VANTAGE Clinical Trial Evaluation of TAVR Using the NAVITOR Valve in a Global Investigation
Phase: NA
Conditions: Symptomatic Severe Aortic Stenosis
Sponsor: Abbott Medical Devices

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NCT Number: NCT04788888 
VANTAGE 
Evaluation of TAVI Using the NAVITOR Valve in a Global Investigation 
Study Document No: ABT-CIP-10342 
Version C 
Date: 26-JUL-2024 
 
 
 
Sponsor 
 
Abbott 
5050 Nathan Lane N  
Plymouth, MN 55442 
USA 
 
European Sponsor: 
St Jude Medical Coordination Center BV 
Da Vincilaan 11 Box F1 
1935 Zaventem 
Belgium  
 
 

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ABT-CIP-10342 
CRD_1003 
 
VANTAGE Clinical Trial 
(Evaluation of TAVI Using the NAVITOR Valve in a Global Investigation)  
 
 
CIP Name 
VANTAGE 
EU Unique Study ID Number 
CIV-21-04-036306 
Study Principal Investigators 
Nicolas van Mieghem, M.D., Ph.D.  
Erasmus University Medical Center  
Rotterdam, Netherlands 
Stephen Worthley, M.D., Ph.D.  
Macquarie University Hospital  
Sydney, Australia 
Planned Number of Sites and 
Regions 
Up to 40 sites in Australia, Europe, and Israel 
Clinical Investigation Type 
Prospective, single-arm, multi-center, international, pre-market 
clinical trial 
Abbott Medical Expert 
Nadim Geloo, M.D. 
Sr. Medical Director, Abbott Structural Heart 
 
Sponsor 
 
Abbott 
5050 Nathan Lane N  
Plymouth, MN 55442 
USA 
 
European Sponsor: 
St Jude Medical Coordination Center BV 
Da Vincilaan 11 Box F1 
1935 Zaventem 
Belgium 
Electronic Data Capture 
Software 
Oracle Clinical 
Core Laboratories 
Echocardiographic Core Laboratory: 
Medstar Health Research Institute 
100 Irving Street, NW Suite 5123 
Washington, DC 20010 
USA 
 
Computed Tomography Core Laboratory: 
University of British Columbia 
St. Paul’s Hospital, Department of Radiology 
1081 Burrard St. 
Vancouver, BC B6Z1Y6 
Canada  

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Clinical Events Committee 
Administration 
Abbott Global Clinical Safety 
6820 Wedgwood Road. N. 
Maple Grove, MN 55311 
USA 
Data Monitoring Committee 
Administration 
Axio 
2601 4th Avenue, Suite 200 
Seattle, WA 98121 
USA 
CIP Author of Current Version  
Lihua Li, M.D., Ph.D. 
Principal Clinical Scientist 
Abbott Structural Heart 

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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 

ABT-CIP-10342 Ver. C 
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STUDY PRINCIPAL INVESTIGATOR  
SIGNATURE PAGE 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
Study Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 

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TABLE OF CONTENTS 
 
1.0  INTRODUCTION ............................................................................................................................... 12 
1.1 
Background and Rationale ......................................................................................................... 12 
1.1.1 
Background ...................................................................................................................... 12 
1.1.2 
Rationale for Conducting this Clinical Investigation ......................................................... 15 
2.0 
CLINICAL INVESTIGATION OVERVIEW ...................................................................................... 15 
2.1 
Clinical Investigation Objective ................................................................................................... 15 
2.2 
Devices To Be Used in the Clinical Investigation ....................................................................... 16 
2.2.1 
Name of the Devices Under Investigation ........................................................................ 16 
2.2.2 
Intended Indication for Use .............................................................................................. 17 
2.2.3 
Description of the Devices Under Investigation ............................................................... 17 
2.2.3.1 
Navitor Valve .............................................................................................................. 17 
2.2.3.2 
FlexNav Delivery System ........................................................................................... 19 
2.2.3.3 
Navitor Loading System ............................................................................................ 21 
2.2.4 
Summary of Preclinical Studies ....................................................................................... 21 
2.2.5 
Device Handling ............................................................................................................... 21 
3.0 
CLINICAL INVESTIGATION DESIGN ............................................................................................ 21 
3.1 
Clinical Investigation Procedures and Follow-up Schedule ........................................................ 22 
4.0 
ENDPOINTS .................................................................................................................................. 24 
4.1 
Primary Endpoints and Rationale ............................................................................................... 24 
4.2 
Secondary Endpoints.................................................................................................................. 24 
4.3 
Descriptive Endpoints ................................................................................................................. 24 
5.0 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................... 26 
5.1 
Subject Population ...................................................................................................................... 26 
5.1.1 
Intermediate Surgical Risk Classification ......................................................................... 26 
5.1.2 
Low Surgical Risk Classification ...................................................................................... 26 
5.2 
Subject Screening and Informed Consent .................................................................................. 26 
5.2.1 
Subject Pre-Screening ..................................................................................................... 26 
5.2.2 
Informed Consent ............................................................................................................ 27 
5.2.2.1 
Special Circumstances for Informed Consent ........................................................ 27 
5.2.3 
Subject Screening ............................................................................................................ 28 
5.3 
Eligibility Criteria ......................................................................................................................... 29 
5.3.1 
General Eligibility Criteria ................................................................................................. 29 

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5.3.2 
Inclusion Criteria .............................................................................................................. 29 
5.3.2.1 
General Inclusion Criteria .......................................................................................... 29 
5.3.2.2 
Imaging Inclusion Criteria ......................................................................................... 29 
5.3.3 
Exclusion Criteria ............................................................................................................. 30 
5.3.3.1 
General Exclusion Criteria ........................................................................................ 30 
5.3.3.2 
Imaging Exclusion Criteria ........................................................................................ 31 
5.4 
Subject Enrollment, Subject Registration, and Study Cohorts .................................................... 32 
5.4.1 
Roll-in Cohort ................................................................................................................... 33 
5.4.2 
Primary Analysis Cohort .................................................................................................. 33 
5.4.3 
Valve-in-Valve (ViV) Cohort ............................................................................................. 33 
5.5 
Subject Discontinuation .............................................................................................................. 34 
5.6 
Number of Subjects .................................................................................................................... 35 
5.7 
Total Expected Duration of the Clinical Investigation ................................................................. 35 
6.0 
TREATMENT AND EVALUATION OF ENDPOINTS ..................................................................... 35 
6.1 
Baseline ...................................................................................................................................... 36 
6.1.1 
Baseline Assessments ..................................................................................................... 36 
6.1.2 
Pre-procedure Antiplatelet/Anticoagulation Medications ................................................. 36 
6.1.3 
Pre-procedure Blood Tests .............................................................................................. 36 
6.2 
Index Procedure ......................................................................................................................... 36 
6.2.1 
Procedures Involved in the Use of the Device Under Investigation ................................. 36 
6.2.2 
Procedural Anticoagulation .............................................................................................. 36 
6.2.3 
Implant Procedure............................................................................................................ 37 
6.3 
Discharge Assessments ............................................................................................................. 38 
6.4 
Follow-up Assessments .............................................................................................................. 38 
6.4.1 
Follow-up Medications ..................................................................................................... 38 
6.4.2 
Follow-up ......................................................................................................................... 38 
6.4.2.1 
30-day Follow-Up........................................................................................................ 39 
6.4.2.2 
12-Month Follow-Up ................................................................................................... 40 
6.4.2.3 
Annual Follow-up ....................................................................................................... 40 
6.4.3 
Unscheduled Follow-up ................................................................................................... 40 
6.4.3.1 
Evaluation of Suspected Neurological Event .......................................................... 40 
6.4.3.2 
Survival Status Check................................................................................................ 41 
6.4.4 
Patient Reported Outcome (PRO) Measures .................................................................. 41 
6.4.5 
Schedule of Events .......................................................................................................... 41 

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6.5 
Requirement for Core Laboratories ............................................................................................ 44 
7.0 
Adverse Events .............................................................................................................................. 44 
7.1 
Definition ..................................................................................................................................... 44 
7.1.1 
Adverse Event.................................................................................................................. 44 
7.1.2 
Serious Adverse Event .................................................................................................... 44 
7.1.3 
Device Deficiency/Device Malfunction ............................................................................. 45 
7.2 
Device Relationship .................................................................................................................... 45 
7.2.1 
Unanticipated (Serious Adverse) Device Effect [U(S)ADE] ............................................. 45 
7.3 
Adverse Event and Device Deficiency/Device Malfunction Reporting ........................................ 45 
7.3.1 
Adverse Event Reporting ................................................................................................. 45 
7.3.2 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC ................. 46 
7.3.3 
Device Deficiency/Malfunction Reporting ........................................................................ 46 
7.3.4 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .................. 47 
8.0 
STATISTICAL CONSIDERATIONS ............................................................................................... 48 
8.1 
Statistical Analyses ..................................................................................................................... 48 
8.1.1 
Primary Safety Endpoint Analysis .................................................................................... 48 
8.1.2 
Primary Effectiveness Endpoint Analysis ......................................................................... 49 
8.1.3 
Secondary Endpoint Analyses ......................................................................................... 50 
8.2 
Sample Size Calculations ........................................................................................................... 50 
8.3 
Timing of Analysis....................................................................................................................... 51 
8.4 
Subgroup Analysis ...................................................................................................................... 51 
8.5 
Multiplicity ................................................................................................................................... 51 
8.6 
Pooling Strategy ......................................................................................................................... 51 
8.7 
Procedures for Accounting for Missing Data .............................................................................. 51 
8.8 
Planned Interim Analysis ............................................................................................................ 52 
8.9 
Statistical Criteria for Termination ............................................................................................... 52 
8.10 
Success Criteria ......................................................................................................................... 52 
8.11 
Deviations from Statistical Plan .................................................................................................. 52 
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................................. 52 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................................... 52 
10.1 
Selection of Clinical Sites and Investigators ............................................................................... 52 
10.2 
Site Principal Investigator Responsibilities ................................................................................. 52 
10.3 
Clinical Investigation Finances and Agreements ........................................................................ 53 
10.4 
CIP Amendments........................................................................................................................ 53 

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10.5 
Measures Taken to Avoid and Minimize Bias ............................................................................. 53 
10.5.1 
Screening by an Interdisciplinary Heart Team ................................................................. 53 
10.5.2 
Use of a Screening Committee ........................................................................................ 53 
10.5.3 
Ascertainment and Adjudication of Adverse Events ........................................................ 54 
10.5.4 
Review of Echocardiographic Images by an Independent Echocardiographic Core 
Laboratory 54 
10.5.5 
Maintaining High Rates of Follow-Up Compliance ........................................................... 54 
10.5.6 
Standardized Administration of Patient-Reported Outcome Measures and Stroke 
Assessment Scales ........................................................................................................................... 55 
10.6 
Training ....................................................................................................................................... 55 
10.6.1 
Site Training ..................................................................................................................... 55 
10.7 
Monitoring ................................................................................................................................... 55 
10.8 
Deviations from CIP .................................................................................................................... 56 
10.9 
Quality Assurance Audit ............................................................................................................. 56 
10.10 Sponsor Auditing ........................................................................................................................ 57 
10.11 Committees ................................................................................................................................ 57 
10.11.1 
Steering Committee ......................................................................................................... 57 
10.11.2 
Screening Committee ...................................................................................................... 57 
10.11.3 
Clinical Events Committee (CEC) .................................................................................... 57 
10.11.4 
Data Monitoring Committee (DMC) .................................................................................. 57 
10.11.5 
Publications Committee ................................................................................................... 58 
11.0 
DATA HANDLING AND RECORD KEEPING ................................................................................ 58 
11.1 
Protection of Personally Identifiable Information ........................................................................ 58 
11.2 
Data Management Plan .............................................................................................................. 59 
11.3 
Source Documentation ............................................................................................................... 59 
11.4 
Case Report Form Completion ................................................................................................... 60 
11.5 
Record Retention ........................................................................................................................ 60 
11.6 
Investigational Devices Accountability ........................................................................................ 60 
12.0 
ETHICAL CONSIDERATION ......................................................................................................... 61 
12.1 
Institutional Review Board/Medical Ethics Committee Review and Approval ............................. 61 
13.0 
CLINICAL INVESTIGATION CONCLUSION ................................................................................. 61 
13.1 
Suspension or Early Termination of the Clinical Investigation .................................................... 62 
13.1.1 
Subject Follow-up for Early Termination or Suspension of Study .................................... 62 
14.0 
PUBLICATION POLICY ................................................................................................................. 62 

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15.0 
RISK ANALYSIS ............................................................................................................................ 63 
15.1 
Anticipated Clinical Benefits ....................................................................................................... 63 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ...................................... 63 
APPENDIX I: ABBREVIATIONS AND ACRONYMS ................................................................................. 64 
APPENDIX II: DEFINITIONS .................................................................................................................... 66 
APPENDIX III: CIP SUMMARY ................................................................................................................ 78 
APPENDIX IV: LITERATURE REVIEW .................................................................................................... 82 
APPENDIX V: LABELS ............................................................................................................................. 83 
APPENDIX VI: INFORMED CONSENT FORM ........................................................................................ 84 
APPENDIX VII: SCREENING AND ASSESSMENT TOOLS .................................................................... 85 
APPENDIX VIII: KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) ................................ 92 
APPENDIX IX: MODIFIED RANKIN SCALE QUESTIONAIRE ................................................................ 93 
APPENDIX X: PERI-PROCEDURAL GUIDELINES ................................................................................. 94 
APPENDIX XI: REVISION HISTORY ....................................................................................................... 95 
APPENDIX XII: SITE CONTACT INFORMATION .................................................................................. 105 
APPENDIX XIII: MONITORING PLAN .................................................................................................... 106 
APPENDIX XIV: CASE REPORT FORMS ............................................................................................. 107 
APPENDIX XV: FORESEEABLE ADVERSE EVENTS AND ASSOCIATED FREQUENCY CATEGORIES
 
108 
APPENDIX XVI: REFERENCES ............................................................................................................ 111 
Abbreviations and definitions used throughout this investigational plan can be found in Appendix I and 
II. An investigational plan summary can be found in Appendix III. Further information regarding the 
literature review is in Appendix IV.  
 

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COMPLIANCE STATEMENT:  
 
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, the 
Declaration of Helsinki, applicable Good Clinical Practices and regulations (e.g., OUS ISO14155:2020) 
and the appropriate local legislation(s). The most stringent requirements, guidelines or regulations must 
always be followed. The conduct of the clinical investigation will be approved by the appropriate 
Institutional Review Board (IRB)/Ethics Committee (EC) of the respective investigational site and by the 
applicable regulatory authorities (e.g., BfArM, MHRA, TGA, etc.).

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1.0  INTRODUCTION 
VANTAGE is a prospective, single-arm, multi-center, international, pre-market clinical trial of the 
Navitor™ Transcatheter Aortic Valve Implantation (TAVI) System at up to 40 sites in Australia, Europe, 
and Israel. This clinical trial is intended to demonstrate the safety and effectiveness of the Navitor TAVI 
system in intermediate and low surgical risk patients with symptomatic, severe native aortic stenosis.  A 
valve-in-valve (ViV) cohort is nested within VANTAGE to evaluate the safety and effectiveness of the 
Navitor TAVI system in patients with failure of a surgical bioprosthetic aortic valve across all surgical risk 
categories. This clinical trial is sponsored by Abbott and will be conducted in accordance with this Clinical 
Investigational Plan (CIP). All investigators involved in the conduct of the clinical investigation will be 
qualified by education, training, or experience to perform their tasks and this training will be documented 
appropriately.  
1.1 
Background and Rationale 
1.1.1 Background  
Aortic stenosis (AS) remains the most common primary valve disease leading to surgery or catheter 
intervention in Europe and North America. Its prevalence increases with age, ranging from approximately 
2% in adults 70-80 years of age to 9% in adults older than 80 years.1 Although symptoms may remain 
latent for a period of time, the progression of AS can lead to the narrowing of aortic valve area by 
approximately 0.3 cm2 per year and an increase in the systolic pressure gradient by as much as 15-
19 mmHg per year. Functional deterioration of the aortic valve is usually coupled with coronary artery 
disease (CAD) and chronic renal insufficiency, leading to clinical symptoms and the need for treatment.2 
Symptomatic, severe aortic stenosis is treated by aortic valve replacement.3 The primary goals of aortic 
valve replacement are to reduce the risk for mortality, which can be as high as 25% per year if left 
untreated, and alleviate clinical symptoms, such as angina and dyspnea.4 While aortic valve replacement 
has traditionally been done surgically, a less invasive transcatheter aortic valve implant technique that 
was first introduced in 2002, has evolved significantly.5 The PARTNER trial was the first randomized trial 
evaluating the use of the balloon-expandable Sapien (Edwards Lifesciences) transcatheter valve in 
patients with severe, symptomatic AS at very high surgical risk. Cohort B of the trial enrolled subjects 
who were not considered suitable candidates for surgical aortic valve replacement (SAVR) and 
demonstrated a reduction in the rate of the composite of all cause death or repeat hospitalization with 
transcatheter aortic valve implantation (TAVI) over standard medical therapy (from 71.6% to 42.5%; P < 
0.001).6 Cohort A of the trial studied subjects at high surgical risk and demonstrated that TAVI was non-
inferior to SAVR in 1-year all-cause mortality (3.4% vs. 6.5%; P = 0.001 for noninferiority).7  
 
By 2012, the TAVI technique was recognized in the ESC/EACTS guidelines on the management of 
valvular heart disease with a Class I indication for patients that are not suitable for surgery and a Class 
IIA indication for patients at high surgical risk.8 In 2014, similar Class I indications for TAVI were included 
in the ACC/AHA valvular heart disease guidelines.9 Also in 2014, two studies were published evaluating 
the use of self-expanding CoreValve (Medtronic) in extreme and high risk patients. The CoreValve 
Extreme Risk Pivotal Trial was a single-arm trial that compared a composite of all-cause mortality or 
major stroke at 1 year to a performance goal. At 1 year, the trial met its primary endpoint with observed 
event rates of 24.3% for all-cause mortality and 4.3% for major stroke (composite rate of 26.0% vs. 
43.0% performance goal; P < 0.0001).10 The CoreValve US Pivotal Trial randomized high surgical risk 
subjects in a 1:1 ratio between TAVI and SAVR. The primary endpoint of all-cause mortality at 1 year 

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was significantly lower in the TAVI arm compared to the SAVR arm (14.2% vs.19.1%; P = 0.04 for 
superiority).11  
 
Further clinical research was conducted to evaluate the safety and effectiveness of TAVI in patients 
considered to be at intermediate surgical risk. The PARTNER 2 clinical trial included Cohort A 
(PARTNER 2 A), which was a randomized comparison of TAVI with the second generation Sapien XT 
valve to SAVR in intermediate risk patients. The primary endpoint was a composite of all-cause mortality 
or disabling stroke at 2 years. The Sapien XT valve was shown to be non-inferior to SAVR for the 
endpoint at 2 years (19.3% vs 21.1%; P=0.001 for non-inferiority; TAVI outcomes: all-cause mortality 
16.7%, disabling stroke 6.2%).12 At 2 years, Sapien XT cohort subjects had a mean aortic valve area of 
1.5 ± 0.4 cm2 with a mean gradient of 10.8 mmHg, and moderate or severe paravalvular leak in 8% of 
subjects.12 A separate observational arm of the PARNTER 2 trial (PARTNER 2 - S3i), which evaluated 
the third generation Sapien 3 valve. The PARTNER 2 – S3i cohort enrolled 1077 intermediate risk 
subjects to be implanted with the Sapien 3 valve and compared a composite of all-cause mortality, 
stroke, and moderate or severe aortic valve regurgitation at 1 year with a propensity matched cohort of 
subjects from the SAVR arm of PARTNER 2 A. This analysis found the outcomes of subjects implanted 
with the Sapien 3 valve to be superior to SAVR in this composite (pooled weighted proportion difference -
9.2%; P < 0.0001; Sapien 3 cohort outcomes: all-cause mortality 7.4%, stroke 4.6%, moderate or severe 
paravalvular regurgitation 1.5%).13 At 1 year, subjects had a mean aortic valve area of 1.7 ± 0.4 cm2 with 
a mean gradient of 11.4 mmHg.13 Based on evidence from PARTNER 2, the AHA/ACC 2017 valvular 
heart disease guidelines were revised to include a class IIA indication for TAVI as a reasonable 
alternative for patients deemed intermediate surgical risk.14,15  
 
In parallel to PARTNER 2, the SURTAVI trial randomized 1746 intermediate risk subjects between TAVI 
with the CoreValve family (CoreValve and Evolut R) of valves and SAVR. The primary endpoint was a 
composite of all-cause mortality or disabling stroke at 2 years, and TAVI was found non-inferior to SAVR 
(Bayesian analysis, estimated incidence 12.6% vs. 14.0%; posterior probability of noninferiority >0.999; 
TAVI cohort outcomes at 2 years: all-cause mortality 12.6%, disabling stroke 2.6%).15 In 2017, with the 
inclusion of the SURTAVI clinical trial results, ESC/EACTS upgraded their guidelines for transcatheter 
intervention in patients suffering from severe aortic stenosis who are determined to be at increased (i.e. 
intermediate and high) surgical risk to a Class I indication and that the decision between TAVI and SAVR 
be made by the local heart team based on individual patient characteristics.3  
 
Since the 2017 AHA/ACC and ESC/EACTS guidelines revisions, results from the PARTNER 3 and 
Evolut Low Risk clinical trials reported the use of TAVI in low surgical risk patients. The PARTNER 3 trial 
randomized 1000 low risk subjects between TAVI with Sapien 3 and SAVR. The primary endpoint was a 
composite of all-cause mortality, stroke, or rehospitalization at 1 year. TAVI with Sapien 3 was shown to 
be superior to SAVR (composite 8.5% vs 15.1%; P = 0.001 for superiority; TAVI cohort outcomes at 1 
year: all-cause mortality 1.0%, stroke 1.2%, rehospitalization 7.3%).16 At 1 year Sapien 3 subjects had a 
mean aortic valve area of 1.7 ± 0.02 cm2 with a mean gradient of 13.7 ± 0.26 mmHg.16 The Evolut Low 
Risk trial randomized 1468 low risk subjects between TAVI with CoreValve family of valves (CoreValve, 
Evolut R, or Evolut PRO) and SAVR. The primary endpoint was a composite of all-cause mortality or 
disabling stroke at 2 years. TAVI was demonstrated to be noninferior to SAVR (Bayesian analysis, 
estimated incidence 5.3% vs. 6.7%; posterior probability of noninferiority >0.999; 1-year all-cause 
mortality 2.4%, stroke 4.1%, disabling stroke 0.8%).17 The echocardiographic results at 1 year show 
TAVI subjects had a mean aortic valve area of 2.3 ± 0.7 cm2 with a mean gradient of 11.2 ± 4.9 mmHg, 
and moderate or severe paravalvular leak in 3.6%.17 

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In 2019, Sapien 3 received CE Mark and FDA approval for the expanded indication to include all surgical 
risk classifications. The Evolut R and Evolut Pro valve indications have also been approved for all 
surgical risk classifications by FDA and have since received CE Mark for all surgical risk classifications. 
In 2020, the ACURATE neo2 aortic valve (Boston Scientific) received CE Mark for all surgical risk 
classifications. Currently, Sapien 3, Evolut R and Evolut Pro valves are the only valves approved for 
lower risk patients in both the US and Europe. These valves have performed well in particular aspects in 
low and intermediate risk patient populations; however, opportunity exists for a single valve to 
demonstrate strong performance across all measures. First, long-term durability of these transcatheter 
aortic valves remains unknown. Second, while Sapien 3 has demonstrated positive outcomes in terms of 
1-year mortality and stroke, the hemodynamic performance (aortic valve area and gradients) has not 
been as good as the Evolut valves. In a similar vein, the self-expanding Evolut valves have not 
performed as well in as Sapien 3 in mortality, or stroke, and have had higher rates of permanent 
pacemaker implant following TAVI; however, Evolut valves have demonstrated excellent hemodynamic 
performance.  
 
Abbott’s self-expanding Portico™ Transcatheter Aortic Valve received CE Mark in 2012 and FDA 
approval in 2021 for use in patients with symptomatic, severe AS who are considered high or extreme 
surgical risk. The Portico Valve was studied in the prospective, randomized-controlled Portico IDE Study, 
in which 750 subjects were randomized 1:1 between implantation with the Portico Valve and 
commercially available valves. The primary safety endpoint was a composite of all-cause mortality, 
disabling stroke, life-threatening bleeding requiring blood transfusion, acute kidney injury requiring 
dialysis, or major vascular complications at 30 days. The primary effectiveness endpoint was a 
composite of all-cause mortality or disabling stroke at 1 year. In the intention-to-treat analysis, the Portico 
Valve was shown to be non-inferior to commercially available valves for both the primary safety endpoint 
at 30 days (13.8% vs 9.6%; P=0.03 for non-inferiority) and the primary effectiveness endpoint at 1 year 
(14.9% vs 13.4%; P=0.006 for non-inferiority). The echocardiographic results at 1 year show Portico 
subjects had a mean aortic valve area of 1.8 ± 0.7 cm2 (vs. 1.7 ± 0.5 cm2) with a mean gradient of 8.6 ± 
3.8 mmHg (vs. 10.6 ± 5.1 mmHg), and moderate or severe paravalvular leak present in 6.3% (vs. 2.1%) 
of subjects. In comparison, at 1 year Sapien 3 and Evolut R/Evolut PRO subjects had a mean aortic 
valve area of 1.6 ± 0.5 cm2 and 1.8 ± 0.5 cm2 with a mean gradient of 12.4 ± 5.3 mmHg and 7.8 ± 3.6 
mmHg respectively.18  
 
Following completion of enrollment of the randomized cohort, the FlexNavTM Delivery System was 
introduced into the Portico IDE study. The FlexNav Delivery System represents a design modification to 
the first-generation Portico Delivery System. Key design features include a hydrophilic stability layer to 
minimize system manipulations and support precise valve placement and an integrated sheath to reduce 
the delivery profile diameter to minimize vessel trauma at the access site. The FlexNav Delivery System 
was studied in 180 subjects via 2 concurrent, prospective, non-randomized single-arm studies (FlexNav 
DS arm within the Portico IDE Study and FlexNav EU CE Mark Study). Compared to the Portico group of 
the randomized cohort, introduction of the FlexNav Delivery System was associated with lower rate of 
major vascular complications (5.0% vs 9.6%). Safety outcomes in the FlexNav cohort were favorable 
with 0.6% mortality and 1.1% disabling stroke rates within 30 days.19  
 
The Navitor Transcatheter Aortic Valve is a design iteration that builds on the Portico Valve system with 
the addition of a fabric outer cuff to the exterior portion of the stent to optimize valve sealing and improve 
paravalvular leak (PVL) performance. The Navitor Valve (23 mm, 25 mm, 27 mm, 29 mm, and 35 mm) 

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has been studied in the PORTICO NG trial, which is a prospective, single-arm, multi-center clinical 
investigation designed to evaluate the safety and effectiveness of the Navitor Valve in subjects with 
symptomatic, severe AS at high or extreme surgical risk. The primary safety endpoint was all-cause 
mortality at 30 days, and the primary effectiveness endpoint was moderate or greater PVL at 30 days. 
Based on data from 260 subjects in Australia, Europe, and the U.S treated with 23, 25, 27 and 29 mm 
Navitor Valves, the rate of all-cause mortality at 30 days was 1.9%, and there were no cases of moderate 
or severe PVL at 30 days as evaluated by an independent core laboratory, resulting in a 30-day rate of 
0% of moderate or greater PVL. The echocardiographic results at 30 days show Navitor subjects had a 
mean aortic valve area of 2.0 ± 0.5 cm2 with a mean gradient of 7.4 ± 3.5 mmHg. 20 The combination of 
the Navitor Valve delivered via the FlexNav Delivery System offers a favorable safety profile with the 
potential for strong hemodynamic performance and with reduced PVL.  
 
