International Multicenter Study of the Navitor/Navitor Vision Transcatheter Aortic Valve Platform (The Intensive Study)
Conditions: Severe Native Aortic Stenosis
Sponsor: IRCCS Policlinico S. Donato

Study Name: INTENSIVE 
Real-World Study 
 
 
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International Multicenter Study of 
the Navitor/Navitor Vision Transcatheter Aortic Valve Platform 
 
The INTENSIVE Study 
 
Protocol Name 
International Multicenter Study of the Navitor/Navitor Vision 
Transcatheter Aortic Valve Platform (The INTENSIVE Study) 
Protocol Acronym 
INTENSIVE 
Version 
2.0 
Date 
18 Jul 2025 
 
Coordinating Investigator 
Luca Testa, MD, PhD 
Contract Professor of Cardiology, “Vita e Salute" University - San 
Raffaele Hospital, Milan, Italy 
Head of Coronary Revascularisation Unit, IRCCS Policlinico S. 
Donato, San Donato M.se, Milan, Italy 
Head of Clinical Research Unit, IRCCS Policlinico S. Donato, San 
Donato M.se, Milan, Italy 
Promoter 
IRCCS Policlinico S. Donato, San Donato M.se, Milan, Italy 
Number of Sites and Regions 
Up to 25 sites in multiple countries (including Germany, Italy, Spain, 
UK, France) 
Number of Patients 
Up to 1000 
Estimated Enrollment 
12 Months 
Clinical Follow-up Duration 
Up to 5 years, per standard of care 
Clinical Investigation Type 
No-profit, Investigator Initiated Observational Study 
Electronic Data Capture 
Catchtrial EDC Platform (www.catchtrial.com) 
CRO 
• 
Regulatory Support, Ethic Committee Submissions: Meditrial 
Srl (www.meditrial.net) 
• 
Trial Management, Monitoring, Data Management and Safety 
Management: IRCCS Policlinico S. Donato, Clinical Research 
Unit, San Donato M.se, Milan, Italy 
 

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PROTOCOL AMENDMENT HISTORY 
 
DOCUMENT HISTORY 
 
Version  
Date [Day-Mon-Year] 
Changes 
Version 1.0 
23 May 2025 
Original Protocol 
Version 2.0 
18 Jul 2025 
8.1Statistical Analyses review 
 
 
 
 
 

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COORDINATING INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title: The INTENSIVE Study 
International Multicenter Study of the Navitor/Navitor Vision Transcatheter Aortic Valve platform 
 
Declaration of the Coordinating Investigator: 
The present Intensive Study protocol was subject to critical review. Its content is consistent with the current 
risk/benefit evaluation of the Medical Device as well as with the ethical and scientific principles of good 
clinical practice, the latest version of the Declaration of Helsinki, the local laws and the regulations and the 
applicable regulatory requirements of the Countries where this Study will be conducted. 
 
 
 
Coordinating Investigator Signature: 
          
 
                            
                        
 
                                                                                                                               18 Jul 2025 
Name: Dr. Luca Testa 
Title: Head of Coronary Revascularisation Unit, 
IRCCS Policlinico S. Donato, San Donato M.se, Milan, Italy 
 
Date 
 
 
 
 

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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I, the undersigned Investigator, am responsible for the conduct of the study at my site and have read and 
understood the specified protocol and all applicable regulatory requirements.  
 
 
Study Principal Investigator 
Printed name: 
 
Signature: 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT HISTORY ......................................................................................................... 2 
COORDINATING INVESTIGATOR SIGNATURE PAGE ............................................................................. 3 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE ............................................................................. 4 
TABLE OF CONTENTS ................................................................................................................................ 5 
INDEX OF TABLES ...................................................................................................................................... 8 
INDEX OF FIGURES .................................................................................................................................... 8 
1 
INTRODUCTION .................................................................................................................................. 9 
1.1 
TAVI Evolving Indications ................................................................................................................. 9 
1.2 
TAVI Indications ................................................................................................................................ 9 
1.3 
TAVI Market Approvals ................................................................................................................... 10 
1.4 
The Navitor/Navitor Vision TAVI ..................................................................................................... 11 
1.5 
Rationale for the Intensive Study .................................................................................................... 11 
2 
CLINICAL STUDY OVERVIEW .......................................................................................................... 12 
2.1 
Clinical Investigation Objective ....................................................................................................... 12 
2.2 
The Navitor System ......................................................................................................................... 12 
2.2.1 
Navitor System Description ................................................................................................. 13 
3 
INTENSIVE STUDY OVERVIEW ....................................................................................................... 17 
4 
ENDPOINTS ....................................................................................................................................... 18 
4.1 
Primary Endpoint ............................................................................................................................. 18 
4.2 
Secondary (Descriptive) Endpoints ................................................................................................. 18 
5 
SUBJECT SELECTION AND WITHDRAWAL ................................................................................... 20 
5.1 
Subject Population .......................................................................................................................... 20 
5.2 
Subject Screening and Informed Consent ...................................................................................... 20 
5.2.1 
Subject Pre-Screening ........................................................................................................ 20 
5.2.2 
Informed Consent ................................................................................................................ 20 
5.2.3 
Subject Pre-Procedure Workup .......................................................................................... 21 
5.3 
Eligibility Criteria .............................................................................................................................. 21 
5.3.1 
General Eligibility Criteria .................................................................................................... 21 
5.3.2 
Inclusion Criteria.................................................................................................................. 22 
5.3.3 
Exclusion Criteria ................................................................................................................ 22 
5.4 
Subject Enrollment Point ................................................................................................................. 22 
5.5 
Subject Discontinuation ................................................................................................................... 22 

