolic images for the aortic annulus measurements, either automatically (e.g., 
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 C.6, Reformatting of Images. 
• 
Trace the perimeter of the basal annulus (Figure 11, 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 11, right). 
 
Figure 11. Example of perimeter measurement (left) and major and minor diameter measurements (right). 
Oblique 
Coronal 
Oblique 
Sagittal 
Double-oblique axial 

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C.8 
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 C.6, Reformatting of Images. 
C.8.1 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 12).  
 
Figure 12. Example of sinus of Valsalva diameters 
 
C.8.2 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 13). 

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Figure 13. Examples of sinus of Valsalva heights; (A) left coronary; (B) non coronary; (C) right coronary 
 
C.9 
Anatomic Suitability and Valve Size Selection 
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 
шϮϱ 
шϭϱ 
26 mm 
62.8 – 72.3 
20 – 23 
шϮϳ 
шϭϱ 
29 mm 
72.3 – 81.6 
23 – 26 
шϮϵ 
шϭϱ 
 

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APPENDIX D. DEFINITIONS: RISK SCORES AND OTHER CO-MORBIDITIES 
D.1 
Risk Scores 
The Logistic EuroSCORE, EuroSCORE II and Society of Thoracic Surgeons’ (STS) risk scores should be 
calculated at baseline for each subject using the online calculator:  
• 
Logistic EuroSCORE: http://euroscore.org/calcold.html 
• 
EuroSCORE II: http://euroscore.org/calc.html 
• 
STS Risk Score: http://riskcalc.sts.org/stswebriskcalc/#/ 
The online calculators provide additional guidance and definitions for each of the parameters used to 
calculate the scores. For the Logistic EuroSCORE and EuroSCORE II, the definitions for each of the 
parameters can be found as notes under the online calculator. The variable definitions for the STS risk 
score model can be accessed by clicking on the field names in the online calculator.  
 
D.2 Other Factors Not Captured by Traditional Risk Score32 
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 (e.g. 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 
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 

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midline and/or adherent 
to posterior table of 
sternum  
 
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 (e.g. TAPSE <15mm, RV end-systolic area >20 
cm2, etc) 
 

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APPENDIX E. DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS 
Definitions of adverse events to be evaluated as clinical safety endpoints, other TAVI-related 
complications, and efficacy events are provided in Sections E.1, E.2, and E.3, respectively.  Site 
investigators and the CEC will code events according to these definitions, using the associated code list 
provided in appendix G, Event Code List. 
E.1 
Safety Endpoint Definitions32 
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). 
 
Myocardial Infarction 
Periprocedural MI 
(≤72 h after the 
index procedure) 
New ischemic symptoms (e.g, chest pain or shortness of breath), or new ischemic signs 
(e.g, 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 

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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  
 
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 (e.g. brain tumor, trauma, 
infection, hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in 
conjunction with the designated 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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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% 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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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 VARC bleeding definitions 
VALVE DYSFUNCTION REQUIRING REPEAT PROCEDURE 
Any valve dysfunction that requires repeat procedure (e.g. balloon valvuloplasty, TAVI, or surgical AVR) 
Note: Repeat procedures are reported on the appropriate e-CRF (Surgical Intervention or Catheter Reintervention) 
 
 
 
 
 

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E.2 
Other TAVI Related Complications 
Complication 
Definition 
Conversion to open surgery 
Conversion to open sternotomy during the TAVI 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 Evolut R prosthesis itself, the 
native leaflets, calcifications, or dissection, occurring during or after the TAVI 
procedure. 
Ventricular septal perforation 
Angiographic or echocardiographic evidence of a new septal perforation 
during or after the TAVI 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 (e.g. 
restrictions due to the Evolut R) of the mitral valve during or after the TAVI 
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 Evolut R within the aortic annulus from its initial position, 
with or without consequences. 
Valve embolization 
The Evolut R moves during or after deployment such that it loses contact 
within the aortic annulus 
Ectopic valve deployment 
Permanent deployment of the Evolut R in a location other than the aortic 
root 
TAV in TAV deployment 
Additional valve prosthesis is implanted within a previously implanted Evolut 
R because of sub-optimal device position and/or function, during or after the 
index procedure. 
Hemolysis 
Red cell destruction as evidenced by plasma free hemoglobin >50 mg/dl 
Minor hemolysis: No intervention required 
Major hemolysis: Requires intervention (e.g. 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 (e.g. reoperation, catheter re-
intervention) or is associated with prosthetic valve dysfunction 
 