The Navitor Titan™ Valve (35 mm) was studied in a separate cohort of 73 subjects within the PORTICO 
NG trial. The rate of all-cause mortality at 30 days was low at 1.4%, and there were no cases of 
moderate or severe PVL at 30 days as evaluated by an independent core laboratory, resulting in a 30-
day rate of 0% of moderate or greater PVL. The echocardiographic results at 30 days show Navitor Titan 
subjects had a mean aortic valve area of 2.5 ± 0.5 cm2 and a mean gradient of 6.0 ± 2.8 mmHg. The 
Navitor Titan Valve delivered via the FlexNav Delivery System offers a favorable safety profile with the 
potential for strong hemodynamic performance and reduced PVL.  
 
The Navitor Transcatheter Aortic Valve Implantation System (including Navitor Valves (23mm-35mm), 
the FlexNav Delivery System and Navitor Loading System) has been approved in multiple geographies 
including Australia, Canada, Europe, Israel, and the United States for the treatment of patients with 
symptomatic, severe AS that are considered high or extreme surgical risk. 
 
1.1.2 Rationale for Conducting this Clinical Investigation 
The safety and effectiveness of the Navitor TAVI System for patients at high and extreme surgical risk 
have been investigated in the PORTICO NG trial. VANTAGE is intended to evaluate the safety and 
effectiveness of the Navitor TAVI System in an intermediate and low surgical risk patient population in 
order to support global regulatory approvals.  
2.0 
CLINICAL INVESTIGATION OVERVIEW 
2.1 
Clinical Investigation Objective 
The objective of the proposed clinical trial is to evaluate the safety and effectiveness of the Navitor TAVI 
System in patients with severe, symptomatic native aortic stenosis who are at intermediate or low risk of 
surgical mortality. This trial will also evaluate the safety and effectiveness of the Navitor TAVI System in 
a valve-in-valve application in patients with symptomatic heart disease due to failure (stenosed, 
insufficient, or combined) of a surgical bioprosthetic aortic valve across all surgical risk categories.  

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2.2 
Devices To Be Used in the Clinical Investigation 
2.2.1 Name of the Devices Under Investigation 
Devices under investigation in this clinical trial include the Navitor Transcatheter Aortic Valve (23 mm, 25 
mm, 27 mm, 29 mm, and 35 mm sizes), FlexNav Delivery System (small and large), and Navitor Loading 
System (small, large, and LG+), collectively named the Navitor TAVI System. Since the commercially 
available version of the Navitor TAVI System and the version labeled as investigational are physically 
identical (Table 1), the commercially available version may be used in VANTAGE in geographies where 
the Navitor TAVI System has been commercially approved for patients with symptomatic, severe aortic 
stenosis who are at high or extreme surgical risk and where the use of the commercially available 
version in this trial has also been approved by the applicable Competent Authority and/or Ethics 
Committee.  
 
Model numbers for the Navitor Valve, FlexNav Delivery System, and Navitor Loading System and their 
regulatory status are provided below in Table 1. The compatible components of the Navitor TAVI System 
are listed in Table 2.  
 
Table 1: Devices Included in the Clinical Trial 
Device name 
Model/Type 
Serial/Lot 
Controlled 
Manufacturer 
Regions 
Regulatory 
Status¶ 
Navitor 23 mm 
Valve 
PRT-NG-
23/NVTR-23* 
Serial numbered 
Abbott Medical   
Australia, Europe, 
and Israel 
 
Approved for high 
and extreme risk in 
Australia, Europe, 
and Israel * 
 
Navitor 25 mm 
Valve 
PRT-NG-
25/NVTR-25* 
Navitor 27 mm 
Valve 
PRT-NG-
27/NVTR-27* 
Navitor 29 mm 
Valve 
PRT-NG-
29/NVTR-29* 
Navitor Titan 35 
mm Valve 
PRT-NG-35 
Serial numbered 
Abbott Medical 
Australia, Europe, 
and Israel 
FlexNav Small 
Delivery System 
FN-DS-SM-IDE/ 
FNAV-DS-SM* 
Serial 
numbered/Lot 
numbered 
Abbott Medical   
Australia, Europe, 
and Israel 
FlexNav Large 
Delivery System 
FN-DS-LG-IDE/ 
FNAV-DS-LG* 
Navitor Small 
Loading System 
PRT-NG-LS-
SM/NVTR-LS-SM* 
Serial 
numbered/Lot 
numbered 
Abbott Medical   
Australia, Europe, 
and Israel 
Navitor Large 
Loading System 
PRT-NG-LS-
LG/NVTR-LS-LG* 
Navitor Titan 
Loading System 
LG+ 
PRT-NG-LS-35 
Serial numbered 
Abbott Medical 
Australia, Europe, 
and Israel 
*Commercial model 
¶The regulatory status listed is current as of the version date of this CIP.  
 
 
Table 2: Compatible Components in the Navitor TAVI System  

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Navitor Valve Catalog Numbers 
FlexNav Delivery System Catalog 
Numbers 
Navitor Loading System Catalog 
Numbers 
PRT-NG-23/NVTR-23* (23 mm)  
or 
PRT-NG-25/NVTR-25* (25 mm) 
FN-DS-SM-IDE/FNAV-DS-SM* 
PRT-NG-LS-SM/NVTR-LS-SM* 
PRT-NG-27/NVTR-27* (27 mm)  
or 
PRT-NG-29/NVTR-29* (29 mm) 
FN-DS-LG-IDE/FNAV-DS-LG* 
PRT-NG-LS-LG/NVTR-LS-LG* 
PRT-NG-35 (35 mm) 
FN-DS-LG-IDE/FNAV-DS-LG* 
PRT-NG-LS-35 
*Commercial model 
 
2.2.2 Intended Indication for Use 
The intended indication for use statements for the products used in this trial are as follows: 
For the native valve application, the Navitor Valve is indicated for transcatheter delivery in patients with 
symptomatic severe native aortic stenosis who are considered intermediate or low surgical risk. For the 
valve-in-valve application, the Navitor Valve is indicated for use in patients, of any surgical risk category, 
with symptomatic heart disease due to failure (stenosed, insufficient, or combined) of a surgical 
bioprosthetic aortic valve. 
The FlexNav Delivery System is indicated for transfemoral or subclavian/axillary delivery of the Navitor 
Valve.  
The Navitor Loading System is indicated for loading the Navitor Valve in the FlexNav Delivery System. 
The Navitor Valve, FlexNav Delivery System, and the Navitor Loading System will be used in accordance 
with the Instructions for Use (IFU). Please refer to the Navitor Transcatheter Aortic Valve Implantation 
System IFU for further details.  
2.2.3 Description of the Devices Under Investigation 
The Navitor Valve was developed based on iterative modifications to the first-generation Portico 
Transcatheter Aortic Valve and is designed to be used in combination with the FlexNav Delivery System 
and Navitor Loading System. 
Key design features of the Navitor Valve include:  
• 
A new fabric outer cuff on the exterior portion of the stent to optimize valve sealing and reduce 
paravalvular leak. 
• 
Minor modifications to the stent design intended to minimize vessel trauma and aid retainer release 
from the delivery system, normalize the aortic/annular to stent height ratio, and provide uniform 
chronic outward radial force across the range of valve sizes to improve valve expansion, stability, 
and sealing. 
2.2.3.1 Navitor Valve 
The Navitor Valve maintains several design features of the first-generation Portico Valve including same 
valve sizes and use range (except for the addition of the 35 mm valve to expand the use range as listed 
in Table 3), open stent cell design to provide easy coronary access and blood flow, repositionable with 
the ability to re-sheath and retrieve, leaflets derived from pericardial bovine tissue, and intra-annular 

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placement of leaflets/cuff within the stent frame for early valve function to maintain hemodynamic stability 
during implant. 
Table 3: Patient Anatomical Specification per the Navitor Valve 
Model Number 
Annulus 
Diameter 
Ascending 
Aorta 
Diameter 
Area 
Perimeter 
Eccentricity 
Ratio¶ 
PRT-NG -23/NVTR-23* 
19-21 mm 
26-36 mm 
277-346 mm2 
60-66 mm 
≥ 0.73 
PRT-NG -25/NVTR-25* 
21-23 mm 
28-38 mm 
338-415 mm2 
66-73 mm 
≥ 0.73 
PRT-NG -27/NVTR-27* 
23-25 mm 
30-40 mm 
405-491 mm2 
72-79 mm 
≥ 0.73 
PRT-NG -29/NVTR-29* 
25-27 mm 
32-42 mm 
479-573 mm2 
79-85 mm 
≥ 0.73 
PRT-NG-35 
27-30 mm 
27-44 mm 
559-707 mm2 
85-95 mm 
≥ 0.73 
*Commercial model 
¶Eccentricity ratio: minor/major diameter ratio 
 
The valve is comprised of three main components: stent, leaflets, and cuff (Figure 1). The stent is made 
from nitinol, a nickel-titanium alloy that has self-expanding properties and is radiopaque. The leaflets are 
made from bovine pericardium and are sutured together into a tri-leaflet configuration on the stent frame.  
The leaflet pericardial tissue is preserved and crosslinked in glutaraldehyde and undergo an anti-
calcification treatment using Linx™ anticalcification technology. A new feature of the Navitor Valve is the 
addition of the outer cuff and updating the inner cuff material from porcine pericardium to fabric (Figure 
1). Both the inner and outer cuff is made from polyethylene fabric and provides the sealing area for 
implantation to provide paravalvular leak reduction by allowing blood to fill any potential voids between 
the native valve and the stent.  
 
 

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Figure 1: Navitor Valve
In addition to the new outer cuff feature, the Navitor Valve incorporates the following key design 
enhancements:
•
Addition of a slight inward curvature to the aortic end of the stent to minimize vessel trauma.
•
Adjusted scaling of the stent across all valve sizes to normalize the aortic/annular to stent height 
ratio.
•
Increased chronic outward radial (COR) force of the 23 mm and 25 mm valves to a common COR 
force across the Navitor family to improve valve expansion, stability and sealing.
The valve is sterilized using a multi-component sterilant (i.e. glutaraldehyde, formaldehyde and ethanol) 
and provided sterile and non-pyrogenic. 
2.2.3.2
FlexNav Delivery System 
The FlexNav Delivery System is an over-the-wire, 0.035”- compatible system that includes a hydrophilic-
coated, integrated sheath to facilitate gradual, controlled deployment of the Navitor Valve in patients with 
a minimum vessel diameter of ≥ 5mm.
The FlexNav Delivery System allows for transfemoral or subclavian/axillary access methods with the 
current range of Navitor Valves size (23, 25, 27, 29, and 35 mm) (Table 4). The FlexNav Delivery 
System has a working length of 107 cm and is composed of a handle at the proximal end. The FlexNav 
Delivery System is available in two sizes with equivalent integrated sheath diameters of 14 F (small) or 
15 F (large), and outer diameters of 6.0 mm (small) and 6.3 mm (large) at the distal end, respectively. 

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Table 4: FlexNav Delivery System Models and Compatibility with Navitor Valve Sizes 
Description 
Catalog 
Number 
Equivalent 
Integrated 
Sheath 
Diameter 
Distal End 
Outer 
Diameter 
Integrated 
Sheath 
Working 
Length 
Delivery 
System 
Length 
Minimum 
Vessel 
Diameter 
Compatible 
Navitor 
Valve Size 
FlexNav Delivery 
System (small) 
FN-DS-SM-
IDE/FNAV-DS-
SM * 
14 F 
6.0 mm 
30 cm 
107 cm 
≥ 5.0 mm 
23 mm and 
25 mm 
FlexNav Delivery 
System (large) 
FN-DS-LG-IDE/ 
FNAV-DS-LG * 
15 F 
6.3 mm 
30 cm 
107 cm 
≥ 5.5 mm 
27 mm, 29 
mm and 35 
mm 
* Commercial model 
 
The FlexNav Delivery System shaft includes a stability layer over the outer member to improve control 
during positioning and deployment of the valve. The FlexNav Delivery System handle functions in a similar 
manner as the first-generation Portico Delivery System with modifications and added labeling. The macro 
slide that facilitates opening and closure of the delivery system is incorporated into the proximal end of the 
handle with two release buttons (Figure 2). 
 
  
 
Figure 2: FlexNav Delivery System- Handle Detail 
 
 
The distal end of the FlexNav Delivery System features an atraumatic, radiopaque tip with hydrophilic 
coating and a radiopaque inner member marker band to aid in visualizing. The FlexNav Delivery System 
includes the same retainer design as the first-generation Portico Delivery system (Figure 3). 
 
 
 
Deployment Indicator 
Valve Capsule Flush Port 
Deployment Lock Button 
Deployment/Re-sheath Wheel 
Macro Slide Release Buttons 
Micro-adjustment Wheel 
Stability Layer Flush Port 
Guidewire/Flush Port 

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Figure 3: FlexNav Delivery System - Distal End Detail  
 
 
2.2.3.3 Navitor Loading System  
The Navitor Loading System is an accessory used to compress and load the Navitor Valve onto the 
FlexNav Delivery System. The Navitor Loading System is similar in design and operation to the current 
FlexNav Loading System with changes to the loading funnel (angle increased) and base insert (flange 
height shortened). Additionally, a stent guide has been introduced to this system to assist in loading 
efficiency. All other Navitor Loading System components (loading base, loading tube, leaflet tester) are 
the same as the FlexNav Loading System. The method of loading the Navitor Valve onto the FlexNav 
Delivery System is also unchanged.  
The Navitor Small Loading System is used for loading the 23 or 25 mm Navitor Valves on the FlexNav 
Small Delivery System, the Navitor Large Loading System is used for loading the 27 or 29 mm Navitor 
Valves on the FlexNav Large Delivery System, and the Navitor Titan Loading System - LG+ is used for 
loading the Navitor Titan 35 mm Valve on the FlexNav Large Delivery System.  
Please refer to the IFU for additional information regarding the device used in this clinical study. 
2.2.4 Summary of Preclinical Studies 
Refer to the Preclinical Studies section of the Investigator’s Brochure (IB) for a summary of the results.  
2.2.5 Device Handling  
Sponsor requires clinical sites to store all investigational products according to the labeling and 
Instructions for Use in a secure area to prevent unauthorized access or use. Refer to Appendix V for the 
product labels and Instructions for Use.  
3.0 
CLINICAL INVESTIGATION DESIGN 
The VANTAGE trial is a prospective, single-arm, multi-center, international, pre-market clinical 
investigation designed to evaluate the safety and effectiveness of the Navitor TAVI System in 
accordance with ISO standard 14155:2020. The trial will register subjects in three cohorts: (1) primary 
analysis cohort (up to 450 subjects), (2) roll-in cohort (up to 40 subjects), and (3) valve-in-valve (ViV) 
cohort (up to 100 subjects). To be eligible for participating in the primary analysis and roll-in cohorts, a 

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patient must have symptomatic, severe native aortic stenosis and have intermediate or low risk for 
surgical valve replacement. To be eligible for participating in the ViV cohort, a patient must have 
symptomatic heart disease due to failure (stenosed, insufficient, or combined) of a surgical bioprosthetic 
aortic valve, and the patient can be in any risk category.A 
Subjects will be enrolled and treated with the Navitor Valve at up to 40 experienced TAVI implant centers 
across Australia, Europe, and Israel. All sites must either have prior Portico or Navitor TAVI system 
experience or must complete roll-in cases. Upon providing informed consent and approval by the 
Screening Committee (SC), subjects will undergo Navitor Valve implantation via a transfemoral or 
alternative access (subclavian or axillary) approach using the site’s anesthesia protocol for TAVI 
procedures. In the trial, the point of enrollment is defined as informed consent signing, whereas the point 
of registration is defined as the insertion of the FlexNav Delivery System (loaded with a Navitor Valve) 
into the subject’s vasculature (the subject is considered attempted with Navitor Valve implantation at this 
point) (Figure 4). Only registered subjects will be included in the analysis. 
There are two co-primary endpoints for the primary analysis cohort, each of which will be tested against 
a literature-derived performance goal. The primary safety endpoint is a composite of all-cause mortality 
or fatal stroke/stroke with disability at 12 months post index Navitor implantation procedure. The primary 
effectiveness endpoint is moderate or greater paravalvular leak (PVL) at 30 days post index Navitor 
implantation procedure. The number of subjects required to be registered in the primary analysis cohort 
is 434. In addition, per ISO 5840-3:2021, the standard for heart valve substitutes implanted by 
transcatheter techniques, 400 patient-years of follow-up are required to assess late adverse events.  
Roll-in and ViV cohorts will be summarized separately and will not contribute to the required sample 
sizes for hypothesis testing or the 400 patient-year requirement. 
Subjects participating in the clinical trial will be followed for a total of 10 years with data collected at 
screening, baseline, procedure, prior to hospital discharge, and follow-up at 30 days, 12 months and 
annually thereafter up to 10 years.B Key assessments required at each visit are described in Section 
6.0. The expected duration of enrollment in the primary analysis cohort is 38 months, and the total 
duration of the clinical study including final data cleaning, reporting, and site close-out is expected to be 
approximately 13.7 years. Follow-up data through 10 years will be submitted as part of a final report to 
respective regulatory agencies. 
The Sponsor has designed this clinical investigation to involve as little pain, discomfort, fear, and any 
other foreseeable risk as possible for subjects. Refer to the Risks Analysis (Section 15.0) of this clinical 
investigation plan for details.  
3.1 
Clinical Investigation Procedures and Follow-up Schedule 
The Flow Chart of this clinical investigation is shown in Figure 4 below. 
 
 
A In Germany, only subjects at high or extreme surgical risk can be included in the ViV cohort. Sites in Switzerland 
will not participate in the ViV enrollment. 
B Subjects in the high or extreme risk category in the ViV cohort will be followed up to 5 years. 

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Figure 4: Clinical Trial Flow Chart 
                         
              
 
Note 1: Reasons for enrolled but not registered may include screen failure, death, and withdrawal. 
Note 2: Subjects in the high or extreme risk category in the ViV cohort will be followed up to 5 years. 
Note 3: Any subject who undergoes an explant of the Navitor Valve during the study follow-up period will be exited from the trial 
30 days following the explant procedure. 

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4.0 
ENDPOINTS 
4.1 
Primary Endpoints and Rationale  
1. Primary Safety Endpoint: 
The primary safety endpoint is a composite of all-cause mortality or fatal stroke/stroke with 
disability at 12 months post index Navitor implantation procedure per the Valve Academic 
Research Consortium (VARC) 3 event definitions21. This endpoint is consistent with other trials 
evaluating the safety and effectiveness of TAVI in intermediate or low risk patients. Previous 
clinical trials testing the safety and effectiveness of TAVI valves in intermediate and low surgical 
risk subjects have used a single composite primary endpoint of all-cause mortality or disabling 
stroke per the VARC-2 event definitions22 (disabling stroke per VARC-2 is equivalent to fatal 
stroke plus stroke with disability per VARC-3).12,15,23 The 12-month timepoint for the VANTAGE 
primary safety endpoint is consistent with PARTNER 2 - S3I, PARTNER 3, and ACURATE IDE 
trials that investigated or are currently investigating TAVI in intermediate and/or low surgical risk 
subjects.  
2. Primary Effectiveness Endpoint: 
The primary effectiveness endpoint is moderate or greater paravalvular leak at 30 days post 
index Navitor implantation procedure, assessed by the echocardiographic core laboratory. This 
endpoint will characterize the performance of the fabric outer cuff of the Navitor valve stent to 
optimize valve sealing and minimize paravalvular leak. Given more than mild paravalvular leak 
following valve deployment is shown to be associated with increased morbidity and mortality 
following aortic valve replacement, moderate or greater paravalvular leak at 30 days is an 
appropriate endpoint to assess the effectiveness of the valve. 24,25 
4.2 
Secondary Endpoints  
1. Mean change in mean transvalvular gradient between baseline and 12 months 
2. Mean change in effective orifice area between baseline and 12 months 
3. Mean change in Kansas City Cardiomyopathy Questionnaire (KCCQ) quality of life score between 
baseline and 12 months 
4.3 
Descriptive EndpointsC 
1. Major adverse events (non-hierarchical composite of all-cause mortality, fatal stroke/stroke with 
disability, type 3/type 4 bleeding, stage 3/stage 4 acute kidney injury, major vascular 
complications, or major access-related non-vascular complications) at 30 days  
2. Non-hierarchical composite of all-cause mortality or all stroke at 12 months  
 
 
C Event definitions for descriptive endpoints #1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 13, 16, 20, 21, 22, and 24 are based on 
the VARC-3 definitions. 

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3. Procedural success defined as successful vascular access, delivery and deployment of the 
Navitor Valve; retrieval of the delivery system and correct positioning of a single Navitor Valve in 
the proper anatomical location and the absence of procedural mortality 
4. Mortality (all-cause, cardiovascular, and valve-related) at 30 days and 12 months  
5. Stroke (All stroke, fatal stroke, stroke with disability, and stroke without disability) at 30 days and 
12 months  
6. Transient ischemic attack (TIA) at 30 days and 12 months 
7. Bleeding (type 4, type 3, and type 2) at 30 days  
8. Major vascular complications at 30 days 
9. Major access-related non-vascular complications at 30 days  
10. Major cardiac structural complications at 30 days  
11. Acute kidney injury (stage 4, stage 3, and stage 2) at 30 days  
12. Permanent pacemaker insertion at 30 days and 12 months  
13. Myocardial infarction at 30 days and 12 months  
14. Coronary obstruction requiring intervention at 30 days and 12 months 
15. Changes in functional status from baseline to follow-up assessments at 30 days and 12 months 
(e.g., New York Heart Association (NYHA) functional classification, six-minute walk test, quality of 
life measure: Kansas City Cardiomyopathy Questionnaire (KCCQ)) 
16. Rehospitalization (procedure-related or valve-related hospitalization, and other cardiovascular 
hospitalization) at 30 days and 12 months  
17. Paravalvular leak (none/trace, mild, moderate or severe) at discharge, 30 days, 12 months and 
annually (when collected) through 10 years  
18. Changes in echocardiographic parameters from baseline to follow-up at 30 days, 12 months and 
annually (when collected) through 10 years (e.g., mean effective orifice area, mean transvalvular 
gradient) 
19. Aortic valve reintervention at 30 days, 12 months, and annually through 10 years 
20. Prosthetic valve endocarditis at 12 months and annually through 10 years  
21. Structural valve deterioration at 12 months and annually through 10 years  
22. Non-structural valve dysfunction at 12 months and annually through 10 years  
23. Successful coronary access as needed at 12 months and annually through 10 years 
24. Clinically significant prosthetic valve thrombosis at 12 months and annually through 10 years  
 
The two co-primary endpoints and three secondary endpoints will be tested for the primary analysis 
cohort. All event-based endpoints will be assessed from the index procedure unless otherwise noted. 

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5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This clinical trial will enroll subjects of all genders who have symptomatic, severe AS and are determined 
to be at intermediate or low surgical risk except for subjects in the ViV cohort. Complete clinical 
investigation eligibility criteria are described in Section 5.3. Subjects must meet all general eligibility 
criteria and provide written informed consent prior to sites conducting any investigation-specific 
procedures not considered standard of care. Informed consent must occur prior to transmission of any 
subject data to the independent computed tomography (CT) and echocardiographic core laboratories, 
Screening Committee (SC) or Sponsor for screening purposes.  
The operative risk determination of study candidates will be based on assessment by the local heart 
team and confirmation by the SC. The assessment of surgical risk will include the Society of Thoracic 
Surgeons (STS) Adult Cardiac Surgery Risk Calculator score and/or EuroSCORE II, indices of frailty, 
and comorbidities not captured by risk calculators, as described below, and current TAVI practice 
guidelines.3,26 
Subject case review will be conducted by the SC to determine primarily the final risk classification. The 
SC charter provides details of the SC process.  
5.1.1 Intermediate Surgical Risk Classification 
To be classified as intermediate surgical risk, the heart team’s estimate of the subject’s 30-day surgical 
mortality risk must be greater than or equal to 3% but less than 7%. This determination will include 
consideration of the surgical risk calculator but will not rely entirely on the surgical risk calculator as 
indices of frailty and other comorbidities will also be considered when making this overall surgical risk 
determination. The final risk classification of the subject will be determined by the SC.  
5.1.2 Low Surgical Risk Classification 
To be classified as low surgical risk, the heart team’s estimate of the subject’s 30-day surgical mortality 
risk must be less than 3%. This determination will include consideration of the surgical risk calculators 
and the absence of indices of frailty or other comorbidities that would elevate the overall surgical risk for 
the subject. The final risk classification of the subject will be determined by the SC. 
5.2 
Subject Screening and Informed Consent 
5.2.1 Subject Pre-Screening 
A member of the site’s clinical investigation team previously trained to the CIP must evaluate patients for 
the general clinical investigation eligibility criteria, and if applicable, will enter the patients into the site-
specific Pre-Screening Log. A patient who does not satisfy all general eligibility criteria prior to informed 
consent is considered a screen failure and should not be enrolled in the clinical investigation. 
Sites will ask patients meeting general inclusion criteria and no general exclusion criteria to sign an 
Informed Consent form following the established Informed Consent process (described in Section 5.2.2) 
if they wish to participate in the clinical investigation.  

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5.2.2 Informed Consent 
The Investigator or his/her authorized designee (if applicable) will conduct the Informed Consent 
process, as required by applicable regulations and the center’s EC. This process will include a verbal 
discussion with the patient on all aspects of the clinical investigation that are relevant to the patient’s 
decision to participate, such as details of clinical investigation procedures, anticipated benefits, and 
potential risks of clinical investigation participation. Sites must inform patients about their right to 
withdraw from the clinical investigation at any time and for any reason without sanction, penalty, or loss 
of benefits to which the patient is otherwise entitled. Withdrawal from the clinical investigation will not 
jeopardize their future medical care or relationship with the investigator.  
 
During the discussion, the Principal Investigator or his/her authorized designee will avoid any improper 
influence on the patient and will respect patient’s legal rights. Financial incentives will not be given to 
patients. Patients may be compensated for travel directly related to the participation in the clinical 
investigation. The site shall provide the patient with the Informed Consent form written in a language that 
is understandable to the patient and that has been approved by the center’s EC. The patient shall have 
adequate time to review, ask questions, and consider participation. The Principal Investigator or his/her 
authorized designee will make efforts to ensure that the patient understands the information provided. If 
the patient agrees to participate, they must sign and date the Informed Consent form, along with the 
person obtaining the consent prior to any clinical investigation-specific procedures. The site will file the 
signed original in the patient’s hospital or research charts and provide a copy to the patient. The dated 
signatures can be electronic. The site will follow local hospital and local EC provisions for documenting 
electronic informed consent form (ICF) signature. 
 
Sites should report any failure to obtain informed consent from a patient to the Sponsor within 5 working 
days and to the reviewing center’s EC according to the EC’s reporting requirements. 
 
If, during the clinical investigation, new information becomes available that can significantly affect a 
subject's future health and medical care, the Principal Investigator or his/her authorized designee (if 
applicable) will provide this information to the subject. If relevant, sites will ask the subject to confirm their 
continuing informed consent in writing. 
 
For information regarding obtaining the trial informed consent template, please see Appendix VI. 
5.2.2.1 Special Circumstances for Informed Consent  
Consistent with the study exclusion criteria listed in Section 5.3.3, this clinical investigation excludes 
individuals unable to make the decision to participate in a clinical investigation on their own or who are 
unable to fully understand all aspects of the investigation that are relevant to the decision to participate, 
or who could be manipulated or unduly influenced as a result of a compromised position, expectation of 
benefits or fear of retaliatory response. Individuals under the age of 18 or age of legal consent are 
excluded from the study population. Individuals unable to read or write are excluded from the study 
population. Pregnant or breastfeeding women are also excluded from the study population. 
All other aspects of the Informed Consent process will follow Section 5.2.2.  
For live or recorded cases to be broadcast at congresses, the subject needs to sign a specific Live Case 
ICF, approved by the EC and by the Sponsor, as well as by the Competent Authorities, as applicable. 
The investigator must obtain Sponsor approval prior to performing a Live Case. 

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Proctoring and/or observation of cases by other medical professionals (whether in-person or virtually) 
does not require special provisions for informed consent.  
5.2.3 Subject Screening 
Once a duly dated and signed Informed Consent form is obtained, sites will perform the below CIP-
specific assessments as part of the clinical investigation screening process: 
 
1. Demographics (age on consent date, gender) 
2. Medical History (including major cardiovascular and arrhythmia history, vascular, and other 
coexisting medical conditions) 
3. Physical Exam (including height, weight, resting heart rate, and blood pressure)  
4. Surgical Risk Assessment tool (STS Risk Score and EuroSCORE II) 
5. New York Heart Association (NYHA) Functional Classification 
6. Frailty Index Assessment (Katz index of Activities of Daily Living, Grip Strength, 5-meter Walk 
Test, Albumin (collected with Laboratory Measurements)) 
7. Forced Expiratory Volume (FEV1) Test, if clinically indicated 
8. Echocardiography to include comprehensive 2D transthoracic echocardiogram (TTE), including 
assessment of aortic valve gradients (mean and peak), areas, indices, degree of regurgitation, 
cardiac output and cardiac index, left ventricle systolic function (global and segmental) 
9. Laboratory Measurements (including complete blood count (CBC) and platelet count, creatinine 
and estimated glomerular filtration rate (eGFR), and albumin) 
10. 12 Lead Electrocardiogram (ECG) 
11. Computed Tomography (CT) Scan with Angiography of chest, abdomen and pelvis including 
aortic root and valve annulus for valve sizing, assessment of suitability of iliofemoral or alternate 
access, and determination of appropriate coaxial angles for optimizing the valve implantation 
procedure. CT covering at least systole is required for valve sizing (please refer to the CT 
Acquisition Protocol from the CT Core Laboratory). CT scan performed up to 12 months prior to 
consent will be acceptable.  
12. Invasive coronary angiography or CT coronary angiography and aortic angiography (if clinically 
indicated or standard of care). Angiography performed up to 12 months prior to consent will be 
acceptable. 
13. Adverse Event Assessment 
 
Data available in the subject’s medical record may be utilized to fulfill screening requirements and testing 
does not need to be repeated if performed within 90 days prior to Informed Consent. CT scan with 
coronary angiography or invasive coronary angiography and aortic angiography (if clinically indicated or 
standard of care) may be performed within 12 months prior to Informed Consent. 
If any clinical and/or laboratory tests are required for patient screening and are not included in a site’s 
standard tests, they must be completed after written informed consent is obtained.  

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All cardiac medications and all medications given for cardiovascular effect may be continued at their 
prescribed dosages for the screening assessments. 
Upon initial screening of eligibility of patients by the heart team, subject case reviews will be conducted 
by the SC to confirm a subject’s eligibility for this trial per the SC Charter. If the SC does not approve the 
subject for study participation, the subject will be exited from the study as a screen failure and will not be 
counted toward the sample size. The Principal Investigator or the delegated clinical investigation 
personnel will record the screen failure in the hospital records and on the screening log.  
Further details regarding methods used for subject screening can be found in Appendix VII.  
5.3 
Eligibility Criteria 
5.3.1 General Eligibility Criteria 
Assessment for general eligibility criteria is based on medical records of the site and interview with a 
candidate patient. Patients must meet ALL general inclusion criteria to participate in the clinical 
investigation. If ANY general exclusion criteria are met, the patient is excluded from the clinical 
investigation and cannot be enrolled. 
If any clinical and/or laboratory tests are required for patient screening and are not included in a site’s 
standard tests, they must be completed after written informed consent is obtained.  
5.3.2 Inclusion CriteriaD 
5.3.2.1 General Inclusion Criteria 
1. Subject who is judged by a Heart Team, including a cardiac surgeon, to be appropriate for 
transcatheter heart valve intervention therapy, and is deemed to be at intermediate or low risk 
for open surgical aortic valve replacement (i.e., heart team estimates risk of surgical mortality < 
7% at 30 days, considering the Society of Thoracic Surgeons (STS) risk score, overall clinical 
status, and other clinical co-morbidities unmeasured by the risk calculator). #,E  
2. New York Heart Association (NYHA) Functional Classification of II, III, or IV # 
3. Subject is of legal age for consent in the host country. 
4. Subject has been informed of the nature of the trial, agrees to its provisions and has provided 
written informed consent as approved by the Ethics Committee (EC) of the respective clinical site. 
5. Able and willing to return for required follow-up visits and assessments 
5.3.2.2 Imaging Inclusion Criteria 
6. Degenerative aortic valve stenosis with echo-derived criteria, defined as: aortic valve area (AVA) 
of ≤ 1.0 cm2 (or indexed EOA ≤ 0.6 cm2/m2) AND either mean gradient ≥ 40 mmHg or peak jet 
 
 
D Eligibility criteria labeled with “#” are not applicable for the ViV cohort. Sites in Switzerland will not participate in 
the ViV enrollment. 
E In France and Switzerland, if a subject is deemed low surgical risk, the subject must be at age 75 or over to be 
included in this trial. 

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velocity ≥ 4.0 m/s or doppler velocity index (DVI) ≤ 0.25. The echocardiogram supporting the 
qualifying AVA baseline measurement must be performed within 90 days prior to informed 
consent) .# 
7. Aortic annulus diameter of 19‐30 mm and ascending aorta diameter of 26-44 mm for the specified 
valve size listed in the IFU, as measured by CT (systolic phase) conducted within 12 months prior 
to informed consent.  
5.3.3 Exclusion Criteria 
5.3.3.1 General Exclusion Criteria 
1. Pregnant or nursing subjects and those who plan pregnancy during the clinical investigation 
follow-up period. A pregnancy test is required for all women of childbearing potential.  
2. Need for emergency surgery for any reason 
3. Life expectancy is less than 2 years in the opinion of the Investigator. 
4. Presence of other anatomic or comorbid conditions, or other medical, social, or psychological 
conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the 
clinical trial or to comply with follow up requirements, or impact the scientific soundness of the 
clinical trial results  
5. Incapacitated individuals, defined as persons who are mentally ill, mentally handicapped, 
individuals with severe dementia or individuals without legal authority 
6. Individuals who are unable to read or write 
7. Currently participating in an investigational drug or device study that has not reached the primary 
endpoint or may confound the results of this trial 
8. Evidence of an acute myocardial infarction [defined as ST-segment elevation myocardial 
infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) with acute 
ischemia symptoms and troponin elevation] within 30 days prior to index procedure 
9. Untreated clinically significant coronary artery disease requiring revascularization 
10. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior 
(except pacemaker or implantable cardioverter defibrillator (ICD) implant) to index procedure or 
planned within 30 days following the index procedure.  
11. Blood dyscrasias as defined: leukopenia (WBC < 3000 mm3), acute anemia (Hb < 9 g/dL), 
thrombocytopenia (platelet count < 50,000 cells/mm³); history of bleeding diathesis or 
coagulopathy 
12. Refuses blood products 
13. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support 
14. Hemodynamic instability requiring inotropic support or mechanical heart assistance 
15. Hypertrophic cardiomyopathy with obstruction 

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16. Active peptic ulcer or upper GI bleeding within 3 months prior to index procedure that would 
preclude anticoagulation 
17. Known intolerance, hypersensitivity, or contraindication, including subjects that meet any of the 
following conditions: 
a. Subjects who cannot take any antiplatelets or anticoagulants*,  
b. Subjects who have sensitivity to contrast media which cannot be adequately 
premedicated,  
c. Subjects who have known hypersensitivity to nitinol (nickel or titanium), or 
d. Subjects who have clinical contraindication that precludes contrast CT imaging 
*Note: Subjects who can take either an antiplatelet or anticoagulant therapy post-procedure will 
be eligible. 
18. Recent (within 6 months prior to index procedure date) cerebrovascular accident (CVA) or a 
transient ischemic attack (TIA) 
19. Renal insufficiency (creatinine > 3.0 mg/dL or eGFR < 30 ml/min/1.73m2) and/or end stage renal 
disease requiring chronic dialysis 
20. Active bacterial endocarditis within 6 months prior to the index procedure 
21. A positive COVID-19 test within 30 days prior to the index procedure 
22. Liver failure (Child-Pugh class B or C) 
23. Subjects with atrial fibrillation who are not on anticoagulants or who are not implanted with a left 
atrial appendage occlusion (LAAO) device 
24. Symptomatic carotid or vertebral artery disease, significant carotid or vertebral artery disease 
requiring intervention, or successful treatment of carotid or vertebral stenosis within 30 days prior 
to index procedure 
25. Severe pulmonary hypertension with pulmonary systolic pressure greater than two-thirds of 
systemic pressure 
26. Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen 
27. Hostile chest or conditions or complications from prior surgery that would make the subject be 
considered high surgical risk (i.e., mediastinitis, radiation damage, abnormal chest wall, porcelain 
aorta, adhesion of aorta or internal mammary artery to sternum, etc.) # 
28. Significant frailty as determined by the heart team (after objective assessment of frailty 
parameters) that would indicate high or extreme surgical risk # 
5.3.3.2 Imaging Exclusion Criteria  
29. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic 
regurgitation 3-4+) # 
30. Aortic valve is a congenital unicuspid or congenital bicuspid valve as verified by 
echocardiography or CT. #  
31. Non-calcified aortic valve # 
32. Severe ventricular dysfunction with LVEF < 30% as measured by resting echocardiogram 

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33. Pre-existing prosthetic heart valve or other implant (such as prosthetic ring or transcatheter edge-
to-edge repair (TEER) clip) in any valve position # (Note: Subjects with a bioprosthetic aortic valve 
may be included in the ViV cohort.) 
34. Severe circumferential mitral annular calcification (MAC) which is continuous with calcium in the 
left ventricular outflow tract (LVOT) # 
35. Prohibitive left ventricular outflow tract calcification # 
36. Severe (greater than or equal to 3+) mitral regurgitation or severe mitral stenosis with pulmonary 
compromise  
37. Severe tricuspid regurgitation or severe right ventricle dysfunction 
38. Echocardiographic or multi-slice computed tomography (MSCT) evidence of intracardiac mass, 
thrombus or vegetation 
39. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal 
luminal diameter 5.5 cm or greater or ascending aortic aneurysm defined as maximal luminal 
diameter 5 cm or greater  
40. Marked aortic tortuosity (hyperacute bend) or severe “unfolding” and tortuosity of the thoracic 
aorta (applicable for transfemoral access only) 
41. Aortic arch atheroma (thick [> 5 mm], protruding or ulcerated) 
42. Significant narrowing (calcification and surface irregularities) of the abdominal or thoracic aorta  
43. Aortic root angulation > 70°  
44. Undue risk of coronary obstruction (e.g., low coronary ostia, narrow Sinus of Valsalva anatomy 
that would prevent adequate coronary perfusion, or bulky aortic valve leaflets in close proximity to 
coronary ostia) 
45. Access vessel characteristics that would preclude safe insertion of the FlexNav Delivery System 
such as severe obstructive calcification, protruding thrombus or severe tortuosity  
46. Minimum access vessel diameter of < 5.0 mm for small FlexNav Delivery System and < 5.5 mm 
for large FlexNav Delivery System 
47. Ascending aorta anatomy that would preclude safe delivery of the valve to the native aortic 
annulus 
48. Eccentricity ratio of the annulus < 0.73 
Refer to country-specific addendums for other details. 
5.4 
Subject Enrollment, Subject Registration, and Study Cohorts 
A patient is considered enrolled in the clinical trial from the moment the patient provides written informed 
consent.  
Consented subjects who undergo study-specific testing and are found to have met exclusion criteria or 
not all inclusion criteria prior to the procedure (or if a site disagrees with and does not accept the 
Screening Committee’s final decision regarding risk classification) will be considered screen failures; 

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these subjects will not be counted toward the sample size of roll-ins, primary analysis subjects, or ViV 
subjects and will be exited from the study without further follow-up.  
In addition, a consented (enrolled) subject is considered registered in the clinical investigation from the 
moment the FlexNav Delivery System (loaded with a Navitor Valve) is inserted into the subject’s 
vasculature. Consented subjects who undergo trial-specific testing and meet trial criteria but do not 
undergo a Navitor implant attempt (defined as insertion of the FlexNav Delivery System into the 
vasculature) will not be registered in the trial. Reasons for enrolled but not registered may include screen 
failure, death, and withdrawal. This includes subjects in whom the implanting physician at the time of the 
procedure but before the insertion of the delivery system into the vasculature determines implantation of 
the Navitor Valve is either not feasible or not in the best interest of the subject. These subjects will not be 
counted toward the sample size of roll-ins, primary analysis subjects or ViV subjects and will be exited 
from the study without further follow up. Only registered subjects will be counted toward the sample size. 
All subjects who undergo a Navitor attempt will be included in either the roll-in cohort as described in 
Section 5.4.1, the primary analysis cohort as described in Section 5.4.2, or the ViV cohort as described 
in Section 5.4.3. Subjects who undergo a Navitor attempt but are not implanted with the Navitor Valve 
will be followed for 30 days and then exited from the study (Figure 4); similarly, any subject who 
undergoes explant of the Navitor Valve during the study follow-up period will be exited from the study 30 
days following the explant procedure. 
5.4.1 Roll-in Cohort 
The requirement for roll-in cases will be determined based on experience of the implanting physicians. If 
neither of the implanting physicians have previous Portico or Navitor clinical experience, a minimum of 
one roll-in subject will be required. A maximum of three roll-in subjects will be allowed per implanting 
physician, and up to 40 roll-in subjects will be permitted in the study. Designation of roll-in or analysis 
subject will be determined by the Sponsor in consultation with the Study PI and communicated to the site 
in advance of the procedure.  
5.4.2 Primary Analysis Cohort 
The primary analysis cohort will include all registered subjects that are not designated as a roll-in subject 
or ViV subject.  A maximum of 450 registered subjects will be included in this cohort.  
If subjects receive a Navitor Valve without meeting all the conditions listed in Section 5.3, they should 
complete all follow-up requirements. These subjects are considered CIP deviations but will be included in 
the primary analysis cohort. 
5.4.3 Valve-in-Valve (ViV) Cohort 
Subjects who have documented failed aortic surgical valve prosthesis regardless of risk classification 
and are deemed eligible to receive a Transcatheter Navitor Valve into the existing bioprosthesis will be 
considered for eligibility in the ViV cohort. The ViV cohort will register up to 100 qualified subjects. 
ViV subjects must meet all the applicable inclusion criteria and none of the applicable exclusion criteria 
with the following exceptions to Section 5.3. Criteria that may not apply include inclusion criterion 
numbers 1, 2 and 6 (the surgical bioprosthetic valve may be stenotic or require replacement due to other 
forms of structural valve deterioration), and exclusion criterion numbers 27, 28, 29, 30, 31, 33, 34, and 
35. If the subject has a bioprosthetic valve in another location, the subjects will be excluded from this 

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trial.  All risk levels will be includedF and SC will assess surgical risk for demographic characterization 
and sub-analysis purposes.  
ViV subjects’ data will not be included in the primary data analysis; however, the data will be analyzed 
descriptively and presented separately. 
5.5 
Subject Discontinuation 
Each subject meeting all general and screening eligibility criteria shall remain in the clinical investigation 
until completion of the required follow-up period; however, a subject’s participation in any clinical 
investigation is voluntary and the subject has the right to withdraw at any time without penalty or loss of 
benefit. Conceivable reasons for discontinuation may include, but not be limited to, the following: 
• 
Subject death 
• 
Subject voluntary withdrawal  
• 
Subject lost-to follow-up as described below  
• 
Subject’s follow-up is terminated according to Section 13.1 
Sites must notify the Sponsor of the reason(s) for subject discontinuation. Investigators must also report 
this to their respective EC as defined by their institution’s procedure(s).  
No additional follow-up is required or data recorded from subjects once withdrawn from the clinical 
investigation, except for the status (deceased/alive). 
However, if a subject withdraws from the investigation due to problems related to the safety or 
performance of the device under investigation, the investigator shall ask for the subject's permission to 
follow his/her status/condition outside of the clinical investigation.  
In case of subject withdrawal of consent, the site should make attempts to schedule the subject for a final 
clinical investigation visit. At this final follow-up visit, the subject will undergo the following assessments: 
• 
Echocardiography to include comprehensive transthoracic echocardiogram, including 
assessment of aortic valve gradients (mean and peak), areas, indices, degree of regurgitation, 
cardiac output and cardiac index, left ventricle systolic function (global and segmental) 
• 
Adverse Event assessment 
Upon completion of trial-specified follow-up (regardless of how follow-up was completed, e.g., 
withdrawal, completion of required follow-up), subjects should be followed per standard of care for 
subjects with severe aortic stenosis that underwent transcatheter aortic valve implantation. Participation 
in this trial does not require subjects to have any unique follow-up requirements once trial participation is 
complete. Valve traceability and identification requirements for such follow-up are the same as for 
commercially approved transcatheter aortic valve implants.  
 
Lost-to-Follow-up 
 
 
 
F In Germany, only subjects at high or extreme surgical risk can be included in the ViV cohort. Sites in Switzerland 
will not participate in the ViV enrollment. 

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If the subject misses two consecutive scheduled follow-up time points and the attempts at contacting the 
subject detailed below are unsuccessful, then the subject is considered lost-to-follow-up. Site personnel 
shall make all reasonable efforts to locate and communicate with the subject (and document these efforts 
in the source documents), including the following, at each contact time point: 
• 
A minimum of two telephone calls on different days over the specified follow-up windows to 
contact the subject should be recorded in the source documentation, including date, time and 
initials of site personnel trying to make contact. 
• 
If these attempts are unsuccessful, the site should send a letter (certified if applicable) to the 
subject. 
• 
If a subject misses one or more non-consecutive follow-up contact time points, it will be 
considered a missed visit. The subject may then return for subsequent visits. If the subject misses 
two consecutive time points and the above-mentioned attempts at communicating with the 
subject are unsuccessful, the subject will be considered lost-to-follow-up.  
 
Note: Telephone contact with General Practitioner, non-clinical investigation cardiologist or relative will 
be considered as subject contact for the purpose of collecting vital status information. The investigational 
site shall retain records of the contact. 
5.6 
Number of Subjects  
Up to 450 subjects will be included in the primary analysis cohort in order to analyze the primary 
endpoints and meet the requirement of 400 patient-years of follow-up to assess late adverse events per 
ISO 5840-3:2021. In addition, up to 100 subjects may be included in the ViV cohort and up to 40 subjects 
may be included in the roll-in cohort. No site may register more than 20% without prior approval from the 
Sponsor. 
5.7 
Total Expected Duration of the Clinical Investigation 
The expected duration of enrollment in the primary analysis cohort is 38 months. The expected duration 
of each subject’s participation is 10 years, including the scheduled visits and data collection for this 
clinical trial. Subjects will be exited from the trial at the conclusion of their 10-year follow-up visit. 
Therefore, the total duration of the clinical investigation is expected to be approximately 13.7 years, 
consisting of approximately 38 months of enrollment, 10 years of follow-up, and 0.5 years for final data 
cleaning, reporting and site close-out.  
6.0 
TREATMENT AND EVALUATION OF ENDPOINTS 
For subjects that have successfully completed screening and been approved by the SC, scheduled visits 
will be performed in the following order: Baseline, Index Procedure, Discharge, 30 days,12 months, and 
annual follow-up assessments to 10 years.  
 
This is an open-label clinical investigation. Investigators and subjects will not be blinded to treatment 
assignment. 

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6.1 
Baseline 
Subjects who are deemed eligible for implantation of a Navitor Valve using the FlexNav Delivery System 
will undergo a baseline visit prior to the procedure. (A separate baseline visit is not required if baseline 
assessments are performed during the screening visit per the site’s practice.)  
6.1.1 Baseline Assessments 
The following baseline assessments will be performed for all subjects prior to the index procedure. 
 
• 
Cardiovascular medications documentation (including dosage) 
• 
Modified Rankin Scale (mRS) Assessment (Refer to Appendix IX for further details) 
• 
Six Minute Walk Test (6MWT) (Refer to Appendix VII for further details) 
• 
Quality of Life Assessment: KCCQ (Refer to Appendix VIII for further details) 
• 
Laboratory Measurements (international normalized ratio (INR) if subject is on warfarin or other 
anticoagulants/vitamin K antagonists in lieu of warfarin)  
• 
Adverse events assessment 
 
All baseline assessments are considered study-related assessments. 
6.1.2 Pre-procedure Antiplatelet/Anticoagulation Medications 
Antiplatelet/Anticoagulation and other medications should be administered pre-procedure per the 
standard of care at the investigational site. 
6.1.3 Pre-procedure Blood Tests 
The following blood tests will be performed at the investigational site within 72 hours prior to the index 
procedure: 
1. 
Cardiac biomarkers (Troponin or CK-MB) 
2. 
Creatinine 
6.2 
Index Procedure 
6.2.1 Procedures Involved in the Use of the Device Under Investigation 
Please refer to IFU for instructions on handling and preparation of the Navitor Valve, FlexNav Delivery 
System, Navitor Loading System. If the devices were not used according to the IFU or other instructions 
in this CIP, complete a Protocol Deviation form. 
6.2.2 Procedural Anticoagulation 
Anticoagulation use during the procedure is left to the physician’s discretion or should be performed, as 
with any other transcatheter valve implantation, considering risks and benefits for the subject. The 
activated clotting time (ACT) should be monitored throughout the procedure (and recorded on source 
documentation). Medications should be adjusted to keep the subject’s ACT > 250 seconds. 

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6.2.3 Implant Procedure 
Navitor implants will be performed by experienced TAVI implanters that are board certified interventional 
cardiologist(s) and/or cardiac surgeon(s) and study investigators. Implanters must complete all required 
Navitor implant procedure training prior to their first Navitor case and be approved to implant by the 
Sponsor.  
It is strongly recommended that the index procedure occur within 14 calendar days following SC 
approval. 
A Navitor Valve may be implanted in a subject who has provided written informed consent and was 
approved by the SC. Although not recommended, if a physician determines it is in the best interest of the 
subject to have a second transcatheter aortic valve placed, a subject may receive an additional 
transcatheter aortic valve. 
Standardized imaging techniques will be used during the index procedure to implant the valve and to 
assess valve performance and coronary patency. Ultrasound guided arterial access is highly 
recommended.  
The following data will be collected during the implant procedure: 
1. Vascular access, deployment, final valve placement, performance, and closure data collection  
2. Other product utilization (e.g., introducer sheaths, guide wires, balloon catheters) 
3. Final hemodynamic assessment of mean aortic valve gradient can be performed by 
echocardiogram or invasive pressure measurement (post-implant only).  
4. Final assessment of aortic regurgitation (including PVL) can be performed by echocardiogram or 
angiography (post-implant only).  
5. Monitor the cardiac rhythm and any rhythm changes throughout the duration of the procedure 
6. Procedural information and imaging (cine-angiogram, intra-procedure echocardiography to be 
stored and provided to the Sponsor for the first 5 procedures at each site and upon request 
thereafter) 
 
A 12-lead ECG is required daily following implant through discharge (refer to Section 6.3); the first one 
should be done as soon after the index procedure as possible.  
 
Investigational sites should follow study-specific guidelines for the assessment of aortic regurgitation and 
implant depth. Refer to Appendix X for a description of standardized methods for measuring aortic 
regurgitation according to VARC-2 criteria and instructions for assessing implant depth in the LVOT.  
During the procedure, the implanting physician may determine implantation of the Navitor Valve is either 
not feasible or not in the best interest of the subject. Reasons may include, but are not limited to, 
anatomy that is not suitable for implantation, inability to gain access, ventricular arrhythmia, or any other 
contraindication.  
All the required information must be recorded on the applicable Case Report Form (CRF). Following the 
procedure, the non-implantable devices (e.g., FlexNav Delivery and Navitor Loading Systems) should be 
securely disposed as per hospital requirements for hazardous materials.  
 

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If there are any concerns noted with the Navitor Valve, FlexNav Delivery System, or the Navitor Loading 
System during the procedure, please notify the Sponsor and return these products to the Sponsor for 
evaluation if possible. See Section 7.3.3 for Device Deficiency/Malfunction reporting requirements.  
6.3 
Discharge Assessments 
The discharge visit will take place at the time of hospital discharge or at 7 days after the procedure, 
whichever occurs first. If the subject is expected to be discharged over the weekend, the discharge tests 
may be completed on the last weekday prior to discharge.  
 