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PROSTHETIC VALVE ENDOCARDITIS 
Any of the following: 
1) Fulfillment of the following Duke criteria47 for definite endocarditis: 
• 
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 Evolut R at autopsy 
 

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E.3 
Efficacy Event Definitions32 
PROSTHETIC VALVE DYSFUNCTION 
Stenosis: mild 
For subjects with BSA ≥ 1.6 m2:  Mean aortic gradient ≥ 20 and ≤40 
mmHg, EOA ≥ 0.8 and ≤ 1.1 cm2 AND/OR DVI ≥ 0.25 and ≤ 0.35 
For subjects with BSA < 1.6 m2:  Mean aortic gradient ≥ 20 and ≤40 
mmHg, EOA ≥ 0.6 cm2 and ≤ 0.9 cm2 AND/OR DVI ≥ 0.25 and ≤ 0.35 
Stenosis: moderate/severe 
For subjects with BSA ≥ 1.6 m2:  Mean aortic gradient > 40 mmHg, EOA 
< 0.8 cm2 AND/OR DVI < 0.25 
For subjects with BSA < 1.6 m2:  Mean aortic gradient > 40 mmHg, EOA 
< 0.6 cm2 AND/OR DVI < 0.25 
Paravalvular regurgitation: moderate 
Moderate paravalvular regurgitation (per echo criteria in CIP) 
Paravalvular regurgitation: severe 
Severe paravalvular regurgitation (per echo criteria in CIP) 
Transvalvular regurgitation: moderate 
Moderate paravalvular regurgitation (per echo criteria in CIP 
Transvalvular regurgitation: severe 
Moderate or severe transvalvular regurgitation (per echo criteria in CIP) 
Notes: 
 
1. 
DVI = Doppler Velocity Index (LVOT VTI/valve VTI) 
2. 
For subjects LVOT diameter > 2.5 cm, the DVI criteria for significant (moderate or severe) stenosis is 0.2 
3. 
Reporting of prosthetic valve dysfunction will be based on core lab values (if available). 
4. 
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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APPENDIX F. RESHEATH AND RECAPTURE DEFINITIONS 
The following definitions are applicable to the data elements on the Implant e-CRF that address the use 
of the resheath and recapture feature. 
Resheath attempt 
An attempt to intentionally resheath only a portion of the Evolut R TAV 
(including the frame) into the capsule of the delivery catheter (e.g. with the 
intent to reposition of the valve during deployment). 
Recapture attempt 
An attempt to intentionally fully resheath the entire Evolut R TAV (including the 
frame) into the capsule of the delivery catheter until there is no gap between 
capsule and the tip (e.g. with the intent to enable re-crossing of the aortic valve 
or retrieval of the system). 
Point of no return 
The point at which the capsule marker is aligned with the distal aspect of the 
spindle (Figure 14C). 
Valve functionality
Functional valve performance is defined as the presence of stable systemic 
ƉƌĞƐƐƵƌĞ;ĂƉƉƌŽǆŝŵĂƚĞůǇхϴϬйŽĨƉƌĞ-implant mean arterial pressure). 
Successful resheath attempt 
Successful resheathing is defined as Evolut R TAV (including frame) was 
resheathed into the capsule of the delivery catheter to the desired amount 
intended, as verified by fluoroscopy.  
Successful full recapture 
attempt 
The entire Evolut R TAV (including the frame) is fully resheathed into the 
capsule of the delivery catheter until there is no gap between the capsule and 
the tip, as verified by fluoroscopy. 
 
Figure 14. (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

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APPENDIX G. 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 bleeding 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 TAVI-Related Complications 
150 
Conversion to open surgery 
151 
Unplanned use of CPB 
152 
Coronary artery obstruction 
153 
Ventricular septal perforation 
154 
Mitral valve apparatus damage or dysfunction 
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 TAVI-related complication 
 
Conduction Disturbances and Arrhythmias 
170 
Atrio-ventricular block, 1° 
171 
Atrio-ventricular block, 2° 
172 
Atria-ventricular block, 3° 

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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 
190 
Mild stenosis 
191 
Moderate/severe stenosis 
192 
Moderate paravalvular regurgitation 
193 
Severe paravalvular regurgitation 
194 
Moderate transvalvular regurgitation 
195 
Severe transvalvular regurgitation 
 
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 
 
 

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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 (≥ 39.0°C) 
802 
Sepsis, confirmed (positive blood culture) 
803 
Sepsis, suspected (by clinical findings) 
804 
Endocarditis, other than Evolut R 
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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