The discharge assessment will include: 
1. Physical Examination (including weight, resting heart rate, and blood pressure)  
2. Cardiovascular medications documentation 
3. Modified Rankin Scale (mRS) 
4. 12-lead ECG: to be done daily following implant through discharge, including observations from 
the daily ECG reviews since procedure (for subjects receiving a new permanent pacemaker, ECG 
should be completed showing the underlying rhythm as well as the current pacing programming) 
5. Echocardiogram (TTE) (within 48 hours prior to the discharge visit) 
6. Laboratory Measurements (Creatinine and Troponin or CK-MB) (within 48 hours prior to the 
discharge visit) 
7. Adverse events assessment 
6.4 
Follow-up Assessments 
 
6.4.1 Follow-up Medications  
Cardiovascular medications administered to subjects during the follow-up period will be at the physician’s 
discretion and recorded on the follow-up case report forms. 
6.4.2 Follow-up  
Required clinical follow-up will be performed at the following intervals for all subjects who were implanted 
with a Navitor Valve: 
 • 30 days (-7/+21 days) follow-up site visit (visit must be conducted even if subject is in hospital) 
• 12 months (365 days + 45 days) follow up site visit 
• 
Annual follow-up at 2 through 10 years (± 60 days) 
The only exceptions to the above follow-up requirements are subjects in the high or extreme risk 
category in the ViV cohort, who will be followed at 30 days, 12 months, and annually through 5 years. 
Subjects with a Navitor implant attempt (registered subjects) that did not have a Navitor Valve implanted 
will only be required to complete the 30-day follow-up visit prior to exiting the study.  

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Dates for follow-up visits will be calculated from the date of the implant procedure. Follow-up 
assessments can be performed at any point within the pre-specified follow-up visit window and should be 
conducted by the same individual who performed the baseline tests whenever possible.  
Every effort should be made by the study site to have the subject return to the investigational site for all 
follow-up visits, except for remote follow-up at 6, 8, and 9 years. In-person follow-up visits including an 
echocardiogram are highly recommended if the subject is experiencing signs or symptoms of aortic 
stenosis or heart failure. If, despite all efforts, the subject is unable to return to the study site during a 
follow-up window, subjects may undergo a remote follow-up assessment to collect applicable data. 
Remote assessments should include telephone contact with the subject and/or a visit to a medical facility 
(i.e. non-investigational site) with all data that can be reasonably and legally collected remotely on the 
study subject. To aid in follow-up compliance, if necessary, an authorized health care representative (e.g. 
Hawthorne Effect) may be utilized to provide in-home visits for both the clinical and echocardiographic 
follow-up. Follow-up visits occurring at non-study sites will be limited to standard of care data collection 
only. Authorization for the release of medical records from non-study facility is the responsibility of the 
investigational site. Any missed testing will be considered a protocol deviation.  
A registered subject may only be followed at another investigational site (e.g. subject moves closer to 
another investigational site) with prior agreement from that site’s Investigator and from the Sponsor. 
Each site will be responsible for performing and interpreting the follow-up echocardiograms for potential 
adverse events. Echocardiograms will be submitted to an independent Echocardiographic Core 
Laboratory for further analysis. Examinations should be recorded in DICOM format and should be de-
identified prior to submitting to the Echocardiographic Core Laboratory. If medically indicated, a subject 
may undergo additional imaging per standard of care (e.g., contrast CT scan or TEE) to evaluate device 
specific findings (e.g., valve thrombosis); if performed, this additional imaging will be submitted to the 
Sponsor and/or appropriate core laboratory for analysis. 
6.4.2.1 30-day Follow-Up 
The 30-day follow-up visit will occur 30 days (-7/+21 days) post-index procedure, and will include the 
following assessments: 
1. Physical Examination (including weight, resting heart rate, and blood pressure)  
2. Cardiovascular medications documentation 
3. NYHA Functional Classification 
4. Modified Rankin Scale (mRS) 
5. Six Minute Walk Test (6MWT)  
6. 12 lead ECG (for subjects receiving a new permanent pacemaker, ECG should be completed 
showing the underlying rhythm as well as the current pacing programming) 
7. Echocardiography (TTE) 
8. Quality of Life Assessment (KCCQ) 
9. Lab Measurements (INR if subject is on warfarin or other anticoagulants/vitamin K 
antagonists in lieu of warfarin) 
10. Adverse events assessment 

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6.4.2.2 12-Month Follow-Up 
The 12-month follow-up visit will take place at 12 months (365 days + 45 days) post-index procedure, 
and will include the following assessments: 
1. Physical Examination (including weight, resting heart rate, and blood pressure)  
2. Cardiovascular medications documentation 
3. NYHA Functional Classification 
4. Modified Rankin Scale (mRS) 
5. Six Minute Walk Test (6MWT)  
6. 12 lead ECG (for subjects receiving a new permanent pacemaker, ECG should be completed 
showing the underlying rhythm as well as the current pacing programming) 
7. Echocardiogram (TTE) 
8. Quality of Life Assessment (KCCQ) 
9. Lab measurements (INR if subject is on warfarin or other anticoagulants/vitamin K 
antagonists in lieu of warfarin) 
10. Adverse events assessment 
6.4.2.3 Annual Follow-up  
The following data should be collected at years 2 through 10 years (± 60 days) post index procedure:  
1. Cardiovascular medications  
2. Adverse event assessment 
3. Modified Rankin Scale (mRS) 
The following are only required at years: 2, 3, 4, 5, 7, and 10 
4. Physical Examination (including weight, resting heart rate, and blood pressure)  
5. NYHA Functional Classification  
6. Quality of Life Assessment (KCCQ) 
7. Echocardiography (TTE) 
6.4.3 Unscheduled Follow-up  
6.4.3.1 Evaluation of Suspected Neurological Event 
If the subject experiences a neurological event (transient ischemic attack (TIA), stroke, or 
encephalopathy) throughout follow-up, the event must be documented on an adverse event form. The 
event (including all available imaging and NIH Stroke Severity (NIHSS)) should be assessed and 
confirmed by a neurologist or neurology fellow. Further evaluation must be performed at an unscheduled 
visit 90 days (± 14 days) from the date of the neurological event. The unscheduled visit will include the 
following assessments: 

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• 
Neurological Assessment conducted by a neurologist or a neurology fellow 
• 
Modified Rankin Score (mRS) 
6.4.3.2 Survival Status Check 
The Sponsor may request a check on each subject’s survival status for subjects.  
6.4.4 Patient Reported Outcome (PRO) Measures 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is the only PRO measure that will be collected 
according to the CIP requirements to assess whether the health of subjects has improved since 
enrollment in the clinical study. 
 
The Principal Investigator, research coordinator or study designee will provide the subject the KCCQ 
before any other elements of visit. It is important the subject understands the meaning of all words and 
instructions in the measures. The subject should be instructed to ask any questions about the measures 
if further explanation is needed. Once the PRO measures are completed, the research coordinator or 
study designee will review for completeness to verify that all questions have been answered according to 
the directions provided. 
6.4.4.1 Kansas City Cardiomyopathy Questionnaire (KCCQ)  
The KCCQ is a 12-item self-administered questionnaire developed to independently measure the 
patient’s perception of their health status, which includes heart failure symptoms, impact on physical and 
social function, and how their heart failure impacts their quality of life (QOL) within a 2-week recall period. 
KCCQ responses are provided along a rating scale continuum with equal spacing from worst to best. On 
average, the 12-item version takes approximately 10 minutes to complete. The concepts quantified in the 
KCCQ are designed to be relevant and appreciable by all heart failure patients specified in the qualified 
context of use. The Flesch Reading Ease is 76 and the Flesch-Kincaid Grade level is 6.7. The tool can 
be used to evaluate the effectiveness of a heart failure medical device studied in a clinical study.  
The tool quantifies six distinct domains (Symptom, Physical Function, Quality of Life, Social Limitation, 
Self-efficacy, Symptom Stability) and two summary scores (Clinical Summary and Overall Summary). 
Scores are transformed to a range of 0-100, in which higher scores reflect better health status. Refer to 
Appendix VIII for the sample questionnaire. 
6.4.5 Schedule of Events 
The study-required activities and standard of care data collection in the clinical study are summarized in 
Table 5. 

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Table 5: Follow-up and Data Collection Requirements 
A Required at years 2, 3, 4, 5, 7, and 10; not required at years 6, 8, and 9. Subjects in the high or extreme risk category in the ViV cohort will be followed up to 5 years. 
Trial Activity 
Screening 
Baseline 
Procedure 
Discharge 
30 days 
[-7/+21 days] 
12 months 
[+45 days] 
Annual visits  
[±60 days] 
Subject Interview and Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
X 
X 
X 
XA 
Surgical Risk Assessment (STS & EuroSCORE II) 
X 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
 
X 
X 
XA 
Frailty Index (Katz Index of ADLs, Grip strength, 5-meter walk, 
Albumin) 
X 
 
 
 
 
 
 
Forced Expiratory Volume (FEV1) Test (if indicated) 
X 
 
 
 
 
 
 
Cardiovascular Medications documentation 
 
X 
 
X 
X 
X 
X 
Invasive coronary angiography or CT coronary angiography and 
Aortic Angiogram (if clinically indicated or standard of care) 
X 
 
 
 
 
 
 
Modified Rankin Scale (mRS) 
 
X 
 
X 
X 
X 
X 
Neurological Assessment 
A neurological assessment and mRS must be performed at 90 days (±14 days) from the date of a suspected 
neurological event 
Six-Minute Walk Test 
 
X 
 
 
X 
X 
 
Non-Invasive Tests 
12 lead Electrocardiogram (ECG) B,C 
X 
 
 XC 
 XB,C 
 XB 
 XB 
 
Cardiac Rhythm  
 
 
X 
 
 
 
 
2D Transthoracic Echocardiogram (TTE) 
X 
 
 XD 
X 
X 
X 
XA 
Angiogram 
 
 
X 
 
 
 
 
CT Scan with Angiography of chest, abdomen and pelvis 
 XE 
 
 
 
 
 
 
Patient Reported Outcome Measure 
KCCQ  
 
X 
 
 
X 
X 
X A 
Laboratory Measurements 
 
 
 
 
 
 
 
CBC and Platelet Count 
X 
 
 
 
 
 
 
Creatinine 
 XF 
 
XG 
X 
 
 
 
INR (if subject is on Warfarin) 
 
X 
 
 
X 
X 
 
Troponin or CK-MB 
 
 
XG 
X 
 
 
 
Albumin (for Frailty Index) 
X 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
Adverse Event Assessment H 
X 
X 
X 
X 
X 
X 
X 
Deviation  
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Device Deficiency 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Withdrawal 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Survival Status 
 
 
 
(X) 
(X) 
(X) 
(X) 
Death 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 

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B For subjects receiving a new permanent pacemaker, ECG should be completed showing the underlying rhythm as well as the current pacing programming. 
C Record a 12-lead ECG following the implant of the valve and daily until day of discharge 
D Copy of echocardiographic examination to be stored at the site and available to the Sponsor upon request.  
E To be done within 12 months prior to consent; CT covering at least systole is required for valve sizing. 
F Includes eGFR 
G To be collected within 72 hours before index procedure  
H Transesophageal echocardiogram (TEE) is also recommended after adverse events of ischemic stroke and myocardial infarction 
 
 
 (X) indicates if applicable 
 

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6.5 
Requirement for Core Laboratories 
Independent core laboratories will be utilized for evaluating CT scans and echocardiograms collected in 
the clinical study. Each investigational site will submit CT scans and echocardiograms to the respective 
core laboratories for evaluation. The core laboratories will provide the study required acquisition 
requirements and documentation of each data submission according to their Standard Operating 
Procedures and study specific charter.  
Data obtained from the core laboratory readings will be used for study purposes only and not for clinical 
treatment of the subject. The Sponsor will use the data provided by the core laboratories in data 
analyses, where measurements were collected by the core laboratory. If the core laboratory determines 
that the imaging examination is unreadable, the site will be responsible for having the subject return for 
another assessment. 
7.0 
Adverse Events 
To comply with worldwide standards and guidelines on clinical investigation adverse event reporting, the 
Sponsor has adopted uniform and worldwide applicable standard definitions and reporting timelines to be 
used and adhered to by the investigators.  
7.1 
Definition 
7.1.1 Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, in the context 
of a clinical investigation, whether or not related to the investigational medical device and whether 
anticipated or unanticipated. 
 
As part of ISO14155 Section 3.2, the Adverse Event definition has the following notes: 
 
Note 1: This definition includes events related to the investigational medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices or comparators. 
7.1.2 Serious Adverse Event 
Serious Adverse Event is an AE that leads to any of the following:  
 
a) death, 
b) serious deterioration in the health of the subject, that resulted in any of the following:  
1. life-threatening illness or injury,  
2. permanent impairment of a body structure or a body function,  

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3. hospitalization or prolongation of patient hospitalization,  
4. medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function, or 
5. chronic disease  
c) fetal distress, fetal death or a congenital physical or mental impairment or birth defect. 
 
Note: A planned hospitalization for a pre-existing condition, or a procedure required by the CIP without a 
serious deterioration in health, is not considered a SAE. 
7.1.3 Device Deficiency/Device Malfunction 
Device deficiency is defined as any inadequacy in the identity, quality, durability, reliability, usability, 
safety or performance of an investigational device, including malfunction, use errors or inadequacy in the 
information supplied by the manufacturer including labeling.  
 
Note 1: The definition includes device deficiencies related to investigational medical device or the 
comparator. 
Note 2: Cyber-security incidents related to the investigational product shall be reported as device 
deficiencies.  
 
A device malfunction is the failure of an investigational medical device perform in accordance with its 
intended purpose when used in accordance with the instructions for use or CIP or IB. 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or device under 
investigation caused or contributed to an AE is to be determined by the Investigator and recorded on 
the appropriate CRF form. Determination should be based on the assessment of temporal relationships, 
evidence of alternative etiology, medical/biologic plausibility and subject condition (pre-existing 
condition). 
7.2.1 Unanticipated (Serious Adverse) Device Effect [U(S)ADE] 
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
7.3 
Adverse Event and Device Deficiency/Device Malfunction Reporting 
7.3.1 Adverse Event Reporting 
Safety surveillance and reporting starts as soon as the subject is enrolled in the clinical investigation. 
Safety surveillance and reporting will continue until sites perform the last follow-up visit, the subject is 
deceased, the subject concludes participation in the clinical investigation, or the subject withdraws from 

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the clinical investigation. Sites will collect all adverse event data, including deaths and device deficiency 
data, throughout the period defined above and will report these events to the Sponsor on a CRF. Sites 
should update additional information regarding an adverse event on the appropriate CRF.  
 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be reported.  
 
 
Non-cardiac related abnormal laboratory values will not be considered AEs unless:  
1. the investigator determined that the value is clinically significant,  
2. the abnormal lab value required intervention, or  
3. the abnormal lab value required subject withdrawal from the clinical investigation. 
 
All adverse events will be collected on each subject through the 10-year follow-up visit.  
 
SAE Reporting 
The investigator must report all SAEs to the Sponsor as soon as possible but no later than 3 calendar 
days from the day the site personnel became aware of the event or as per the investigative site’s local 
requirements, if the requirement is more stringent than those outlined. 
Sites must record the date the site staff became aware that the event met the criteria of an SAE in the 
source document. The Investigator will further report the SAE to the local EC according to the institution’s 
EC reporting requirements. 
The Sponsor will provide an offline form to allow the investigator to report SAEs in the event the entry 
cannot be made in the electronic data capture system (EDC), and site must use this offline form to report 
SAEs by email to AdverseEvent@abbott.com. This does not replace the EDC reporting system. Sites 
must still enter all information in the EDC system as soon as feasible.  
7.3.2 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC 
The Sponsor requires the Investigator to report any potential USADE to the Sponsor within 3 calendar 
days of the investigator’s knowledge of the event, unless local requirements are more stringent, and to 
the EC per EC requirements.  
7.3.3 Device Deficiency/Malfunction Reporting 
All device deficiencies/malfunctions should be reported on the Device Deficiency CRF form.  
 
The investigator must report all device deficiencies/malfunctions to the Sponsor as soon as possible but 
no later than 3 calendar days from the day the site personnel became aware of the event or as per the 
investigative site’s local requirements, if the requirement is more stringent than those outlined.  
Sites must report device deficiencies/malfunctions to the EC per the investigative site’s local 
requirements. 
 
Sites should return the device, if not implanted or not remaining in the subject, to the Sponsor.  
 

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An offline form will be made available to allow the investigator to report device deficiencies/malfunctions 
in the event that the entry cannot be made in the EDC system, and sites must use this offline form to 
report device deficiencies/malfunctions by email to AdverseEvent@abbott.com. This does not replace 
the EDC reporting system. All information must still be entered in the EDC system as soon as feasible.  
7.3.4 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
The Sponsor will report SAEs and reportable device deficiencies/malfunctions to the country regulatory 
authority, per local requirements.  
The Sponsor’s Clinical Safety Team will submit the clinical investigation SAEs and device 
deficiencies/malfunctions reportable per MedDEV 2.7/3 regulations to the European Competent 
Authorities (per MDCG 2020-10/1 after May 2021). Contact details are provided in Appendix XII.  
Note: Reportable device deficiencies include device deficiencies that might have led to an SAE if a) 
suitable action had not been taken or b) intervention had not been made or c) if circumstances had been 
less fortunate. These are handled under the SAE reporting system. 
 
 

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8.0 
STATISTICAL CONSIDERATIONS 
The following section describes the statistical methods for the primary analysis cohort (subjects with 
stenosis of the native aortic valve) unless otherwise specified. Data on roll-in and ViV cohorts will be 
descriptively summarized. The ViV cohort will be summarized relative to data from studies in which 
patients with a failed surgical bioprosthetic aortic valve were treated with TAVI for the valve-in-valve 
application. 27,28 Additional details on statistical analyses, including justification of clinical investigation 
design, sensitivity analyses, poolability analyses, subgroup analyses, and analysis of descriptive 
endpoints, will be maintained in a separate Statistical Analysis Plan (SAP). 
8.1 
Statistical Analyses 
8.1.1 
Primary Safety Endpoint Analysis 
The primary safety endpoint is a composite of all-cause mortality or fatal stroke/stroke with disability at 
12 months post index Navitor implantation procedure as adjudicated by the CEC per the VARC-3 event 
definitions.G  
The hypothesis testing of the primary safety endpoint will be performed for the mixed-risk (mixed 
intermediate and low risk) group based on the attempted population described in Section 8.1.1. If the 
primary safety endpoint is met, the trial will have demonstrated that the Navitor TAVI System is safe in 
the intermediate and low risk populations.  
 
Specifically, the following hypotheses will be tested: 
H10: pMixed ≥ PGMixed 
H1a: pMixed < PGMixed 
where pMixed is the primary safety endpoint event rate in the mixed intermediate and low risk group at 12 
months and PGMixed is the performance goal for a mixed intermediate and low risk group. This hypothesis 
will be tested at a one-sided significance level of 0.025 and the null hypothesis will be rejected if the 
97.5% upper confidence bound (UCB) for the event rate, pMixed, is less than the performance goal, 
PGMixed. The 12-month event rate will be estimated using the Kaplan-Meier (KM) method, and the 
standard error of KM estimate will be calculated using Greenwood method.  
The performance goal for the mixed-risk group (PGMixed) is determined by the proportion of the study 
population registered in the trial that is intermediate risk (propInt) or low risk (propLow). The performance 
goals in the intermediate risk and low risk groups are PGInt and PGLow, respectively. The mixed-risk group 
performance goal is determined by: 
PGMixed = (propInt * PGInt) + (propLow * PGLow) 
The 12-month primary safety endpoint event rates for the Navitor TAVI System in the intermediate and 
low risk groups are assumed to be 8.3% and 2.7%, respectively, based on published data from other 
TAVI pivotal trials (SURTAVI, PARTNER 2-S3i, Evolut Low Risk, and PARTNER 3). Per the 
recommendation of ISO 5840-3:2021, the international standard for heart valve substitutes implanted by 
 
 
G A composite of all-cause mortality or fatal stroke/stroke with disability per VARC-3 is equivalent to a composite of 
all-cause mortality or disabling stroke per VARC-2 as previously mentioned in Section 4.1. 

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transcatheter techniques, the risk-specific performance goal is set at twice the expected event rate in the 
corresponding risk group. Hence, the performance goals in the intermediate risk group (PGInt) and low 
risk group (PGLow) are set to be 16.6% and 5.4%, respectively. Assuming a 1:1 ratio between 
intermediate and low risk groups, with 262 registered subjects, there is 85% power at a one-sided 2.5% 
significance level assuming event rates of 8.3% and 2.7% in the intermediate and low risk groups, 
respectively, with the performance goal set at 11%, and an attrition rate of 10% at 12 months (due to 
withdrawal or loss to follow-up prior to 365 days). The proportion of intermediate risk group in this trial will 
be controlled to be between 50% and 70% to ensure there is representation of both intermediate and low 
risk subjects in the trial. A ratio of 1:1 is used for the assumed mix based on the minimum proportion of 
the intermediate risk group in the range (50%) that is required in the trial. The sample size of 262 
subjects provides at least 85% power for all scenarios within the range of proportions of intermediate risk 
group between 50% and 70%. The justifications for the expected rates and performance goals are 
provided in the SAP. 
The first 262 consecutively registered subjects will be used to test this hypothesis. 
8.1.2 Primary Effectiveness Endpoint Analysis 
The primary effectiveness endpoint is moderate or greater PVL at 30 days post index Navitor 
implantation procedure, assessed by the echocardiographic core laboratory.  
 
The hypothesis testing of the primary effectiveness endpoint will be performed based on the implanted 
population (described in Section 8.1.2) in whom a functional Navitor Valve remains implanted at 30 
days. If the primary effectiveness endpoint is met, the trial will have demonstrated that the Navitor TAVI 
System is effective in the intermediate and low risk populations. Given TAVI devices have the same 
anatomical considerations regardless of a subject’s surgical risk category, the expected event rate and 
performance goal for the primary effectiveness endpoint do not need to be adjusted according to the 
subject’s risk classification. Based on published data from other TAVI pivotal trials (SURTAVI, PARTNER 
2-S3i, Evolut Low Risk, and PARTNER 3), the 30-day primary effectiveness endpoint event rate for the 
Navitor TAVI System is assumed to be 3.3%. The performance goal, set to be twice the expected event 
rate based on the ISO 5840-3:2021 recommendation, is 6.6%. 
 
Specifically, the following hypothesis will be tested:  
H20: π ≥ 6.6% 
H2a: π < 6.6% 
where π is the proportion of subjects who have moderate or greater PVL at 30 days. π will be estimated 
as a binomial proportion. The hypothesis will be tested at a one-sided significance level of 0.025, and the 
null hypothesis will be rejected if the 97.5% upper confidence bound (UCB) for the proportion, π, is less 
than the performance goal of 6.6%. The 97.5% UCB will be calculated by the Clopper-Pearson method 
for exact confidence intervals for binomial proportion. 
With 390 subjects, there is approximately 85% power at a one-sided 2.5% significance level, assuming 
an event rate of 3.3%. With an approximately 10% attrition rate at 30 days (due to death or withdrawal 
prior to the 30-day visit, missing echo images, or inability of echo core lab to assess PVL on echo 
image), the sample size needed is 434 subjects. The justifications for the expected rate and the 
performance goal are provided in the SAP. 
All registered subjects with available 30-day PVL data will be used to test this hypothesis. 

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8.1.3 Secondary Endpoint Analyses 
The following are secondary endpoints for the primary analysis cohort:  
1. Mean change in mean transvalvular gradient between baseline and 12 months 
The null and alternative hypotheses are stated as: 
H30: ∆µ3,12 months - Baseline ≥ -10 mmHg 
H3a: ∆µ3,12 months - Baseline < -10 mmHg 
where ∆µ3,12 months - Baseline is the mean paired difference in mean transvalvular gradient from 
baseline to 12 months. 
This secondary endpoint will be assessed in the implanted population in whom a functional 
Navitor Valve remains implanted at 12 months. 
2. Mean change in effective orifice area between baseline and 12 months 
The null and alternative hypotheses are stated as: 
H40: ∆µ4,12 months - Baseline ≤ 0.4 cm2  
H4a: ∆µ4,12 months - Baseline > 0.4 cm2  
where ∆µ4,12 months - Baseline is the mean paired difference in effective orifice area from baseline to 12 
months. 
This secondary endpoint will be assessed in the implanted population in whom a functional 
Navitor Valve remains implanted at 12 months. 
3. Mean change in KCCQ quality of life score between baseline and 12 months 
The null and alternative hypotheses are stated as: 
H50: ∆µ5,12 months - Baseline ≤ 5 
H5a: ∆µ5,12 months - Baseline > 5 
where ∆µ5,12 months - Baseline is the mean paired difference in KCCQ quality of life score from baseline 
to 12 months.  
This secondary endpoint will be assessed in the attempted population. 
All secondary endpoint hypothesis tests will be performed with one-sample t-test at one-sided 
significance level of 0.025.  
8.2 
Sample Size Calculations 
The sample size (which includes attrition) required for evaluation of the primary safety endpoint and 
primary effectiveness endpoint are 262 and 434 subjects, respectively. The primary effectiveness 
endpoint requires a larger sample size (N=434) and therefore determines the overall sample size of the 
trial.  

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8.3 
Timing of Analysis 
The analysis in the primary analysis cohort for regulatory approval submission will be conducted after (1) 
the first 262 consecutively registered subjects have been followed for 12 monthsH, (2) all registered 
subjectsI have been followed for 30 daysJ, and (3) 400 patient-years of follow-up have been completed. 
The first 262 consecutively registered subjects will be used for the hypothesis testing of the primary 
safety endpoint, and all registered subjects will be used for the hypothesis testing of the primary 
effectiveness endpoint. 
8.4 
Subgroup Analysis 
Subgroup analysis will be performed to examine the consistency of the primary endpoints across 
baseline risk categories, specifically by risk group (intermediate vs low risk), and sex (male vs female). 
For each subgroup, KM estimates on the primary safety endpoint will be reported along with 95% 
confidence intervals, while proportional rate estimates on the primary effectiveness endpoint event will be 
reported along with 95% exact confidence intervals.  
8.5 
Multiplicity 
The study will be successful if both primary safety and effectiveness endpoints are met. If both primary 
endpoints are met, fixed sequence procedure in the pre-specified order of secondary endpoints listed 
below will be used. 
1. The secondary endpoint (#1) of change in mean transvalvular gradient between baseline and 12 
months. 
2. The secondary endpoint (#2) of change in mean effective orifice area between baseline and 
12 months.  
3. The secondary endpoint (#3) of change in KCCQ quality of life score between baseline and 
12 months.  
If one hypothesis test in the secondary endpoint sequence is not statistically significant, the subsequent 
tests will not be performed. Hence, no additional multiplicity adjustment is needed. 
8.6 
Pooling Strategy  
Additional information regarding the planned pooling strategy in this clinical study will be maintained in a 
separate SAP. 
8.7 
Procedures for Accounting for Missing Data 
Tipping point analyses will be performed to evaluate the impact of missing data on the primary safety and 
effectiveness endpoints analysis result. Details are provided in the SAP. 
 
 
H This includes subjects who die, withdraw, or are lost to follow-up before 365 days. 
I If more than 434 subjects are registered before enrollment completion for this cohort, all registered subjects will be 
included in the hypothesis testing of the primary effectiveness endpoint. 
J This includes subjects who die, withdraw, or are lost to follow-up before the 30-day follow-up visit. 

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8.8 
Planned Interim Analysis 
No interim analyses are planned for this study. 
8.9 
Statistical Criteria for Termination 
There are no statistical criteria for termination of this clinical investigation. 
8.10 
Success Criteria 
The study will be considered successful if both the primary safety and effectiveness endpoints are met. 
8.11 
Deviations from Statistical Plan 
The Sponsor will document any major changes to the statistical plan in an amendment to the statistical 
plan and any less significant changes to the planned analyses in the final report.  
 
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents for performing clinical 
investigation-related monitoring, audits, EC review and regulatory inspections. 
Subjects providing informed consent are agreeing to allow clinical investigation monitors or regulatory 
authorities, including foreign countries, to review in confidence any records identifying the subjects in this 
clinical investigation. This information may be shared with regulatory agencies; however, the Sponsor 
undertakes not to otherwise release the subject's personal and private information. 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Selection of Clinical Sites and Investigators 
The Sponsor will select investigators qualified by training and experience to participate in the clinical 
investigation. Sites will be selected based upon review of a recent site assessment, if applicable, and the 
qualifications of the investigators who will participate in the clinical investigation. A list of the participating 
sites will be provided upon request (refer to Appendix XII).  
 
All investigators involved in the conduct of the clinical investigation will be qualified by education, training, 
or experience to perform their tasks and this training will be documented appropriately. 
10.2 
Site Principal Investigator Responsibilities 
The role of the Site Principal Investigator is to implement and oversee the management of the day-to-day 
conduct of the clinical investigation, as well as ensure data integrity and the rights, safety and well-being 
of the subjects involved in the clinical investigation. The principal investigator shall support monitoring 
and reporting to EC and local Competent Authorities as necessary, throughout the conduct of the clinical 
investigation. The principal investigator is responsible for ensuring adequate training and qualification of 
the investigation site team and for maintaining oversight of their activities. The principal investigator may 

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delegate tasks to members of the investigation site team but retains responsibility for the clinical 
investigation. This also applies when activities are outsourced to an external organization by the principal 
investigator, in which case he/she shall exercise oversight to ensure the integrity of all tasks performed 
and any data generated by this external organization. 
10.3 
Clinical Investigation Finances and Agreements 
Abbott will finance the clinical investigation and will compensate investigational sites for participation in 
the clinical investigation per the conditions of agreement between Abbott and the investigational site. 
10.4 
CIP Amendments  
The Sponsor will provide approved CIP amendments to the Investigators prior to implementing the 
amendment. The Principal Investigator is responsible for notifying the EC or equivalent committee of the 
CIP amendment (administrative changes) or obtaining EC’s approval of the CIP amendment (changes in 
subject care or safety), according to the instructions provided by the Sponsor with the CIP amendment.  
 
Sites must document in writing acknowledgement/approval of the CIP amendment by the EC prior to 
implementation of the CIP amendment. Sites must also provide copies of this documentation to the 
Sponsor. 
 
For a history of CIP Amendments please see Appendix XI. 
10.5 
Measures Taken to Avoid and Minimize Bias 
The clinical trial will include the following measures to minimize bias in the conduct of the study and 
analysis of clinical data. 
10.5.1 Screening by an Interdisciplinary Heart Team 
At each investigational site, a heart team consisting of at least of one cardiac surgeon and one 
interventional cardiologist will be responsible for screening patients for surgical risk classification for 
participation in the clinical study. It is strongly recommended for the heart team to assess all available 
TAVI patients as potential candidates for the study. 
10.5.2 Use of a Screening Committee 
An independent Screening Committee (SC), consisting of interventional cardiologists and cardiac 
surgeons considered experts in the field of aortic valve replacement with a focus on TAVI, will be 
responsible for ensuring all subjects’ clinical eligibility per the SC Charter. SC review and approval, with 
voting members independent of the implanting site and the Sponsor, are required prior to implanting a 
subject with the Navitor Valve. The SC ensures subjects’ risk classification is done consistent with the 
trials used to derive the primary endpoint performance goal and therefore the hypothesis test is making a 
valid assessment. The Committee’s decision on whether to include the subject in the study will be 
documented and communicated to the enrolling investigational site by the Sponsor. If the SC considers 
the subject ineligible for participation in the study, the subject will be exited from the study and the reason 
for exclusion will be documented in the reviewers’ feedback form. 

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The composition, guiding policies, and operating procedures governing the SC in this clinical study are 
further defined in the SC Charter.  
10.5.3 Ascertainment and Adjudication of Adverse Events  
An independent Clinical Events Committee (CEC), consisting of, at a minimum, an interventional 
cardiologist, cardiothoracic surgeon, and a neurologist (for possibly neurological-related events only) will 
review and adjudicate pre-specified events reported by investigators in the clinical study as defined in the 
CEC Charter. Pre-specified clinical events defined in the primary and descriptive endpoints will be 
adjudicated in a consistent manner according to the VARC-3 definitions.21 The CEC will have final 
adjudication responsibilities for subject outcomes related to primary and descriptive outcome measures 
which will be outlined in a CEC charter. The CEC reduces bias by consistently applying adverse event 
definitions following VARC-3. This consistency allows for the performance goal to be fairly assessed as it 
was derived from previous clinical trials. Also, the independent adjudication allows for the results of this 
study to be descriptively compared to other studies in intermediate and low surgical risk populations.  
Adaptations for subsequent VARC definitions will also be captured in the CEC charter.  
10.5.4 Review of Echocardiographic Images by an Independent Echocardiographic Core 
Laboratory 
An independent Echocardiographic Core Laboratory will be utilized for the analysis of all study visit 
echocardiograms according to the echocardiographic protocol.  
Echocardiograms collected post implantation will be assessed for hemodynamic performance and aortic 
regurgitation (total regurgitation and paravalvular leak (PVL)) according to the Echo Core Laboratory 
Standard Operating Procedure Manual. The independent echocardiogram assessment allows for the 
results of this study to be descriptively compared to other studies in intermediate and low surgical risk 
populations. Each site is responsible for performing the echocardiogram according to the core laboratory 
imaging protocol, forwarding the examination to the core laboratory for analysis and providing local 
interpretation of the echocardiogram for clinical assessment. The echocardiographic core laboratory will 
be responsible for submitting their data to the Sponsor.  
10.5.5 Maintaining High Rates of Follow-Up Compliance  
The Sponsor will work with investigational sites to maintain a high follow-up compliance as follows: 
1. Site must clearly communicate the requirement for follow-up visits to the patient during the 
consenting process and obtain reasonable assurance that the patient has the intention and 
means to return for visits.  
2. Sponsor will monitor each sites’ subject follow-up compliance and communicate performance 
to the site as needed. Site should continue to communicate the importance of follow-up visits 
to each subject. 
3. Sites will be informed to promptly reschedule any missed subject visits, and to reinforce the 
necessity of a follow-up visit to the subject. 
4. Sites are advised to involve Sponsor if Sponsor assistance is needed to maintain high follow-
up compliance. Example: To cover costs associated with alternate transportation if a 
scheduled visit may be missed due to transportation/travel issues. 

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5. Sites should document reasons for any missed visits and/or subject withdrawals from the 
study. 
6. Sites should monitor their follow-up rates closely to promptly identify and address any issues. 
Additionally, investigational sites will be educated on the importance of maintaining low rates of 
withdrawals and will be expected to make all effort to maintain low withdrawals during study conduct.  
10.5.6 Standardized Administration of Patient-Reported Outcome Measures and Stroke 
Assessment Scales  
A standardized script will be used when administering patient-reported outcome (PRO) measures to 
minimize bias and undue influence. All PRO measures must be completed by the subject or his/her legal 
representative (where allowed per local regulations). In the latter case, a note to file must be completed 
to document the inability of the subject to complete the measures(s). 
The Modified Rankin Scale (mRS) must be completed by an assessor who has a current certificate that 
demonstrates completion of an accredited training program for this stroke scale. Standardized PRO 
measures and assessment scales minimize bias in the reporting of clinical events and perceived patient 
outcomes, thus allowing for a more robust comparison to results captured from other studies utilizing 
these same measures. 
10.6 
Training 
10.6.1 Site Training 
All Investigators and clinical investigation personnel are required to attend Sponsor training sessions, 
which may be conducted at an Investigator's meeting, a site initiation visit, or other training sessions. 
Remote (e.g., telephone, on-line, etc.) or self-training may take place as determined necessary by the 
sponsor. Training of Investigators and clinical investigation personnel will include, but is not limited to, the 
CIP requirements, investigational device usage, electronic case report form completion, and clinical 
investigation personnel responsibilities. All Investigators and clinical investigation personnel that are 
trained must sign a training log (or an equivalent) upon completion of the training. Prior to signing the 
training log, Investigators and clinical investigation personnel must not perform any CIP-related activities 
that are not considered standard of care at the site.  
10.7 
Monitoring 
 
Sponsor and/or designee will monitor the clinical investigation over its duration according to the CIP-
specific monitoring plan which will include the planned extent of source data verification.  
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following criteria 
are met:  
 
• 
The investigator understands and accepts the obligation to conduct the clinical investigation 
according to the CIP and applicable regulations and has signed the Investigator Agreement or the 
Clinical Trial Agreement.  

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• 
The Investigator and his/her staff should have sufficient time and facilities to conduct the clinical 
investigation and should have access to an adequate number of appropriate subjects to conduct 
the clinical investigation.  
• 
Sites must have source documentation (including original medical records) to substantiate proper 
informed consent procedures, adherence to CIP procedures, adequate reporting and follow-up of 
adverse events, accuracy of data collected on case report forms, and device information.  
• 
The Investigator/site will permit access to such records and will maintain a monitoring visit sign-in 
log at the site. The Investigator will agree to dedicate an adequate amount of time to the 
monitoring process. The Investigator and/or research coordinator will be available for monitoring 
visits. It is expected that the Investigator will provide the monitor with a suitable working 
environment for review of clinical investigation-related documents. 
For instructions for obtaining the Monitoring Plan, please reference Appendix XIII. 
10.8 
Deviations from CIP 
The Investigator should not deviate from the CIP for any reason except in cases of medical emergencies 
when the deviation is necessary to protect the rights, safety, and well-being of the subject, or to eliminate 
an apparent immediate hazard to the subject. In that event, the Investigator will notify Sponsor 
immediately by phone or in writing.  
 
The Sponsor will not grant any waivers for CIP deviations. Sites must report all deviations to the Sponsor 
using the Deviation CRF. The Sponsor will monitor the occurrence of CIP for evaluation of investigator 
compliance to the CIP and regulatory requirements and handle according to written procedures. 
Investigators will determine the cause of deviations, implement corrective actions and inform their EC or 
equivalent committee of CIP deviations in accordance with their specific EC or equivalent committee 
reporting policies and procedures.  
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or 
company representative will attempt to secure compliance by one or more of the following (and not 
limited to):  
• Visiting the investigator and/or delegate 
• Telephoning the investigator and/or delegate 
• Corresponding with the investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the CIP, or any other conditions of the clinical 
investigation may result in further escalation in accordance with the Sponsor’s written procedures, 
including securing compliance or, at its sole discretion, the Sponsor may terminate the investigator's 
participation in the clinical investigation.  
10.9 
Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical investigation records, including 
source documentation, for inspection during a Quality Assurance audit.  

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If an investigator is contacted by a Regulatory Agency in relation to this clinical investigation, the 
Investigator will notify Sponsor immediately. The Investigator and Research Coordinator must be 
available to respond to reasonable requests and audit queries made during the audit process. The 
Investigator must provide the Sponsor with copies of all correspondence that may affect the review of the 
current clinical investigation (e.g., Form FDA 483, Inspectional Observations, Warning Letters, Inspection 
Reports, etc.). The Sponsor may provide any needed assistance in responding to regulatory audits. 
10.10 
Sponsor Auditing 
Sponsor audits may be conducted for the clinical study in accordance with the below requirements:  
1. The Sponsor shall prepare an audit plan as well as the operating procedures for the related duties 
and conduct audits in accordance with the audit plan and the operating procedures. 
2. Individuals engaged in auditing (hereinafter referred to as "auditor") shall be different than those 
in charge of medical device development or monitoring. 
3. The auditor shall prepare an audit report documenting the matters confirmed in the audit to certify 
and verify that the audit has been conducted and submit them to the Sponsor. 
10.11 
Committees 
The clinical trial will utilize the following committees.  
10.11.1 Steering Committee 
 
The Steering Committee is responsible for overseeing the scientific and operational aspects of the 
clinical investigation. This committee will meet regularly to monitor subject enrollment, general data 
collection and non-compliance with the CIP at individual centers, to review and act upon 
recommendations of the Data Monitoring Committee (DMC), to review operational issues that may arise 
and warrant a CIP amendment or other corrective action, and to determine policy regarding the primary 
results publication arising from data generated from the performance of the clinical investigation. 
10.11.2 Screening Committee  
Refer to Section 10.5.2 for Screening Committee.  
10.11.3 Clinical Events Committee (CEC) 
The CEC is an independent adjudication body comprised of qualified physicians who are not participants 
in the clinical investigation. The CEC will review and adjudicate pre-specified events reported by 
investigators or identified by Safety personnel for the clinical investigation as defined in the CEC charter 
and according to definitions provided in this CIP.  
10.11.4 Data Monitoring Committee (DMC) 
The DMC is an independent multidisciplinary group restricted to individuals free of apparent significant 
conflicts of interest. The source of these conflicts may be financial, scientific, or regulatory in nature. The 
DMC is typically composed of at least two physicians with experience relevant to the clinical investigation 
and a biostatistician.  

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The DMC will serve in an advisory role to the Sponsor to ensure safety by reviewing cumulative data 
from the clinical investigation at prescribed intervals for safeguarding the interests of enrolled subjects 
and those patients yet to be enrolled, as well as the continuing validity and scientific merit of the clinical 
investigation. The composition, frequency of the meetings, and the statistical monitoring guidelines are 
described in detail in the DMC charter. 
The DMC may make a recommendation for modifications or termination of the clinical investigation 
based on any perceived safety concerns regardless of statistical significance. The recommendations of 
the DMC are not binding, and all final decisions related to clinical investigations modifications rest with 
the Sponsor.  
10.11.5 Publications Committee  
A Publication Committee shall be established to oversee clinical investigations publications, including 
publication planning and authorship determinations. Publication Committee membership may include 
members of the Steering Committee, Principal Investigators, a representative of the Sponsor, and a 
statistician. The Publication Committee will determine policy and strategies regarding individual 
presentations and/or publications arising from clinical investigation generated data. The committee will 
also review all external requests for accessing clinical investigation-related data and strategies aligning 
with the Sponsor’s presentation and publication team expectations. The committee will also follow the 
Sponsor’s applicable policies and Standard Operating Procedures. 
11.0 DATA HANDLING AND RECORD KEEPING  
Sponsor and/or its affiliates will maintain documentation of the systems and procedures used in data 
collection for the duration of the clinical investigation.  
 
CRF data collection will be performed through a secure web portal and only authorized personnel will 
access the EDC system using a unique username and password to enter, review or correct data. 
Passwords and electronic signatures will be strictly confidential.  
 
The data will be subjected to consistency and validation checks within the EDC system and 
supplemental review by the Sponsor.  
 
At the end of the clinical investigation, completed CRF images with the date-and-time stamped electronic 
audit trail indicating the user, the data entered, and any reason for change (if applicable) will be provided 
to the investigational sites, if requested.  
 
For the duration of the clinical investigation, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical investigation progress records, 
laboratory reports, CRFs, signed ICFs, device accountability records (if applicable), correspondence with 
the EC and clinical investigation monitor/Sponsor, adverse event reports, and information regarding 
subject discontinuation or completion of the clinical investigation. 
11.1 
Protection of Personally Identifiable Information 
The Sponsor respects and protects personally identifiable information collected or maintained for this 
clinical investigation.  

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The Sponsor implements technical and physical access controls to ensure that Personal Information is 
accessible only to and processed only on a ‘need to know’ basis, including periodic review of access 
rights, and revocation of access when an individual’s employment is terminated or the individual 
transitions to a role that does not require access to Personal Information, and appropriate restrictions on 
physical access to premises, facilities, equipment, and records containing Personal Information. 
 
The Sponsor requires the investigational sites to enter only pseudonymous Personal Information (key-
coded) necessary to conduct the clinical investigation, such as the patient’s medical condition, treatment, 
dates of treatment, etc., into Sponsor’s data management systems. The Sponsor discloses as part of the 
clinical investigation informed consent process that some Sponsor representatives still may see Personal 
Information at the participating sites for technical support of the participating physicians on the device 
implant or procedures, monitoring and quality control purposes. All parties will observe confidentiality of 
Personal Information always throughout the clinical investigation. All reports and data publications will 
preserve the privacy of each subject and confidentiality of his/her information. 
 
The Sponsor data management systems and processes were designed, developed, and tested 
according to industry standards to appropriately safeguard Confidential Information (including any 
Personal Information) against unauthorized access and/or interference by third parties, intrusion, theft, 
destruction, loss or alteration. Clinical Investigation data are encrypted in transit and at rest.  
 
The Sponsor maintains a Privacy Incident procedure that complies in all respects with Applicable Law 
and industry best practices. 
11.2 
Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, data cleaning, and 
issuing and resolving data discrepancies, and database locking. If appropriate, the Sponsor may update 
the DMP throughout the duration of the clinical investigation. The Sponsor will track and document 
control all revisions. 
11.3 
Source Documentation 
 
Regulations and GCP require the Investigator to maintain information in the subject’s original medical 
records that corroborates data collected on the CRFs. To comply with these regulatory 
requirements/GCP, sites should include the following information in the subject record at a minimum and 
if applicable to the clinical investigation: 
• 
Medical history/physical condition of the subject before involvement in the clinical investigation 
sufficient to verify CIP entry criteria 
• 
Dated and signed notes on the day of entry into the clinical investigation referencing the Sponsor, 
CIP number, subject ID number, and a statement that informed consent was obtained 
• 
Dated and signed notes from each subject visit (for specific results of procedures and 
examinations) 

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• 
AEs reported and their resolution, including supporting documents, such as discharge 
summaries, catheterization laboratory reports, ECGs, and lab results including documentation of 
site awareness of SAEs and of investigator assessment of device relationship for SAEs. 
• 
CIP-required laboratory reports and 12-lead ECGs, reviewed and annotated for clinical 
significance of out of range results (if applicable).  
• 
Notes regarding CIP-required and prescription medications taken during the clinical investigation 
(including start and stop dates) 
• 
Subject’s condition upon completion of or withdrawal from the clinical investigation 
• 
Any other data required to substantiate data entered into the CRF 
• 
Patient reported outcome measures may be completed using CRF worksheets. This serves as 
source documentation. 
11.4 
Case Report Form Completion 
 
Site research personnel trained on the CIP and CRF completion will perform the primary data collection 
clearly and accurately based on source-documented hospital and/or clinic chart reviews. The investigator 
will ensure accuracy, completeness, legibility, and timeliness of the data reported to the Sponsor on the 
CRFs and in all required reports. 
 
Sites will collect data on all subjects who sign an informed consent form, including subjects who may not 
meet all inclusion/exclusion criteria during screening at the index procedure. 
 
Only authorized site personnel will be permitted to enter the CRF data through the EDC system deployed 
by the Sponsor. The Sponsor will use an electronic audit trail to track any subsequent changes of the 
entered data. 
 
For instructions for obtaining the trial case report forms, please see Appendix XIV. 
11.5 
Record Retention 
The Sponsor and Investigator/Site will archive and retain all documents pertaining to the clinical 
investigation as per the applicable regulatory record retention requirements. The Investigator must obtain 
permission from Sponsor in writing before destroying or transferring control of any clinical investigation 
records. 
11.6 
Investigational Devices Accountability 
The Sponsor ships investigational products only to the Principal Investigator (the responsible leader of 
the investigational site) or his/her legal designee of each site, after site activation and shipping 
authorization is complete.  
 
The Investigator or an authorized designee must maintain adequate records of the receipt and 
disposition of each investigational device, including serial number, date received, date used, subject 
identification, and final device disposition. 
 

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Storage locations for the devices at investigational sites must be locked with access restricted only to 
investigators and authorized personnel.  
 
Sites must return all investigational devices associated with a device failure or device deficiency 
immediately to the Sponsor in biohazard or protective packaging.  
 
The clinical investigation will use the electronic Device Accountability Log supplied by the Sponsor for 
device accountability. The electronic Device Accountability Log documents the disposition of all 
investigational devices used as reported by Device case report form and unused product that have been 
returned to Sponsor. 
 
12.0 ETHICAL CONSIDERATION 
 
12.1 
Institutional Review Board/Medical Ethics Committee Review and Approval 
The Principal Investigator at each investigational site will obtain EC approval for the CIP and ICF/other 
written information provided to the patient prior to consenting and enrolling patients in this clinical 
investigation. The site must receive the approval letter prior to the start of this clinical investigation and 
provide a copy to the Sponsor.  
 
Sites will submit any amendments to the CIP as well as associated ICF changes to the EC and written 
approval obtained prior to implementation, according to each institution’s EC requirements.  
 
No changes will be made to the CIP or ICF or other written information provided to the patient without 
appropriate approvals, including EC, the Sponsor, and the regulatory agencies (if applicable).  
 
Until the clinical investigation is completed, the Investigator will advise his/her EC of the progress of this 
clinical investigation, per EC requirements. Written approval must be obtained from the EC yearly to 
continue the clinical investigation, or according to each institution’s EC requirements.  
 
Sites will not perform any investigative procedures, other than those defined in this CIP, on the enrolled 
subjects without the written agreement of the EC and the Sponsor. 
 
13.0 CLINICAL INVESTIGATION CONCLUSION 
The clinical investigation will be concluded when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators or the Sponsor has provided formal 
documentation of clinical investigation closure. 
 
The Sponsor will submit the clinical investigation report within one year of the end of the investigation to 
the investigational sites, Competent Authorities, and reviewing ECs.  

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13.1 
Suspension or Early Termination of the Clinical Investigation 
While no formal statistical rule for early termination of the clinical investigation for insufficient 
effectiveness of the device under investigation is defined, the Sponsor reserves the right to discontinue 
the clinical investigation at any stage or reduce the follow-up period with suitable written notice to the 
investigator. Possible reason(s) may include, but are not limited to: 
• 
Unanticipated ADE event occurs and it presents an unreasonable risk to the participating subjects 
• 
An oversight committee (e.g., Steering Committee, Executive Committee, Data Monitoring 
Committee) makes a recommendation to stop or terminate the clinical investigation which is 
agreed with by the sponsor.  
• 
Further product development is cancelled. 
13.1.1 Subject Follow-up for Early Termination or Suspension of Study 
If the Sponsor suspends or prematurely terminates the clinical investigation at an individual site in the 
interest of safety, the Sponsor will inform all other Principal Investigators. 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing 
resources to fulfill the obligations from the CIP and existing agreements for following the subjects 
enrolled in the clinical investigation. Details for such subjects follow up will be provided. The Principal 
Investigator or authorized designee will promptly inform the enrolled subjects at his/her site, if 
appropriate. 
 
The investigator will be requested to return all clinical investigation materials (including devices) to the 
Sponsor and provide a written statement to the EC (if applicable). All applicable clinical investigation 
document shall be subject to the same retention policy as detailed in Section 11.0 of the CIP. 
 
A Principal Investigator, EC, or regulatory authority may also suspend or prematurely terminate 
participation in the clinical investigation at the investigational site(s) for which they are responsible. The 
investigators will follow the requirements specified in the Clinical Trial Agreement. 
 
If a suspended investigation is to be resumed, a prior approval should be obtained from the EC and a 
notification should be sent to the regulatory bodies, and if subjects were informed of suspension, they 
shall be informed of the resumption of the clinical investigation. 
14.0 PUBLICATION POLICY 
The data and results from the clinical investigation are the sole property of the Sponsor. The Sponsor 
shall have the right to access and use all data and results generated during the clinical investigation. The 
Investigators will not use this clinical investigation-related data without the written consent of the Sponsor 
for any purpose other than for clinical investigation completion or for generation of publication materials, 
as referenced in the Clinical Trial Agreement. Single-center results from within this clinical investigation 
are not allowed to be published or presented before the multi-center results are published. The Sponsor 
must review and approve any proposals for publications or presentations by the investigators in a timely 
manner in compliance with the Sponsor’s publication policy set forth in the Clinical Trial Agreement. 
 

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The Sponsor will be responsible for registering this clinical investigation on ClinicalTrials.gov website, in 
accordance with the International Committee of Medical Journal Editors guidelines, or any other 
applicable guidelines. The Sponsor shall be responsible for any such registration and results posting as 
required by the ClinicalTrials.gov website. Institution and/or Principal Investigator(s) shall not take any 
action to register the clinical investigation. A full report of the pre-specified outcomes, regardless of the 
results, will be made public through the ClinicalTrials.gov website no later than 12 months after clinical 
investigation completion, as required by section 801 of the FDA Amendments Act. If this clinical 
investigation is terminated early, the Sponsor will make every effort to hasten the release of the pre-
specified outcomes through the ClinicalTrials.gov website. 
15.0 RISK ANALYSIS 
 
15.1 
Anticipated Clinical Benefits 
While there are no guaranteed clinical benefits associated with participation in this clinical study, it is 
expected that patients implanted with a Navitor Valve with the FlexNav Delivery System will experience 
similar improvements in hemodynamic function and symptoms related to severe aortic stenosis as 
patients implanted with other commercially available transcatheter valves. This includes hemodynamic 
improvements and reduction of clinical symptoms including chest pain, fatigue, shortness of breath, 
dizziness, and fainting.  
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Risks associated with the specified device and procedure, together with their likely incidence, are 
described in Appendix XV. There may be risks related to the device under investigation that are 
unknown at present. Likewise, the exact frequency of the risk may be unknown. 
Commercially available models of the Navitor TAVI system may be used in VANTAGE in geographies 
where an approval has been obtained from the applicable Competent Authority and/or EC. Since the 
commercial units and the clinical units are physically identical and the procedures involved are also the 
same, there are no additional risk concerns associated with the use of the commercial units in 
VANTAGE.  
 

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APPENDIX I: ABBREVIATIONS AND ACRONYMS 
The following is a list of abbreviations and acronyms used in the CIP. 
 
Abbreviation 
Term 
6MWT 
Six Minute Walk Test 
ACT 
Activated Clotting Time 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AHA 
American Heart Association 
AMI 
Acute Myocardial Infarction 
AP 
Attempted Population 
AS 
Aortic Stenosis 
AVA 
Aortic Valve Area 
AVR 
Aortic Valve Replacement 
BARC 
Bleeding Academic Research Consortium 
BNP 
B-type Natriuretic Peptide 
BUN 
Blood urea nitrogen 
BVF 
Bioprosthetic Valve Failure 
CAD 
Coronary Artery Disease 
CBC 
Complete Blood Count 
CE 
Conformité Européene (European Conformity) 
CEC 
Clinical Events Committee 
CIP 
Clinical Investigation Plan 
CPB 
Cardiopulmonary Bypass 
eCRF 
Electronic Case Report Form 
CT 
Computed Tomography 
CVA 
Cerebral Vascular Accident 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
Echo 
Echocardiography 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
EOA 
Effective Orifice Area 
EU 
European Union 
GI 
Gastro Intestinal 
GFR 
Glomerular filtration rate 
HALT 
Hypoattenuated Leaflet Thickening 
HVD 
Hemodynamic Valve Deterioration 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IDC 
Implantable Cardioverter Defibrillator 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 

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INR 
International Normalized Ratio 
IP 
Implanted Population 
IRB 
Investigational Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KM 
Kaplan-Meier 
LAAO 
Left Atrial Appendage Occlusion 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
LVOT 
Left Ventricular Outflow Tract 
MAC 
Mitral Annular Calcification 
MI 
Myocardial Infarction 
MR 
Mitral Regurgitation 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NSTEMI 
Non-ST-Segment Elevation Myocardial Infarction 
NYHA 
New York Heart Association 
PCI 
Percutaneous Coronary Intervention 
PI 
Principal Investigator 
PRO 
Patient Reported Outcome 
PVL 
Paravalvular Leak 
QoL 
Quality of Life 
RA 
Right Atrium 
RV 
Right Ventricular 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAVR 
Surgical Aortic Valve Replacement 
SC 
Screening Committee 
STEMI 
ST-Segment Elevation Myocardial Infarction 
STS 
Society of Thoracic Surgeons 
SVD 
Structural Valve Deterioration 
TAVI 
Transcatheter Aortic Valve Implantation 
TEE 
Transesophageal Echocardiogram (same as TOE) 
TEER 
Transcatheter Edge-to-Edge Repair 
TIA 
Transient Ischemia Attack 
TTE 
Transthoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Effect 
UCB 
Upper Confidence Bound 
USA 
United States of America (same as US) 
VARC  
Valve Academic Research Consortium  
ViV 
Valve-in-Valve 
WBC 
White Blood Cell 

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APPENDIX II: DEFINITIONS 
The following are definitions to be used in this clinical investigation. While some terms have not been 
used in the main body of the CIP they may be used for coding of adverse events.  
 
ACUTE KIDNEY INJURY21 
1.  STAGE 1  
• 
Increase in serum creatinine ≥150–200% (≥1.5–2.0x increase) within 7 days compared 
with baseline OR 
• 
Increase of ≥0.3 mg/dL (≥26.4 mmol/L) within 48 hours of the index procedure  
2. STAGE 2  
• 
Increase in serum creatinine ≥200–300% (≥2.0–3.0x increase) within 7 days compared 
with baseline  
3. STAGE 3  
• 
Increase in serum creatinine ≥300% (≥3.0x increase) within 7 days compared with 
baseline OR  
• 
Serum creatinine ≥4.0 mg/dL (≥354 μmol/L) with an acute increase of ≥0.5 mg/dL (≥44 
μmol/L) procedure 
4. STAGE 4 
• 
AKI requiring new temporary or permanent renal replacement therapy 
 
ADVERSE EVENT 32  
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the medical device under investigation and whether anticipated or unanticipated. 
1. SERIOUS ADVERSE EVENT 
Serious Adverse Event (SAE) is an AE that led to any of the following:  
• 
death, 
• 
serious deterioration in health of the subject, that either resulted in any of the following: 
o life-threatening illness or injury 
o permanent impairment of a body structure or a body function 
o hospitalization or prolongation of patient hospitalization 
o medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
o chronic disease  
• 
fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note: A planned hospitalization for a pre-existing condition, or a procedure required by the CIP 
without a serious deterioration in health, is not considered a SAE. 
2. ADVERSE DEVICE EFFECT (ADE) 

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An adverse event related to the use of an investigational medical device. 
 
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. 
 
This definition includes any event resulting from the use error or from intentional misuse of the 
investigational medical device. 
 
3. SERIOUS ADVERSE DEVICE EFFECT (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event.  
 
4. UNANTICIPATED ADVERSE DEVICE EFFECT (UADE) 
As defined in 21 CFR §812.3, unanticipated adverse device effects (UADE) are defined as any 
serious adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the CIP or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects.  
 
5. ANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (ASADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has been 
previously identified in the risk analysis report. 
 
6. UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
A 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. 
 
7. DEVICE DEFICIENCY (DD) 
A device deficiency is defined as an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. Device deficiencies include malfunctions, use 
errors and inadequate labeling. 
 
BLEEDING AND TRANSFUSION21 
Overt bleeding that fulfills one of the following criteria: 
1. Type 1 
• 
Overt bleeding that does not require surgical or percutaneous intervention, but does 
require medical intervention by a health care professional, leading to hospitalization, an 
increased level of care, or medical evaluation (BARC 2) 
• 
Overt bleeding that requires a transfusion of 1 unit of whole blood/red blood cells (BARC 
3a) 
2. Type 2 
• 
Overt bleeding that requires a transfusion of 2–4 units of whole blood/red blood cells 
(BARC 3a) 

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• 
Overt bleeding associated with a hemoglobin drop of >3 g/dL (>1.86 mmol/L) but <5 g/d 
(<3.1 mmol/L) (BARC 3a) 
3. Type 3 
• 
Overt bleeding in a critical organ, such as intracranial, intraspinal, intraocular, pericardial 
(associated with haemodynamic compromise/tamponade and necessitating intervention), 
or intramuscular with compartment syndrome (BARC 3b, BARC 3c) 
• 
Overt bleeding causing hypovolemic shock or severe hypotension (systolic blood pressure 
<90 mmHg lasting >30 min and not responding to volume resuscitation) or requiring 
vasopressors or surgery (BARC 3b) 
• 
Overt bleeding requiring reoperation, surgical exploration, or re-intervention for the 
purpose of controlling bleeding (BARC 3b, BARC 4) 
• 
Post-thoracotomy chest tube output ≥2 L within a 24-h period (BARC 4) 
• 
Overt bleeding requiring a transfusion of ≥5 units of whole blood/red blood cells (BARC 
3a) 
• 
Overt bleeding associated with a haemoglobin drop ≥5 g/dL (≥3.1 mmol/L) (BARC 3b) 
4. Type 4 
• 
Overt bleeding leading to death. Should be classified as: 
o Probable: Clinical suspicion (BARC 5a) 
o Definite: Confirmed by autopsy or imaging (BARC 5b) 
 
 
CARDIAC STRUCTURAL COMPLICATIONS21 
1. Major 
One of the following: 
• 
Cardiac structure perforation, injury, or compromise resulting in death, VARC type ≥2 
bleeding, haemodynamic compromise or tamponade, or requiring unplanned surgical or 
percutaneous intervention 
• 
New pericardial effusion resulting in death, VARC type ≥2 bleeding, haemodynamic 
compromise or tamponade, or requiring unplanned surgical or percutaneous intervention 
• 
Coronary obstruction resulting in death, haemodynamic compromise, myocardial 
infarction, or unplanned surgical or percutaneous intervention. Coronary obstruction may 
be acute (during the procedure) or delayed (after completion of the procedure). 
• 
Coronary artery access difficulties for needed coronary angiography or intervention, 
resulting in death, haemodynamic compromise, myocardial infarction, coronary or aortic 
root injury, compromise in aortic valve prosthesis integrity, unplanned surgical or 
percutaneous intervention, or the inability to perform the intended procedure 
2. Minor 
One of the following: 
• 
Cardiac structure perforation, injury, or compromise not resulting in death, VARC type ≥2 
bleeding, haemodynamic compromise or tamponade, or requiring unplanned surgical or 
percutaneous intervention 
• 
New pericardial effusion not resulting in death, VARC type ≥2 bleeding, haemodynamic 
compromise or tamponade, or requiring unplanned surgical or percutaneous intervention 

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• 
Coronary obstruction not resulting in death, haemodynamic compromise, myocardial 
infarction, or unplanned surgical or percutaneous intervention 
• 
Coronary artery access difficulties for needed coronary angiography or intervention, not 
resulting in death, haemodynamic compromise, myocardial infarction, coronary or aortic 
root injury, compromise in aortic valve prosthesis integrity, unplanned surgical or 
percutaneous intervention, or the inability to perform the intended procedure 
 
 
DEATH (MORTALITY)21 
1. ALL-CAUSE MORTALITY 
2. CARDIOVASCULAR MORTALITY 
Death meeting one of the following criteria: 
• 
Related to heart failure, cardiogenic shock, bioprosthetic valve dysfunction, myocardial 
infarction, stroke, thromboembolism, bleeding, tamponade, vascular complication, 
arrhythmia or conduction system disturbances, cardiovascular infection (e.g. mediastinitis, 
endocarditis) or other clear cardiovascular cause 
• 
Intraprocedural death 
• 
Sudden death 
• 
Death of unknown cause 
3. VALVE-RELATED MORTALITY 
Death presumed to be related to bioprosthetic valve dysfunction 
4. NON-CARDIOVASCULAR MORTALITY 
Death clearly related to a non-cardiovascular cause: such as respiratory failure not related to 
heart failure, (e.g. pneumonia), renal failure, liver failure, infection (e.g. urosepsis), cancer 
trauma, and suicide) 
 
 
HOSPITALIZATION (or REHOSPITALIZATION)21  
Any admission after the index hospitalization or study enrollment to an inpatient unit or hospital ward for 
≥ 24h, including an emergency department stay. Hospitalizations planned for pre-existing conditions are 
excluded unless there is worsening of the baseline condition. Visits to urgent care centers or emergency 
departments < 24 hours may also be included if substantive intensification of therapy changes (e.g. heart 
failure episodes) are enacted (e.g. intravenous diuretics, significant increases in drug therapy dosages or 
addition of new pharmacotherapy agents). Hospitalization is further categorized:  
 
1. CARDIOVASCULAR HOSPITALIZATION  
• 
Procedure-related or Valve-related Hospitalization  
o Hospitalization for new complications such as stroke, bleeding (e.g. 
hemothorax, retroperitoneal hematoma), pericardial effusion, vascular or access-
site complication (e.g. limb ischemia, wound infection), new conduction 
disturbance or arrhythmia (e.g. atrioventricular block, atrial fibrillation), acute 
kidney injury, or any other procedure-related new complication, including 
periprocedural valve-related heart failure (e.g. paravalvular leak, worsening LV 
function, worsening sub-valvular obstruction)  

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o Exacerbation or deterioration of previous in-hospital periprocedural 
complication (e.g. ventilator-induced pneumonia, recurrent pericardial or pleural 
effusion, recurrent hemothorax, valve-related heart failure)  
o Bioprosthetic valve dysfunction such as valve thrombosis, endocarditis, 
structural valve deterioration, or non-structural valve dysfunction  
o Bleeding complications related to oral anticoagulation or antiplatelet therapy 
for valve-related thromboembolic prevention or atrial fibrillation 
o Heart failure related hospitalizations requiring that new or worsening heart 
failure be the predominant reason for a hospital stay ≥ 24h on the basis of 
symptoms and signs of heart failure with confirmation by diagnostic tests and 
necessitating treatment using intravenous or mechanical heart failure therapies. 
Includes primary (cardiac related) and secondary (non-cardiac related)  
• 
Oher Cardiovascular Hospitalization  
o Cardiovascular hospitalization not directly related to the index procedure or 
the untreated native aortic valve  
Including: acute myocardial infarction or chronic coronary artery disease, 
hypertension, arrhythmia (not related to the procedure or aortic valve), heart failure 
from other specific and proven etiologies (e.g. cardiomyopathies, concomitant 
untreated non-aortic valvular disease, severe right ventricular dysfunction), 
peripheral vascular disease  
 
2. NON-CARDIOVASCULAR HOSPITALIZATION  
o Hospitalization not due to cardiovascular causes as defined above  
Including: non-cardiovascular infection and sepsis (e.g. urosepsis), respiratory 
failure that is not related to heart failure (e.g. pneumonia), renal failure, liver failure, 
delirium or dementia, cancer, trauma, or psychiatric illness 
 
 
MYOCARDIAL INFARCTION21 
1. Type 1 (Spontaneous MI) (>48 h after the index procedure) 
• 
Detection of a rise and/or fall of cTn values with at least one value above the 99th 
percentile URL with at least one of the following: 
o Symptoms of acute ischaemia 
o New ischaemic ECG changes (new ST-segment or T-wave changes or new LBBB) 
o New pathologic Q-waves in ≥2 contiguous leads 
o Imaging evidence of a new loss of viable myocardium or new wall motion 
abnormality in pattern consistent with an ischaemic aetiology  
o Identification of a coronary thrombus by angiography or autopsy 
• 
Post-mortem demonstration of an atherothrombus in the artery supplying the infarcted 
myocardium, or a macroscopically large circumscribed area of necrosis with or without 
intramyocardial haemorrhage, meets the type 1 MI criteria regardless of cTn 
values(troponin)  
2. Type 2 (Imbalance between myocardial oxygen supply and demand) 

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• 
Detection of a rise and/or fall of cTn values with at least one value above the 99th 
percentile URL, and evidence of an imbalance between myocardial oxygen supply and 
demand unrelated to coronary thrombosis, requiring at least one of the following: 
o Symptoms of ischaemia 
o ECG changes indicative of new ischaemia (new ST-segment or T-wave changes or 
new LBBB) 
o New pathologic Q-waves in ≥2 contiguous leads 
o Imaging evidence of a new loss of viable myocardium or new wall motion abnormality  
3. Type 3 (MI associated with sudden cardiac death) 
• 
Patients who suffer cardiac death, with symptoms suggestive of myocardial ischaemia 
accompanied by presumed new ischaemic ECG changes or ventricular fibrillation but die 
before blood samples for biomarkers can be obtained, or before increases in cardiac 
biomarkers can be identified, or MI is detected by autopsy examination. 
4. Type 4A (Criteria for PCI-related MI ≤ 48 h after the index procedure) 
• 
In patients with normal baseline CK-MB: The peak CK-MB measured within 48 h of the 
procedure ≥10x the local laboratory ULN or CKMB ≥5x ULN with one or more of the 
following: 
o New pathologic Q-waves in ≥2 contiguous leads 
o New persistent LBBB 
o Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm 
diameter branch 
o Substantial new loss of viable myocardium on imaging related to the procedure 
• 
In the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level 
measured within 48 h of the procedure rises to ≥70x the local laboratory ULN or ≥35x ULN 
with one or more of the following: 
o New pathologic Q-waves in ≥2 contiguous leads 
o New persistent LBBB 
o Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm 
diameter branch 
o Substantial new loss of viable myocardium on imaging related to the procedure 
• 
In patients with elevated baseline CK-MB (or cTn): The CK-MB (or cTn) rises by an 
absolute increment equal to those levels recommended above from the most recent pre-
procedure level plus new ECG changes as described. 
5. Type 4B (Stent thrombosis) 
• 
Stent thrombosis as documented by angiography or autopsy using the same criteria 
utilized for type 1 MI. 
o Acute: 0 to 24 h 
o Subacute: >24 h to 30 days 
o Late: >30 days to 1 year 
o Very late: >1 year after stent implantation  
6. Type 5 Periprocedural (post-SAVR, TAVR or CABG) MI (≤48 h after the index procedure) 

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• 
In patients with normal baseline CK-MB: The peak CK-MB measured within 48 h of the 
procedure ≥10x the local laboratory ULN or CKMB ≥5x ULN with one or more of the 
following: 
o New pathologic Q-waves in ≥2 contiguous leads 
o New persistent LBBB 
o Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm 
diameter branch 
o Substantial new loss of viable myocardium on imaging related to the procedure 
• 
In the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level 
measured within 48 h of the procedure rises to ≥70x the local laboratory ULN or ≥35x ULN 
with one or more of the following: 
o New pathologic Q-waves in ≥2 contiguous leads 
o New persistent LBBB 
o Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm 
diameter branch 
o Substantial new loss of viable myocardium on imaging related to the procedure 
• 
In patients with elevated baseline CK-MB (or cTn): The CK-MB (or cTn) rises by an 
absolute increment equal to those levels recommended above from the most recent pre-
procedure level plus new ECG changes as described. 
 
 
NEW-ONSET ATRIAL FIBRILLATION (OR FLUTTER)21 
Is diagnosed as any arrhythmia within hospitalization that has the ECG characteristics of atrial fibrillation 
(or flutter) and lasts sufficiently long to be recorded on a 12-lead ECG, or at least 30 s on a rhythm strip. 
 
 
NON-STRUCTURAL VALVE DYSFUNCTION21 
Any abnormality, not intrinsic to the prosthetic valve, resulting in valve dysfunction. Examples include 
residual intra- or paraprosthetic aortic regurgitation; leaflet entrapment by pannus, tissue, or suture; 
inappropriate positioning or sizing; dilatation of the aortic root after stentless prostheses or aortic valve 
sparing operations; prosthesis-patient mismatch; and embolization 
Clinical Presentation 
• 
Subclinical: Any bioprosthetic valve dysfunction associated with absent or mild 
haemodynamic changes, AND absent symptoms or sequelae 
• 
Bioprosthetic valve failure (BVF): 
o Stage 1: Any bioprosthetic valve dysfunction associated with clinically expressive 
criteria (new-onset or worsening symptoms, LV dilation/hypertrophy/dysfunction, or 
pulmonary hypertension) or irreversible Stage 3 haemodynamic valve deterioration 
(HVD) 
o Stage 2: Aortic valve reoperation or re-intervention 
o Stage 3: Valve-related death 
PROSTHETIC VALVE ENDOCARDITIS21 
Any one of the following 
• 
Fulfilment of the Duke endocarditis criteria33 

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• 
Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary to 
infection by histological or bacteriological studies during a re-operation 
• 
Evidence of abscess, pus, or vegetation confirmed on autopsy 
Clinical Presentation 
• 
Subclinical: Any bioprosthetic valve dysfunction associated with absent or mild 
haemodynamic changes, AND absent symptoms or sequelae 
• 
Bioprosthetic valve failure (BVF): 
o Stage 1: Any bioprosthetic valve dysfunction associated with clinically expressive 
criteria (new-onset or worsening symptoms, LV dilation/hypertrophy/dysfunction, or 
pulmonary hypertension) or irreversible Stage 3 haemodynamic valve deterioration 
(HVD) 
o Stage 2: Aortic valve reoperation or re-intervention 
o Stage 3: Valve-related death 
 
 
PROSTHETIC VALVE REGURGITATION CRITERIA21 
 
 
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in 
the descending aorta 
PW Doppler 
Absent or brief early 
diastolic 
Intermediate 
Prominent, holodiastolic 
Circumferential extent of 
paraprosthetic AR 
less than (<) 10% 
10–29% 
greater than or equal 
(>) 30% 
Quantitative Parameters 
Regurgitant volume 
(ml/beat) 
less than (<) 30 ml 
30–59 ml 
greater than or equal 
(>) 60 ml 
Regurgitant fraction 
less than (<) 30% 
30–49% 
greater than or equal 
(>) 50% 
EROA (cm2) 
0.10 cm2 
0.10-0.29 cm2 
≥0.30 cm2 
 
 
STROKE/NEUROLOGICAL EVENTS21 
Categories of Neurological Events 
1. Overt Central Nervous System (CNS) injury (NeuroARC Type 1) 
• 
All Stroke 
o Ischemic Stroke: Acute onset of focal neurological signs or symptoms conforming to a 
focal or multifocal vascular territory within the brain, spinal cord, or retina (NeuroARC 
Type 1a or 1aH) and fulfilling one of the following criteria: 
 
Signs or symptoms lasting ≥24 h or until death, with pathology or neuroimaging 
evidence of CNS infarction, or absence of other apparent causes 
 
Symptoms lasting <24 h, with pathology or neuroimaging confirmation of CNS 
infarction in the corresponding vascular territory 
o Hemorrhagic Stroke: Acute onset of neurological signs or symptoms due to 
intracranial bleeding from intracerebral or subarachnoid hemorrhage not due to 
trauma (NeuroARC Types 1b or 1c) 

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o Stroke, not otherwise specified: Acute onset of neurological signs or symptoms 
persisting ≥24 h or until death but without sufficient neuroimaging or pathology 
evidence to be classified (NeuroARC Type 1d) 
• 
Symptomatic hypoxic-ischemic injury: Non-focal (global) neurological signs or 
symptoms with diffuse brain, spinal cord, or retinal cell death confirmed by pathology or 
neuroimaging and attributable to hypotension or hypoxia (NeuroARC Type 1e) 
2. Covert CNS injury (NeuroARC Type 2) 
• 
Covert CNS infarction or hemorrhage: Neuroimaging or pathological evidence of CNS 
focal or multifocal ischemia (NeuroARC Type 2a or 2aH) or hemorrhage (NeuroARC 2b) 
without acute neurological symptoms consistent with the lesion or bleeding location 
3. Neurologic dysfunction (acutely symptomatic) without CNS injury (NeuroARC Type 3) 
• 
TIA: Transient focal neurological signs or symptoms lasting <24 h presumed to be due to 
focal brain, spinal cord, or retinal ischemia, but without evidence of acute infarction by 
neuroimaging or pathology, or with no imaging performed (NeuroARC Type 3a or Type 
3aH) 
• 
Delirium without CNS injury: Transient non-focal neurological signs or symptoms, 
typically of variable duration, without evidence of infarction on neuroimaging or pathology, 
or with no imaging performed (NeuroARC Type 3b) 
Stroke Grading 
Acute Stroke Severity 
• 
Mild neurological dysfunction: NIHSS 0-5  
• 
Moderate neurological dysfunction: NIHSS 6-14  
• 
Severe neurological dysfunction: NIHSS ≥1 
Stroke Disability 
• 
Fatal Stroke: death resulting from a stroke 
• 
Stroke with disability: mRS score of ≥2 at 90 days and increase of ≥1 from pre-stroke 
baseline 
• 
Stroke without disability: mRS score of 0 (no symptoms) or 1 (able to carry out all usual 
duties and activities) at 90 days or no increase in mRS category from pre-stroke baseline 
 
STRUCTURAL VALVE DETERIORATION21 
Intrinsic permanent changes to the prosthetic valve, including wear and tear, leaflet disruption, flail 
leaflet, leaflet fibrosis and/or calcification, or strut fracture or deformation.  
Clinical Presentation 
• 
Subclinical: Any bioprosthetic valve dysfunction associated with absent or mild 
haemodynamic changes, AND absent symptoms or sequelae 
• 
Bioprosthetic valve failure (BVF): 
o Stage 1: Any bioprosthetic valve dysfunction associated with clinically expressive 
criteria (new-onset or worsening symptoms, LV dilation/hypertrophy/dysfunction, or 
pulmonary hypertension) or irreversible Stage 3 haemodynamic valve deterioration 
(HVD) 
o Stage 2: Aortic valve reoperation or re-intervention 
o Stage 3: Valve-related death 

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To be graded using the following stages: 
StageA 
Description 
Definition 
1 
Morphological valve deterioration 
Evidence of structural valve deterioration, 
nonstructural valve dysfunction (other than 
paravalvular regurgitation or prosthesis- patient 
mismatch), thrombosis, or endocarditis without 
significant haemodynamic changes 
2 
Moderate hemodynamic valve 
deterioration  
Increase in mean transvalvular gradient ≥10 mmHg 
resulting in mean gradient ≥20 mmHgB with 
concomitant decrease in EOA ≥0.3 cm2 or ≥25% 
and/or decrease in Doppler velocity index ≥0.1 or 
≥20% compared to echocardiographic assessment 
performed 1 to 3 months post-procedure,  
OR  
new occurrence or increase of ≥1 grade of 
intraprosthetic AR resulting in ≥ moderate AR. 
3 
Severe hemodynamic valve 
deterioration 
Increase in mean transvalvular gradient ≥20 mmHg 
resulting in mean gradient ≥30 mmHgB with 
concomitant decrease in EOA ≥0.6 cm2 or ≥50% 
and/or decrease in Doppler velocity index ≥0.2 or 
≥40% compared to echocardiographic assessment 
performed 1 to 3 months post-procedure,  
OR  
new occurrence, or increase of ≥2 grades, of 
intraprosthetic AR resulting in ≥ severe AR. 
A When assessing the presence and severity of hemodynamic valve deterioration, it is important to differentiate 
true-hemodynamic changes versus inter-echo variability in the measurement of gradient, EOA, DVI, or AR. In 
particular, one should use the same window for continuous-wave Doppler interrogation when comparing gradients 
in early (1 to 3 months) post AVR echo versus follow-up echo. Each case with potential hemodynamic valve 
deterioration should be individually adjudicated to confirm presence, stage, and etiology. Hemodynamic valve 
deterioration may be caused by structural valve deterioration but also by non-structural dysfunction including valve 
thrombosis and endocarditis. The assessment of valve leaflet morphology and structure is key to make differential 
diagnosis between the different etiologies of hemodynamic valve deterioration. 
B This criterion for hemodynamic dysfunction assumes normal flow. 
 
 
CLINICALLY SIGNIFICANT VALVE THROMBOSIS21 
Any thrombus attached to or near an implanted valve that occludes part of the blood ﬂow path (as 
confirmed by imaging), interferes with valve function, or is sufﬁciently large to warrant treatment. 
Clinical sequelae of a thromboembolic event (e.g. stroke, TIA, retinal occlusion, other evidence of 
systemic thromboembolism) or worsening valve stenosis/regurgitation (e.g. signs of heart failure, 
syncope) and  
• 
Hemodynamic valve deterioration Stage 2 or 3 or 
• 
Confirmatory imaging (CT evidence of HALT or TEE findings) 
In the absence of clinical sequelae, both: 
• 
Hemodynamic valve deterioration Stage 3 and 
• 
Confirmatory imaging (CT evidence of HALT or TEE findings) 

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Timing 
• 
Acute: Within 0–24 h of the index procedure 
• 
Subacute: >24 h and ≤30 days after the index procedure 
• 
Late: >30 days and ≤1 year after the index procedure 
• 
Very late: >1 year after the index procedure 
Response to Anticoagulant Therapy (≥3 months) 
• 
Resolved: Partial or complete resolution of symptoms, imaging findings, and HVD 
• 
Persistent: No improvement in symptoms, imaging findings, or HVD 
• 
Recurrent: Recurrence of symptoms, imaging findings, or HVD 
Certainty of Diagnosis 
• 
Definite: Histopathological confirmation 
• 
Probable: Haemodynamic changes and imaging findings compatible with valve 
thrombosis, with resolution of haemodynamic changes and imaging findings following 
anticoagulation therapy 
• 
Possible: Imaging demonstrated findings compatible with leaflet thrombosis formation, but 
either haemodynamic changes or imaging findings persist following anticoagulation 
therapy or anticoagulation therapy is not (yet) administered 
 
  
VASCULAR AND ACCESS-RELATED COMPLICATIONS21 
VACULAR COMPLICATIONS 
1. MAJOR VASCULAR COMPLICATIONS 
One of the following: 
• 
Aortic dissection or aortic rupture 
• 
Vascular (arterial or venous) injury (perforation, rupture, dissection, stenosis, ischaemia, 
arterial or venous thrombosis including pulmonary embolism, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, infection) or compartment 
syndrome resulting in death VARC type ≥2 bleeding, limb or visceral ischaemia, or 
irreversible neurologic impairment 
• 
Distal embolization (non-cerebral) from a vascular source resulting in death, amputation, 
limb or visceral ischemia, or irreversible end-organ damage 
• 
Unplanned endovascular or surgical intervention resulting in death, VARC type ≥2 
bleeding, limb or visceral ischaemia, or irreversible neurologic impairment 
• 
Closure device failure resulting in death, VARC type ≥2 bleeding, limb or visceral 
ischaemia, or irreversible neurologic impairment 
 
2. MINOR VASCULAR COMPLICATIONS 
One of the following: 
• 
Vascular (arterial or venous) injury (perforation, rupture, dissection, stenosis, ischaemia, 
arterial or venous thrombosis including pulmonary embolism, arteriovenous fistula, 
pseudoaneurysm, haematoma, retroperitoneal haematoma, infection) not resulting in 
death, VARC type ≥2 bleeding, limb or visceral ischaemia, or irreversible neurologic 
impairment 

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• 
Distal embolization treated with embolectomy and/or thrombectomy, not resulting in death, 
amputation, limb or visceral ischaemia, or irreversible end-organ damage 
• 
Any unplanned endovascular or surgical intervention, ultra-sound guided compression, or 
thrombin injection, not resulting in death, VARC type ≥2 bleeding, limb or visceral 
ischaemia, or irreversible neurologic impairment 
• 
Closure device failure not resulting in death, VARC type ≥2 bleeding, limb or visceral 
ischaemia, or irreversible neurologic impairment 
 
ACCESS-RELATED NON-VASCULAR COMPLICATIONS 
1. MAJOR ACCESS-RELATED NON-VASCULAR COMPLICATIONS  
One of the following: 
• 
Non-vascular structure, non-cardiac structured perforation, injury, or infection resulting in 
death, VARC type ≥2 bleeding, irreversible nerve injury or requiring unplanned surgery or 
percutaneous intervention  
• 
Non-vascular access site (e.g. trans-apical left ventricular) perforation, injury, or infection 
resulting in death, VARC type ≥2 bleeding, irreversible nerve injury or requiring unplanned 
surgery or percutaneous intervention 
 
2. MINOR ACCESS-RELATED NON-VASCULAR COMPLICATIONS 
One of the following: 
• 
Non-vascular structure, non-cardiac structured perforation, injury, or infection not resulting 
in death, VARC type ≥2, irreversible nerve injury, or requiring unplanned surgery or 
percutaneous intervention 
• 
Non-vascular access site (e.g. trans-apical left ventricular) perforation, injury, or infection 
not resulting in death, VARC type ≥2 bleeding, irreversible nerve injury or requiring 
unplanned surgery or percutaneous intervention 
 
 
 
 

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APPENDIX III: CIP SUMMARY 
Clinical 
Investigation 
Name and 
Number 
VANTAGE Trial (ABT-CIP-10342) 
CIP Name 
VANTAGE  
Title 
Evaluation of TAVI Using the Navitor™ Valve in a Global Investigation 
Objective 
The objective of the proposed clinical trial is to evaluate the safety and 
effectiveness of the Navitor TAVI System in patients with severe, symptomatic 
native aortic stenosis who are at intermediate or low risk of surgical mortality. 
This trial will also evaluate the safety and effectiveness of the Navitor TAVI 
System in a valve-in-valve application in patients with symptomatic heart 
disease due to failure (stenosed, insufficient, or combined) of a surgical 
bioprosthetic aortic valve across all surgical risk categories. 
Device Under 
Investigation 
• 
Navitor Transcatheter Aortic Valve (23 mm, 25 mm, 27 mm, 29 mm, and 35 
mm sizes) 
• 
Navitor Loading System (small, large, and LG+) 
• 
FlexNav Delivery System (small and large) 
Number of 
Subjects Required 
for Inclusion in 
Clinical 
Investigation 
Navitor Valve implantation is expected in Australia, Europe, and Israel 
(1) Primary Analysis Cohort: up to 450 registered subjects 
(2) Roll-in Cohort: Up to 40 registered subjects  
(3) Valve-in-valve (ViV) Cohort: Up to 100 registered subjects 
Clinical 
Investigation 
Design 
The VANTAGE trial is a prospective, single-arm, multi-center, international, 
premarket clinical trial designed in accordance with ISO standard 14155:2020. 
To be eligible for participating in the primary analysis and roll-in cohorts, a 
patient must have symptomatic, severe native aortic stenosis and have 
intermediate or low risk for surgical valve replacement. To be eligible for 
participating in the ViV cohort, a patient must have symptomatic heart disease 
due to failure (stenosed, insufficient, or combined) of a surgical bioprosthetic 
aortic valve, and the patient can be in any risk category.K 
Subjects will be enrolled and treated with the Navitor Valve at up to 40 
experienced TAVI implant centers across Australia, Europe, and Israel and 
followed for 10 years. All sites must have prior Navitor TAVI system experience 
or must complete roll-in cases.  
Primary 
Endpoint(s) 
The primary safety endpoint is a composite of all-cause mortality or fatal 
stroke/stroke with disability at 12 months post index Navitor Valve implantation 
procedure. The primary effectiveness endpoint is moderate or greater 
 
 
K In Germany, only subjects at high or extreme surgical risk can be included in the ViV cohort. Sites in Switzerland 
will not participate in the ViV enrollment. 

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paravalvular leak at 30 days post index Navitor Valve implantation procedure. 
Both of the primary endpoints will be evaluated in a mixed-risk group including 
both intermediate and low risk subjects and will be tested against literature-
derived performance goals.   
Subject Follow-up 
For subjects that have successfully completed screening and been approved by 
the Screening Committee, scheduled visits will be performed at: Baseline, Index 
Procedure, Discharge, 30 days,12 months, and annual follow-up assessments 
to 10 years. Echocardiograms are required at 30 days, 12 months and 2, 3, 4, 
5, 7, and 10 years.  
Note: Subjects in the high or extreme risk category in the ViV cohort will be 
followed up to 5 years. 
Key Inclusion 
Criteria 
• 
Subject who is judged by a Heart Team, including a cardiac surgeon, to 
be appropriate for transcatheter heart valve intervention therapy, and is 
deemed to be at intermediate or low risk for open surgical aortic valve 
replacement (i.e., heart team estimates risk of surgical mortality < 7% at 30 
days, considering the Society of Thoracic Surgeons (STS) risk score, 
overall clinical status, and other clinical co-morbidities unmeasured by the 
risk calculator) # 
(Note: In France and Switzerland, if a subject is deemed low surgical risk, 
the subject must be at age 75 or over to be included in this trial. Refer to 
country-specific addendums for other details.) 
• 
New York Heart Association (NYHA) Functional Classification of II, III, or IV 
# 
• 
Degenerative aortic valve stenosis with echo-derived criteria, defined as: 
aortic valve area (AVA) of ≤ 1.0 cm2 (or indexed EOA ≤ 0.6 cm2/m2) AND 
either mean gradient ≥ 40 mmHg or peak jet velocity ≥ 4.0 m/s or doppler 
velocity index (DVI) ≤ 0.25. The echocardiogram supporting the qualifying 
AVA baseline measurement must be performed within 90 days prior to 
informed consent. # 
• 
Aortic annulus diameter of 19‐30 mm and ascending aorta diameter of 26-
44 mm for the specified valve size listed in the IFU, as measured by CT 
(systolic phase) conducted within 12 months prior to informed consent.  
Key Exclusion 
Criteria 
• 
Untreated clinically significant coronary artery disease requiring 
revascularization 
• 
Any percutaneous coronary or peripheral interventional procedure 
performed within 30 days prior (except pacemaker or ICD implant) to index 
procedure or planned within 30 days following the index procedure.  
• 
Blood dyscrasias as defined: leukopenia (WBC < 3000 mm3), acute anemia 
(Hb < 9 g/dL), thrombocytopenia (platelet count < 50,000 cells/mm³); history 
of bleeding diathesis or coagulopathy 
• 
Active peptic ulcer or upper GI bleeding within 3 months prior to index 
procedure that would preclude anticoagulation  
• 
Known intolerance, hypersensitivity, or contraindication, including subjects 
that meet any of the following conditions: 

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a. Subjects who cannot take any antiplatelets or anticoagulants*,  
b. Subjects who have sensitivity to contrast media which cannot be 
adequately premedicated,  
c. Subjects who have known hypersensitivity to nitinol (nickel or 
titanium), or 
d. Subjects who have clinical contraindication that precludes contrast 
CT imaging 
*Note: Subjects who can take either an antiplatelet or anticoagulant therapy 
post-procedure will be eligible. 
• 
Recent (within 6 months prior to index procedure date) cerebrovascular 
accident (CVA) or a transient ischemic attack (TIA) 
• 
Renal insufficiency (creatinine > 3.0 mg/dL or estimated GFR < 30 
ml/min/1.73m2) and/or end stage renal disease requiring chronic dialysis 
• 
Active bacterial endocarditis within 6 months prior to the index procedure 
• 
Liver failure (Child-Pugh class B or C) 
• 
Subjects with atrial fibrillation who are not on anticoagulants or who are not 
implanted with a left atrial appendage occlusion (LAAO) device 
• 
Symptomatic carotid or vertebral artery disease, significant carotid or 
vertebral artery disease requiring intervention, or successful treatment of 
carotid or vertebral stenosis within 30 days prior to index procedure 
• 
Severe pulmonary hypertension with pulmonary systolic pressure greater 
than two-thirds of systemic pressure 
• 
Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen 
• 
Hostile chest or conditions or complications from prior surgery that would 
make the patient be considered high surgical risk (i.e., mediastinitis, 
radiation damage, abnormal chest wall, porcelain aorta, adhesion of aorta 
or internal mammary artery to sternum, etc.) # 
• 
Significant frailty as determined by the heart team (after objective 
assessment of frailty parameters) that would indicate high or extreme 
surgical risk # 
• 
Mixed aortic valve disease (aortic stenosis and aortic regurgitation with 
predominant aortic regurgitation 3-4+) # 
• 
Aortic valve is a congenital unicuspid or congenital bicuspid valve as 
verified by echocardiography or CT  
• 
Non-calcified aortic valve #  
• 
Severe ventricular dysfunction with LVEF < 30% as measured by resting 
echocardiogram 
• 
Pre-existing prosthetic heart valve or other implant (such as prosthetic ring 
or transcatheter edge-to-edge repair (TEER) clip) in any valve position # 
(Note: Subjects with a bio-prosthetic aortic valve may be included in the ViV 
cohort.) 
• 
Severe circumferential mitral annular calcification (MAC) which is 
continuous with calcium in the left ventricular outflow tract (LVOT) # 
• 
Prohibitive left ventricular outflow tract calcification # 

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• 
Severe (greater than or equal to 3+) mitral regurgitation or severe mitral 
stenosis with pulmonary compromise  
• 
Echocardiographic or multi-slice computed tomography (MSCT) evidence of 
intracardiac mass, thrombus, or vegetation 
• 
Significant aortic disease, including abdominal aortic or thoracic aneurysm 
defined as maximal luminal diameter 5.5cm or greater or ascending aortic 
aneurysm defined as maximal luminal diameter 5cm or greater.  
• 
Marked aortic tortuosity (hyperacute bend) or severe “unfolding” and 
tortuosity of the thoracic aorta (applicable for transfemoral access only) 
• 
Aortic arch atheroma ( [> 5 mm], protruding or ulcerated) 
• 
Significant narrowing (calcification and surface irregularities) of the 
abdominal or thoracic aorta 
• 
Aortic root angulation > 70° 
• 
Undue risk of coronary obstruction (e.g., low coronary ostia, narrow Sinus of 
Valsalva anatomy that would prevent adequate coronary perfusion, or bulky 
aortic valve leaflets in close proximity to coronary ostia) 
• 
Access vessel characteristics that would preclude safe insertion of the 
FlexNav Delivery System such as severe obstructive calcification, 
protruding thrombus or severe tortuosity  
• 
Minimum access vessel diameter of < 5.0 mm for small FlexNav Delivery 
System and < 5.5 mm for large FlexNav Delivery System 
• 
Ascending aorta anatomy that would preclude safe delivery of the valve to 
the native aortic annulus 
• 
Eccentricity ratio of the annulus < 0.73 
# Criterion not applicable for ViV cohort 
Note: The ViV subjects can be in any risk category except in Germany, where only subjects at high or 
extreme surgical risk can be included in the ViV cohort. 
 
 
 

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APPENDIX IV: LITERATURE REVIEW 
A review of Intermediate and Low Risk TAVI literature is contained in the Investigator’s Brochure. 
 
 

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APPENDIX V: LABELS 
Device labeling and Instructions For Use are provided under separate cover and are available upon 
request from the Sponsor. 
 

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APPENDIX VI: INFORMED CONSENT FORM 
 
A template informed consent form will be provided under a separate cover. 

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APPENDIX VII: SCREENING AND ASSESSMENT TOOLS 
1. SURGICAL RISK ASSESSMENT 
This clinical study requires the use of two surgical risk assessment tools: 
1. The Society of Thoracic Surgeons’ (STS) Short-term / Operative Risk Calculator, Adult 
Cardiac Surgery Database STS ACSD Operative Risk Calculator 
(https://acsdriskcalc.research.sts.org) 
2. Euro SCORE II (http://euroscore.org/calc.html) 
2. FRAILTY ASSESSMENTS 
The Frailty Index Data Collection Form will be used as an assessment tool to determine if frailty is a 
risk factor for subjects prior to enrollment. This assessment will be performed after the informed 
consent has been obtained and prior to procedure. The assessment can be administered by either an 
investigator or research coordinator. 
The frailty assessment consists of four evaluations: 
I. 
Katz Index of Independence in Activities of Daily Living  
II. 
Grip Strength 
III. 
5 Meter walk test 
IV. 
Nutritional Deficiency (Albumin) 
 
I. Katz Index of Independence in Activities of Daily Living Activities  
 
Points (1 or 0)  
Independence 
(1 Point) 
NO supervision, direction or personal 
assistance 
Dependence 
(0 Points) 
WITH supervision, direction, personal 
assistance or total care 
BATHING  
Points: ________  
(1 POINT) Bathes self completely or 
needs help in bathing only a single part of 
the body such as the back, genital area or 
disabled extremity  
(0 POINTS) Need help with bathing more than 
one part of the body, getting in or out of the tub or 
shower. Requires total bathing  
DRESSING  
Points: ________  
(1 POINT) Get clothes from closets and 
drawers and puts on clothes and outer 
garments complete with fasteners. May 
have help tying shoes.  
(0 POINTS) Needs help with dressing self or 
needs to be completely dressed.  
TOILETING  
Points: ________  
(1 POINT) Goes to toilet, gets on and off, 
arranges clothes, cleans genital area 
without help. 
(0 POINTS) Needs help transferring to the toilet, 
cleaning self or uses bedpan or commode. 
TRANSFERRING  
Points: ________  
(1 POINT) Moves in and out of bed or 
chair unassisted. Mechanical transfer aids 
are acceptable. 
(0 POINTS)Needs help in moving from bed to 
chair or requires a complete transfer. 
CONTINENCE  
Points: ________  
(1 POINT) Exercises complete self control 
over urination and defecation.  
(0 POINTS) Is partially or totally incontinent of 
bowel or bladder.  

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FEEDING  
Points: ________  
(1 POINT) Gets food from plate into mouth 
without help. Preparation of food may be 
done by another person.  
(0 POINTS) Needs partial or total help with 
feeding or requires parenteral feeding.  
 
TOTAL Points:______________ 
 
 
 
 
II. Grip strength  
Subjects elbow should be at a 90 degree angle without arm supported or resting on table or against 
chest wall. Each grasp should be completed with the dynamometer in the dominant hand. 
 
Grasp 1____________ Grasp 2___________ Grasp3____________ Average_____________ 
 
Grip Strength, stratified by gender and body mass index (BMI) quartiles  
 
Gender 
BMI 
Cutoff for grip strength (Kg) criterion for 
frailty 
Male 
≤24 
≤29 
 24.1–26 
≤30 
26.1–28 
≤31 
>28 
≤32 
Female 
≤ 23 
≤17 
23.1–26 
≤17.3 
26.1–29 
≤18 
>29 
≤21 
 
 
III. 5-Meter Walk Time  
This examination should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. The walking course must be 5 meters in length (15 feet). The 
time to walk this distance is to be recorded.  
 
 _______________seconds 
 
Walk Time, stratified by gender and height  
Gender 
Height 
Cutoff values for Time to Walk 5 meters 
criterion for frailty 
Male 
 ≤ 173 cm 
≥ 7sec 
 > 173 cm 
≥ 6sec 
Female 
≤159 cm 
≥ 7sec 
> 159 cm 
≥ 6sec 

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IV. Nutritional Deficiency 
A blood albumin level is measured. Frailty is defined as a level < 3.5 mg/ml. Albumin lab values 
performed ≤ 90 days prior to informed consent, per standard of care, may be utilized. 
3. NYHA FUNCTIONAL CLASSIFICATION 
 
4. QUESTIONNAIRES 
The KCCQ and mRS questionnaires will be provided under separate cover (Appendices VIII and 
IX).  
5. Six Minute Walk Test  
This Six Minute Walk (6MWT) Test measures the distance that a patient can quickly walk on a 
flat, hard surface in a period of 6 minutes. It evaluates the global and integrated responses of all 
the systems involved during exercise, including the pulmonary and cardiovascular systems, 
systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism. It 
does not provide specific information on the function of each of the different organs and systems 
involved in exercise or the mechanism of exercise limitation, as is possible with maximal 
cardiopulmonary exercise testing. 
 
SAFETY ISSUES  
Class I 
Patient has cardiac disease but without resulting limitations of 
ordinary physical activity. Ordinary physical activity (e.g., walking 
several blocks or climbing stairs) does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. Limiting symptoms may occur 
with marked exertion. 
Class II 
 
 Patient has cardiac disease resulting in slight limitation of ordinary 
physical activity. Patient is comfortable at rest. Ordinary physical 
activity such as walking more than two blocks or climbing more than 
one flight of stairs results in limiting symptoms (e.g., fatigue, 
palpitation, dyspnea, or anginal pain). 
Class III 
 
 Patient has cardiac disease resulting in marked limitation of physical 
activity. Patient is comfortable at rest. Less than ordinary physical 
activity (e.g., walking one to two level blocks or climbing one flight of 
stairs) causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Patient has dyspnea at rest that increases with any physical activity. 
Patient has cardiac disease resulting in inability to perform any 
physical activity without discomfort. Symptoms may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 

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1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible. The appropriate location of a crash cart should be determined by 
the physician supervising the facility.  
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (metered dose inhaler or nebulizer). A telephone or other means should be in 
place to enable a call for help.  
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of 
Basic Life Support by an American Health Association–approved cardiopulmonary 
resuscitation course. Advanced cardiac life support certification is desirable. Training, 
experience, and certification in related health care fields (registered nurse, registered 
respiratory therapist, certified pulmonary function technician, etc.) are also desirable. A 
certified individual should be readily available to respond if needed.  
4. Physicians are not required to be present during all tests. The physician ordering the test 
or a supervising laboratory physician may decide whether physician attendance at a 
specific test is required.  
5. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or 
as directed by a physician or a protocol. 
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable 
dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
Technicians must be trained to recognize these problems and the appropriate responses. If a test 
is stopped for any of these reasons, the patient should sit or lie supine as appropriate depending 
on the severity or the event and the technician's assessment of the severity of the event and the 
risk of syncope. The following should be obtained based on the judgment of the technician: blood 
pressure, pulse rate, oxygen saturation, and a physician evaluation. Oxygen should be 
administered as appropriate.  
 
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the 
previous month and myocardial infarction during the previous month. Relative contraindications 
include a resting heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, 
and a diastolic blood pressure of more than 100 mm Hg.  
Patients with any of these findings should be referred to the physician ordering or supervising the 
test for individual clinical assessment and a decision about the conduct of the test. The results 
from a resting electrocardiogram done during the previous 6 months should also be reviewed 
before testing. Stable exertional angina is not an absolute contraindication for a 6MWT, but 
patients with these symptoms should perform the test after using their antiangina medication, and 
rescue nitrate medication should be readily available. A deviation from the Clinical Investigation 
Plan will need to be collected if the subject is unable to complete this test. 
LOCATION 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a hard 
surface that is seldom traveled. If the weather is comfortable, the test may be performed 
outdoors. The walking course must be 30 m in length. A 100-ft hallway is, therefore, required. The 
length of the corridor should be marked every 3 m. The turnaround points should be marked with 

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a cone (such as an orange traffic cone). A starting line, which marks the beginning and end of 
each 60-m lap, should be marked on the floor using brightly colored tape.  
PROCEDURE 
REQUIRED EQUIPMENT  
• 
Countdown timer (or stopwatch)  
• 
Mechanical lap counter  
• 
Two small cones to mark the turnaround points  
• 
A chair that can be easily moved along the walking course  
• 
Worksheets on a clipboard  
• 
A source of oxygen  
• 
Sphygmomanometer  
• 
Telephone  
• 
Automated electronic defibrillator  
PATIENT PREPARATION  
• 
Comfortable clothing should be worn.  
• 
Appropriate shoes for walking should be worn.  
• 
Patients should use their usual walking aids during the test (cane, walker, etc.).  
• 
The patient's usual medical regimen should be continued.  
• 
A light meal is acceptable before early morning or early afternoon tests.  
• 
Patients should not have exercised vigorously within 2 hours of beginning the test.  
• 
This test should be performed about the same time of day for each interval to minimize 
intraday variability.  
• 
A "warm-up" period before the test should not be performed.  
• 
The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, measure pulse 
and blood pressure, and make sure that clothing and shoes are appropriate. Complete the 
first portion of the worksheet. 
Baseline Measurements 
1. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary equipment 
(lap counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point.  
Instruct the patient as follows:  
“The object of this test is to walk as far as possible for 6 minutes. You will walk 
back and forth in this hallway. Six minutes is a long time to walk, so you will be 
exerting yourself. You will probably get out of breath or become exhausted. You 
are permitted to slow down, to stop, and to rest as necessary. You may lean 
against the wall while resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly 
around the cones and continue back the other way without hesitation. Now I'm 
going to show you. Please watch the way I turn without hesitation." 
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.  

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"Are you ready to do that? I am going to use this counter to keep track of the 
number of laps you complete. I will click it each time you turn around at this 
starting line. Remember that the object is to walk AS FAR AS POSSIBLE for 6 
minutes, but don't run or jog.  
Start now, or whenever you are ready."  
Position the patient at the starting line. You should also stand near the starting line during the 
test. Do not walk with the patient. As soon as the patient starts to walk, start the timer.  
Do not talk to anyone during the walk. Use an even tone of voice when using the standard 
phrases of encouragement. Watch the patient. Do not get distracted and lose count of the laps. 
Each time the participant returns to the starting line, click the lap counter once (or mark the lap 
on the worksheet). Let the participant see you do it. Exaggerate the click using body language, 
like using a stopwatch at a race.  
After the first minute, tell the patient the following (in even tones):  
"You are doing well. You have 5 minutes to go."  
 
When the timer shows 4 minutes remaining, tell the patient the following:  
"Keep up the good work. You have 4 minutes to go."  
 
When the timer shows 3 minutes remaining, tell the patient the following:  
"You are doing well. You are halfway done."  
 
When the timer shows 2 minutes remaining, tell the patient the following:  
"Keep up the good work. You have only 2 minutes left."  
 
When the timer shows only 1 minute remaining, tell the patient:  
"You are doing well. You have only 1 minute to go."  
 
Do not use other words of encouragement (or body language to speed up).  
 
If the patient stops walking during the test and needs a rest, say this:  
"You can lean against the wall if you would like; then continue walking 
whenever you feel able."  
 
Do not stop the timer. If the patient stops before the 6 minutes are up and refuses to continue 
(or you decide that they should not continue), wheel the chair over for the patient to sit on, 
discontinue the walk, and note on the worksheet the distance, the time stopped, and the 
reason for stopping prematurely.  
 
When the timer is 15 seconds from completion, say this:  
"In a moment I'm going to tell you to stop. When I do, just stop right where you 
are and I will come to you."  
 
When the timer rings (or buzzes), say this: "Stop!"  
 

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Walk over to the patient. Consider taking the chair if they look exhausted. Mark the spot where 
they stopped. 
 

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APPENDIX VIII: KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) 
 
A copy of the Kansas City Cardiomyopathy questionnaire will be provided under a separate cover. 

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APPENDIX IX: MODIFIED RANKIN SCALE QUESTIONAIRE 
 
A copy of the Modified Rankin Scale (mRS) questionnaire will be provided under a separate cover. 

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APPENDIX X: PERI-PROCEDURAL GUIDELINES 
Assessment of aortic regurgitation 
Angiography will be performed >5 minutes after valve deployment. Use projection where the valve frame 
is aligned / in-plane. Left ventricular (LV) apex must be included in the imaging field. The pigtail catheter 
should be located in the upper third part of the frame, give 20-30 mL non-diluted contrast for at least 5 
heart cycles.  
 
Echocardiography: Use color-Doppler in the short-axis, long-axis and 5 chamber views. The 
circumferential extent of the regurgitant jet determine the degree of paravalvular leak (PVL); <10% = mild 
(I), 10-29% = moderate (II), >30% = severe (III-IV). 
 
The pressure in the left ventricle and in the ascending aorta should be determined simultaneously after 
the procedure. The gradient between diastolic blood pressure (DBP) in the aorta and left ventricular end 
diastolic pressure (LVEDP) should be calculated over several cardiac cycles to evaluate the severity of 
paraprosthetic aortic regurgitation (PAR). 
 
To adjust the gradient for the respective systolic blood pressure (SBP) of the patient, the dimensionless 
AR index may be calculated according to the following formula: [(DBP - LVEDP)/SBP] x100.  
 
Assessment of implant depth 
For implantation depth, use the angiography with the valve frame aligned with the imaging plane and 
measure both the distance from the non-coronary cusp (NCC) and left coronary cusp (LCC) to the 
ventricular end of the frame (two measurements in Figure 5 blow).  
 
 

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APPENDIX XI: REVISION HISTORY 
This CIP may be amended as appropriate by the Sponsor. Rationale will be included with each amended 
version in the revision history table below. The version number and date of amendments will be 
documented. 
 
EC and relevant Regulatory Authorities, if applicable, will be notified of amendments to the CIP. 
Amendment 
Number 
Version 
Date 
Details 
Rationale 
Not 
Applicable 
A 
24 January 
2021 
First release of CIP 
NA 
1 
B 
16 
September 
2022 
• 
Named this CIP as 
VANTAGE – OUS to 
separate it from 
VANTAGE – North 
America and revised the 
list of global study PIs and 
regional study PIs 
accordingly  
• 
Updated the regulatory 
approval status to reflect 
the approval of Navitor CE 
Mark for high and extreme 
risk  
• 
Defined the point of 
registration in the study 
(Section 3 and Figure 4) 
• 
Added the Navitor 35 mm 
valve (Navitor Titan) to the 
study (Navitor updates to 
include the 35 mm valve in 
Device Description 
(Section 2.2), Clinical 
Study Design (Section 3), 
Eligibility Criteria (Section 
5.3), and Risk Analysis 
(Section 15). 
• 
Added the commercially 
available version of the 
Navitor system for use in 
the study (Section 2.2) 
• 
Shortened the required 
follow-up duration for 
subjects at high or 
extreme risk in the ViV 
• 
To add clarity  
 
 
 
 
 
 
 
• 
To update information 
 
 
 
 
• 
To add clarity and 
simplify wording 
 
• 
To add a larger size of 
the Navitor Valve for 
product size extension 
 
 
 
 
 
 
 
• 
To provide an 
alternative for study 
device supply to 
facilitate the trial 
conduct 
• 
The required follow-up 
duration was shortened 
for subjects at high or 
extreme risk in the ViV 

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cohort from 10 years to 5 
years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Set a range (50%-70%) 
for the proportion of 
intermediate risk subjects 
to be registered in the 
primary analysis cohort  
• 
Changed the sample size 
required for hypothesis 
testing of the primary 
endpoint from 162 to 186 
subjects  
 
 
 
 
 
 
 
 
 
• 
Changed event definitions 
from VARC-2 to VARC-3 
(Appendix II) 
• 
Updated endpoints 
(Section 4): 
• 
Modified the primary 
endpoint  
• 
Modified the 
descriptive endpoints 
cohort due to two 
reasons: (1) Subjects at 
high or extreme risk 
generally have more co-
morbidities and hence a 
shorter life expectancy 
than subjects at low and 
intermediate risk, and 5 
years of follow-up is 
appropriate for this 
group of subjects, and 
(2) Five years of follow-
up is aligned with the 
follow-up requirement in 
other comparable 
studies for subjects at 
high or extreme risk. 
• 
To ensure a good 
representation of both 
intermediate and low 
risk subjects in the trial 
as requested by MHRA 
• 
The required sample 
size was adjusted due 
to a change in the 
assumed ratio (changed 
from 2:1 to 1:1) between 
intermediate risk 
subjects and low risk 
subjects to reflect the 
minimum requirement of 
the proportion of 
intermediate risk 
subjects (50%) for the 
hypothesis testing of the 
primary endpoint. 
• 
To align with the VARC-
3 definitions published 
in 2021 
• 
To make necessary 
changes in endpoints 
according to the VARC-
3 event definitions 
 
 
 
 

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for the composite 
endpoints, mortality, 
stroke, bleeding, 
acute kidney injury, 
rehospitalization, 
and prosthetic valve 
thrombosis) 
• 
Added three 
descriptive endpoints 
(major access-
related non-vascular 
complications, major 
cardiac structural 
complications, and 
non-structural valve 
dysfunction) per the 
VARC-3 definitions  
• 
Updated eligibility criteria 
(Section 5.3): 
• 
Added an imaging 
exclusion criterion: 
eccentricity ratio < 
0.73 (Imaging 
Exclusion Criteria 
(IEC) #48) 
• 
Deleted IEC #30 
listed in version A  
 
• 
Expanded the 
allowed ranges of 
aortic annular 
diameter and 
ascending aorta 
diameters (Imaging 
Inclusion Criteria 
(IIC) #7)  
• 
Removed both MRI 
and 3D TEE as 
alternative imaging 
modalities for valve 
sizing if CT cannot 
be obtained (IIC #7) 
 
• 
Modified the 
definition of acute 
myocardial infarction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To be consistent with 
the IFU  
 
 
 
 
 
 
• 
This criterion was 
removed as it is 
considered redundant. 
• 
To reflect the addition of 
the Navitor 35 mm 
valve  
 
 
 
 
 
• 
To streamline the core 
lab process for 
screening as there 
would be very few 
patients in this scenario 
requiring alternative 
imaging 
• 
To align with a more 
contemporary AMI 
definition 
 
 

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(AMI) to be excluded 
(General Exclusion 
Criteria (GEC) #8) 
• 
Modified and 
combined the criteria 
on hypersensitivity 
and contraindication 
to antiplatelet 
medications, 
anticoagulants, 
contrast, nitinol, or 
CT imaging (GEC 
#17) 
 
 
 
 
• 
Modified the 
language on atrial 
fibrillation to include 
the LAAO device 
(GEC #23) 
• 
Removed the cutoff 
<10 mm for low 
coronary ostium 
height (IEC #44)  
• 
Modified the 
language on General 
Inclusion Criteria 
(GIC) #1, IIC #6 and 
GEC #21 and #27 
and IEC #30, #31, 
#41, and #42 for 
completeness or 
better clarity 
• 
Updated screening 
requirements (Section 
5.2.3): 
o Modified the 
language to 
indicate that 2D 
Transesophageal 
Echocardiogram 
(TEE) is no longer 
allowed  
o Removed lab 
measurements of 
 
• 
Combined two criteria 
for a better organization 
and modified the 
language to indicate 
that dual anti-platelet 
therapy (DAPT) post-
procedure is not 
required and a subject 
is eligible if the subjects 
can take either 
antiplatelet or 
anticoagulant therapy 
post-procedure  
 
• 
Updated to be more 
complete  
 
 
 
• 
To make this criterion 
less rigid 
 
 
• 
To add clarity 
 
 
 
 
 
 
 
 
• 
To add clarity and 
remove unnecessary 
lab tests to reduce the 
burdens for subjects 
and sites  
 
 
 
 
 
 
 
 
 

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BUN, and BNP or 
Pro-BNP  
o Added the 
language that CT 
covering at least 
systole is required 
for valve sizing 
o Removed both MRI 
and 3D TEE as 
alternative imaging 
modalities for valve 
sizing if CT cannot 
be obtained  
o Modified the 
language on 
angiography to 
include invasive 
coronary 
angiography 
• 
Updated laboratory test 
requirements: 
• 
Removed BUN, 
BNP/Pro-BNP, and 
CK from all visits 
• 
Removed CBC 
and platelet count 
after baseline 
• 
Removed 
creatinine, CK-
MB/troponin after 
discharge 
• 
Updated the post-implant 
echo requirement for 
assessing mean aortic 
valve gradient and aortic 
regurgitation (including 
PVL)  
 
• 
Added a time window of 
48 hours for the 
echocardiography and 
laboratory test 
requirements at discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To remove unnecessary 
lab tests to reduce the 
burdens for subjects 
and sites 
 
 
 
 
 
 
 
 
• 
To reflect that invasive 
pressure measurement 
and angiography can 
also be used to assess 
the gradient and aortic 
regurgitation (including 
PVL), respectively 
• 
To provide more 
flexibility for the sites to 
perform these 
assessment as it may 
not be always feasible 
for the sites to perform 
them on the day of 
discharge 
• 
To obtain weight for 
calculating indexed 
echocardiographic 

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• 
Added physical 
examination to follow-up 
visits 
 
 
• 
Added language on 
NIHSS to unscheduled 
visit 
• 
Updated the Table on 
Follow-up and Data 
Collection Requirements 
(Table 5) 
• 
Added language on six-
minute walk test 
• 
Revised language related 
to the Screening 
Committee (SC) 
throughout the CIP 
 
• 
Updated Risk 
Management documents 
referenced in Section 15.3 
 
• 
Updated necessary 
language throughout the 
CIP per ISO14155:2020 
and the MDR 
requirements 
 
 
• 
Updated the list of 
anticipated adverse 
events and associated 
frequency categories in 
APPENDIX XV 
 
 
 
• 
Updated projected 
enrollment duration 
• 
Clarifications 
• 
Corrections 
parameters at follow-up 
visits 
• 
To align with the VARC-
3 definitions 
 
• 
To be consistent with 
changes made in the 
main text 
 
• 
Updated to be complete 
 
• 
To consolidate and 
simplify SC-related 
language and refer 
details to the SC 
Charter 
• 
To simplify the 
documents referenced 
as one document has 
all references  
• 
To comply with the 
mandatory language in 
the Abbott CIP template 
according to 
ISO14155:2020 and the 
MDR requirements  
 
• 
Updated according to 
Abbott’s internal 
periodic risk evaluation 
process based on 
available clinical study 
report data, literature 
data, and/or expert 
medical opinion 
• 
To align with current 
enrollment projection 
 
2 
C 
July 26, 
2024 
• 
Changed the CIP name 
from “VANTAGE – OUS“ 
to “VANTAGE” on the 
cover page, and in 
• 
Updated to reflect the fact 
that US and Canada will 
not be added to 
VANTAGE. This CIP 

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Section 1.0 and 
APPENDIX II.  Updated 
the Compliance 
Statement. Removed the 
language of VANTAGE-
OUS and VANAGE-North 
America (Section 1.0 and 
Section 3.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
amendment consolidates 
three country-specific 
CIPs (VANTAGE-OUS 
CIP (ABT-CIP-10342), 
VANTAGE-UK CIP (ABT-
CIP-10411), and 
VANTAG-Germany CIP 
(ABT-CIP-10423)), each 
of which includes different 
endpoints and other 
requirements mandated 
by different competent 
authorities. Country-
specific requirements not 
included in this CIP will be 
captured in separate 
country-specific 
addendums. After 
approval of this protocol 
amendment, all country-
specific CIPs will be 
retired, and this CIP will 
be the only CIP for the 
VANTAGE trial going 
forward. 
 
 
 
• 
Updated the device name 
to the Navitor TAVI 
System throughout the 
document 
• 
To be consistent with the 
IFU 
 
 
 
 
• 
Added Israel (the cover 
page, Section 1.0, Section 
2.0, Section 3.0, and 
APPENDIX II) 
• 
To reflect the addition of a 
site in Israel 
 
 
 
• 
Added new clinical data 
for the Navitor Titan (35 
mm) Valve (Section 1.1.1)  
• 
To include new clinical 
data on Navitor Titan (35 
mm) valve 
 
 
 
• 
Updated the approval 
status of the Navitor TAVI 
System (Section 2.2.1 and 
Table 1) 
• 
To update the approval 
status of the study device 
 
 
 
 
• 
Updated Endpoints 
(Section 3.0, Section 4.0, 
and Section 8.0):  
o Changed “the primary 
endpoint” to “the 
• 
These changes reflect 
consolidated changes 
from three country-
specific CIPs. 
 

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primary safety 
endpoint” 
o Added the primary 
effectiveness endpoint 
(moderate or greater 
PVL at 30 days) from 
the VANTAGE-
Germany CIP  
o Added three secondary 
endpoints (change of 
mean transvalvular 
gradient, effective 
orifice area, and KCCQ 
between baseline and 
12 months) from the 
VANTAGE-UK CIP 
 
 
 
• 
Removed the language of 
“590 registered subjects” 
(Section 3.0, Section 5.6, 
and Appendix III) 
• 
To remove unnecessary 
wording 
 
 
 
• 
Updated the requirements 
for data analysis and 
regulatory submission 
(Sections 3.0 and Section 
8.4) 
• 
To reflect the update of 
the sample sizes required 
for primary endpoints 
testing  
 
 
 
• 
Added footnotes (Section 
5.0, 8.0, and Appendix III) 
to:  
• 
Clarify inclusion 
requirement for low-risk 
subjects in France and 
Switzerland  
• 
Clarify sample sizes for 
endpoint analyses 
• 
Clarify inclusion 
requirement for the ViV 
cohort in Germany  
• 
To add clarity 
 
 
 
• 
Added language from 
German CIP that subjects 
should be followed per 
standard of care after 
completion of the trial 
(Section 5.5) 
• 
To add clarity 
 
 
 
• 
Clarified neurological 
assessment to include 
mRS (Table 5) 
• 
To add clarity and be 
consistent with Section 
6.4.3.1 

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• 
Updated AE definition per 
ISO14155:2020 (Section 
7.1.1 and Appendix II) 
• 
Update to comply with 
ISO14155:2020 
 
 
 
• 
Added SAE/device 
deficiency report email 
(Section 7.3) 
• 
To add the sponsor’s 
contact email for SAE and 
device deficiency report 
 
 
 
• 
Updated statistical 
assumptions (Section 
8.0): 
o Primary safety 
endpoint: The 
expected rates were 
reduced from 10% to 
8.3% in the 
intermediate risk group 
and reduced from 5% 
to 2.7% in the low risk 
group, respectively. 
The performance goals 
were reduced from 
20% to 16.6% in the 
intermediate risk group 
and reduced from 10% 
to 5.4% in the low risk 
group, respectively. 
The sample size 
(including attrition) 
increased from 186 to 
262 subjects. 
o Primary effectiveness 
endpoint: The 
expected rate was 
reduced from 3.5% to 
3.3%. The 
performance goal was 
reduced from 7% to 
6.6%. The sample size 
(including attrition) 
increased from 410 to 
434 subjects. 
• 
The expected event rates 
and performance goals 
have been updated to be 
more robust and reflect 
recent publications on 
pivotal TAVI trials in low 
and intermediate risk. The 
sample sizes have been 
updated accordingly. 
 
 
 
• 
Clarified the statistical 
considerations for the ViV 
cohort (Section 8.0) 
• 
To add clarity 
 
 
 
• 
Defined the analysis 
populations (attempted 
and implanted population) 
(Section 8.1) 
• 
To consolidate the 
definition of analysis 
populations from three 
country-specific CIPs 

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• 
Removed the justification 
details for the expected 
rate and the performance 
goals (Section 8.0) 
• 
To move the details to the 
Statistical Analysis Plan 
(SAP) 
 
 
 
• 
Removed the analysis 
details for the descriptive 
endpoints (Section 8.0) 
• 
To move details to the 
SAP 
 
 
 
• 
Modified the timing for 
data analysis and 
regulatory submission 
(Section 8.4) 
• 
To update accordingly 
with the study design 
changes  
 
 
 
 
• 
Added subgroup analysis 
method for the primary 
effectiveness endpoint 
(Section 8.5) 
• 
To update accordingly 
with the consolidated 
primary effectiveness 
endpoint from the 
VANTAGE-Germany CIP 
 
 
 
• 
Updated the multiplicity 
adjustment plan (Section 
8.6) 
• 
To update accordingly 
with the consolidated 
endpoints in this CIP 
 
 
 
• 
Simplified tipping point 
analysis (Section 8.8)  
• 
To simplify wording as 
details is provided in SAP  
 
 
 
• 
Updated the success 
criteria in Section 8.11 
• 
To clarify the study 
success requirement 
 
 
 
• 
Added new clinical data to 
support the risk to benefit 
rationale (Section 15.6) 
• 
To reflect the updated 
clinical data 
 
 
 
 
• 
Updated the frequency 
categories of foreseeable 
adverse events (Appendix 
XV) 
• 
Updated according to 
Abbott’s periodic risk 
evaluation process based 
on available clinical study 
report data, literature 
data, and/or expert 
medical opinion 
 
 
 
• 
Updated the surgical risk 
assessment tools 
(Appendix VII) 
• 
To provide the up-to-date 
assessment tools 
 
 
 
• 
Corrections 
• 
To correct typos  

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APPENDIX XII: SITE CONTACT INFORMATION 
Contact information for each participating clinical site is available under separate cover by contacting the 
Sponsor at: 
 
Abbott 
Structural Heart Clinical Affairs 
5050 Nathan Lane North 
Plymouth, Minnesota USA 55442 
1 (651) 756 5400 
 
 

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APPENDIX XIII: MONITORING PLAN 
A copy of the Monitoring Plan can be obtained upon request from the Sponsor Clinical Project Manager 
for the clinical investigation. 
 
 

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APPENDIX XIV: CASE REPORT FORMS 
 
Clinical investigation case report forms will be provided under a separate cover. 
 
 
 

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APPENDIX XV: FORESEEABLE ADVERSE EVENTS AND ASSOCIATED FREQUENCY 
CATEGORIES 
Potential risks associated with the Navitor Valve implant procedure are similar to those for standard TAVI 
procedure. Although anticipated risks for Navitor are described below, due to the nature of this study, 
there may also be other risks, which are not known at this time. Likewise, the exact frequency of the risk 
may be unknown. 
 
ANTICIPATED ADVERSE EVENTS 
Anticipated AE frequency category 
Very common: ≥10% 
Common: ≥1.0% to <10% 
Uncommon: ≥0.1% to <1.0% 
Rare: ≥0.01% to <0.1% 
Very rare: < 0.01% 
Access site complications (e.g., pain, bleeding, infection, 
hematoma, pseudoaneurysm, etc.) 
Very common 
Acute coronary obstruction 
Uncommon 
Acute myocardial infarction 
Common 
Allergic reaction to antiplatelet agents, contrast medium, or 
valve components 
Rare 
Aortic rupture 
Uncommon 
Ascending aorta trauma 
Uncommon 
Atrio-ventricular node block 
Very Common 
Blood cell disorders: hemolytic anemia; thrombocytopenia 
Common 
Cardiac arrhythmias 
Very Common 
Conduction system injury 
Very common 
Dissection 
Uncommon 
Embolism 
Uncommon 
Endocarditis 
Common 
Heart Failure 
Common 
Hemodynamic compromise 
Very Common 
Hemolysis 
Rare 
Haemorrhage (Bleeding) 
Very Common 
Hypertension/Hypotension 
Common  

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Infection  
Common  
Myocardial ischemia 
Common  
Mitral valve insufficiency 
Rare 
Multi-organ failure 
Very rare 
Non-structural dysfunction (i.e., entrapment by pannus, 
paravalvular leak, inappropriate sizing or positioning) 
 Common 
Pericardial effusion 
Uncommon  
Perforation of the myocardium or a blood vessel 
Uncommon  
Pannus  
 Uncommon  
Regurgitation 
Common 
Renal insufficiency or renal failure (Acute kidney injury) 
Common 
Respiratory failure: acute pulmonary edema 
Common  
Sepsis 
Uncommon  
Stroke 
Common 
Structural deterioration (i.e., calcification, leaflet tear) 
Rare 
Thrombosis 
Common 
Tamponade 
Common  
Transient ischemic attack 
Common 
Valve embolization or migration  
Common  
Vessel dissection or spasm 
Common  
It is possible these complications could lead to: 
Transfusion 
Very Common 
Conversion to open surgical procedure 
Uncommon 
Reoperation  
Uncommon 
Emergent balloon valvuloplasty 
Uncommon 
Emergent percutaneous coronary intervention (PCI) 
Uncommon 

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Emergent surgery (i.e., coronary artery bypass, heart valve 
replacement) 
Uncommon 
Explantation  
Uncommon 
Permanent disability  
Rare  
Death  
Common 
Permanent pacemaker  
Very Common 

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APPENDIX XVI: REFERENCES 
 
 
 
1 
Iung, B. & Vahanian, A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol 8, 
162-172, doi:10.1038/nrcardio.2010.202 (2011). 
2 
Bonow, R. O. et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the 
management of patients with valvular heart disease: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to 
revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed 
by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and 
Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 52, e1-142, 
doi:10.1016/j.jacc.2008.05.007 (2008). 
3 
Baumgartner, H. et al. 2017 ESC/EACTS Guidelines for the management of valvular heart 
disease. Eur Heart J 38, 2739-2791, doi:10.1093/eurheartj/ehx391 (2017). 
4 
Murakami, T. et al. Changes in patterns of left ventricular hypertrophy after aortic valve 
replacement for aortic stenosis and regurgitation with St. Jude Medical cardiac valves. Artif 
Organs 24, 953-958, doi:10.1046/j.1525-1594.2000.06641.x (2000). 
5 
Cribier, A. et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific 
aortic stenosis: first human case description. Circulation 106, 3006-3008, 
doi:10.1161/01.cir.0000047200.36165.b8 (2002). 
6 
Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who 
cannot undergo surgery. N Engl J Med 363, 1597-1607, doi:10.1056/NEJMoa1008232 (2010). 
7 
Smith, C. R. et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N 
Engl J Med 364, 2187-2198, doi:10.1056/NEJMoa1103510 (2011). 
8 
Vahanian, A. et al. Guidelines on the management of valvular heart disease (version 2012): the 
Joint Task Force on the Management of Valvular Heart Disease of the European Society of 
Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J 
Cardiothorac Surg 42, S1-44, doi:10.1093/ejcts/ezs455 (2012). 
9 
Nishimura, R. A. et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular 
Heart Disease: a report of the American College of Cardiology/American Heart Association Task 
Force on Practice Guidelines. Circulation 129, e521-643, doi:10.1161/cir.0000000000000031 
(2014). 
10 
Popma, J. J. et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in 
patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 63, 1972-1981, 
doi:10.1016/j.jacc.2014.02.556 (2014). 
11 
Adams, D. H. et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N 
Engl J Med 370, 1790-1798, doi:10.1056/NEJMoa1400590 (2014). 
12 
Leon, M. B. et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk 
Patients. N Engl J Med 374, 1609-1620, doi:10.1056/NEJMoa1514616 (2016). 
13 
Thourani, V. H. et al. Transcatheter aortic valve replacement versus surgical valve replacement in 
intermediate-risk patients: a propensity score analysis. Lancet 387, 2218-2225, 
doi:10.1016/s0140-6736(16)30073-3 (2016). 
14 
Nishimura, R. A. et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the 
Management of Patients With Valvular Heart Disease: A Report of the American College of 

ABT-CIP-10342 Ver. C 
Study Name: VANTAGE  
Clinical Investigation Plan 
 
 
 
 
 
Page 112 of 113 
 
 
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll 
Cardiol 70, 252-289, doi:10.1016/j.jacc.2017.03.011 (2017). 
15 
Reardon, M. J. et al. Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk 
Patients. N Engl J Med 376, 1321-1331, doi:10.1056/NEJMoa1700456 (2017). 
16 
Mack, M. J. et al. Transcatheter Aortic-Valve Replacement with a Balloon-Expandable Valve in 
Low-Risk Patients. N Engl J Med 380, 1695-1705, doi:10.1056/NEJMoa1814052 (2019). 
17 
Popma, J. J. et al. Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-
Risk Patients. N Engl J Med 380, 1706-1715, doi:10.1056/NEJMoa1816885 (2019). 
18 
Makkar, R. R. et al. Self-expanding intra-annular versus commercially available transcatheter 
heart valves in high and extreme risk patients with severe aortic stenosis (PORTICO IDE): a 
randomised, controlled, non-inferiority trial. Lancet 396, 669-683, doi:10.1016/s0140-
6736(20)31358-1 (2020). 
19 
Fontana, G. P. et al. Safety Profile of an Intra-Annular Self-Expanding Transcatheter Aortic Valve 
and Next-Generation Low-Profile Delivery System. JACC Cardiovasc Interv 13, 2467-2478, 
doi:10.1016/j.jcin.2020.06.041 (2020). 
20 
Reardon, M. J. et al. 30-Day Clinical Outcomes of a Self-Expanding Transcatheter Aortic Valve: 
The International PORTICO NG Study. JACC Cardiovasc Interv 16, 681-689, 
doi:10.1016/j.jcin.2023.02.002 (2023). 
21 
Varc-3 Writing, C. et al. Valve Academic Research Consortium 3: Updated Endpoint Definitions 
for Aortic Valve Clinical Research. J Am Coll Cardiol 77, 2717-2746, 
doi:10.1016/j.jacc.2021.02.038 (2021). 
22 
Kappetein, A. P. et al. Updated standardized endpoint definitions for transcatheter aortic valve 
implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J 33, 
2403-2418, doi:10.1093/eurheartj/ehs255 (2012). 
23 
Popma, J. J. et al. Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-
Risk Patients. N Engl J Med 380, 1706-1715, doi:10.1056/NEJMoa1816885 (2019). 
24 
Deharo, P. et al. Long-Term Prognosis Value of Paravalvular Leak and Patient-Prosthesis 
Mismatch following Transcatheter Aortic Valve Implantation: Insight from the France-TAVI 
Registry. J Clin Med 11, doi:10.3390/jcm11206117 (2022). 
25 
Kodali, S. K. et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N 
Engl J Med 366, 1686-1695, doi:10.1056/NEJMoa1200384 (2012). 
26 
Otto, C. M. et al. 2017 ACC Expert Consensus Decision Pathway for Transcatheter Aortic Valve 
Replacement in the Management of Adults With Aortic Stenosis: A Report of the American 
College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 
69, 1313-1346, doi:10.1016/j.jacc.2016.12.006 (2017). 
27 
Edwards SAPIEN 3 Transcatheter Heart Valve System. Summary of Safety and Effectiveness 
Data. https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140031S028b.pdf. (2017). 
28 
Medtronic CoreValve System: Summary of Safety and Effectiveness Data. 
https://www.accessdata.fda.gov/cdrh_docs/pdf13/P130021S010B.pdf.  (2015). 
29 
Turina, J., Hess, O., Sepulcri, F. & Krayenbuehl, H. P. Spontaneous course of aortic valve 
disease. Eur Heart J 8, 471-483, doi:10.1093/oxfordjournals.eurheartj.a062307 (1987). 
30 
Otto, C. M. et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart 
Disease. Journal of the American College of Cardiology 0, doi:doi:10.1016/j.jacc.2020.11.018. 
31 
Sondergaard, L. et al. Thirty-day and one-year outcomes of the Navitor transcatheter heart valve 
in patients with aortic stenosis: the prospective, multicentre, global PORTICO NG Study. 
EuroIntervention 19, 248-255, doi:10.4244/EIJ-D-22-01108 (2023). 

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32 
ISO. Clinical Investigation of Medical Devices for Human Subjects — Good Clinical Practice. ISO 
14155: 2020.  (2020). 
33 
Durack, D. T., Lukes, A. S. & Bright, D. K. New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 96, 200-
209, doi:10.1016/0002-9343(94)90143-0 (1994).