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5.6 
Number of Subjects ......................................................................................................................... 23 
5.7 
Total Expected Duration of the Clinical Investigation ..................................................................... 23 
6 
TREATMENT AND EVALUATION OF ENDPOINTS ......................................................................... 24 
6.1 
Baseline ........................................................................................................................................... 24 
6.1.1 
Baseline Assessments ........................................................................................................ 24 
6.1.2 
Pre-procedure Antiplatelet/Anticoagulation Medications .................................................... 24 
6.1.3 
Pre-procedure Blood Tests ................................................................................................. 24 
6.2 
Index Procedure .............................................................................................................................. 24 
6.2.1 
Procedures Involved in the Use of the Device .................................................................... 24 
6.2.2 
Procedural Anticoagulation ................................................................................................. 24 
6.2.3 
Implant Procedure ............................................................................................................... 24 
6.3 
Discharge Assessments .................................................................................................................. 26 
6.4 
Follow-up Assessments .................................................................................................................. 26 
6.4.1 
Follow-up Medications ........................................................................................................ 26 
6.4.2 
Follow-up ............................................................................................................................. 26 
6.4.3 
Unscheduled Follow-up ....................................................................................................... 28 
6.4.4 
Patient Reported Outcome (PRO) Measures ..................................................................... 28 
6.4.5 
Schedule of Assessments (SoA) ......................................................................................... 28 
7 
ADVERSE EVENTS AND INCIDENTS REPORTING ....................................................................... 30 
7.1 
Requirements and definitions .......................................................................................................... 30 
7.2 
Reporting  ........................................................................................................................................ 31 
8 
STATISTICAL CONSIDERATIONS ................................................................................................... 31 
8.1 
Statistical Analyses ......................................................................................................................... 31 
Sample Size Calculation and Assumptions ................................................................................................ 31 
8.2 
Timing of Analysis ........................................................................................................................... 32 
8.3 
Subgroup Analysis .......................................................................................................................... 32 
8.4 
Planned Interim Analysis ................................................................................................................. 32 
8.5 
Statistical Criteria for Termination ................................................................................................... 32 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................................... 32 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................... 32 
10.1 
Selection of Clinical Sites and Investigators ................................................................................... 32 
10.2 
Site Principal Investigator Responsibilities ..................................................................................... 32 
10.3 
Protocol Amendments ..................................................................................................................... 33 
10.4 
Site Training .................................................................................................................................... 33 
10.5 
Monitoring ........................................................................................................................................ 33 

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10.6 
Protocol Deviations ......................................................................................................................... 33 
10.7 
Study Steering Committee .............................................................................................................. 33 
11 
DATA HANDLING AND RECORD KEEPING .................................................................................... 34 
11.1 
Protection of Personally Identifiable Information ............................................................................. 34 
11.2 
Case Report Form Completion ....................................................................................................... 34 
11.3 
Record Retention ............................................................................................................................ 35 
12 
ETHICAL CONSIDERATION ............................................................................................................. 35 
12.1 
Ethics Committee Review and Approval ......................................................................................... 35 
13 
CLINICAL INVESTIGATION CONCLUSION ..................................................................................... 35 
13.1 
Suspension or Early Termination of the Clinical Investigation ........................................................ 35 
13.1.1 
Subject Follow-up for Early Termination or Suspension of Study ....................................... 36 
14 
PUBLICATION POLICY ..................................................................................................................... 36 
15 
STUDY RISK BENEFIT ANALYSIS ................................................................................................... 36 
15.1 
Anticipated Clinical Benefits ............................................................................................................ 36 
15.2 
Potential procedure risks ................................................................................................................. 37 
15.3 
Risks Associated with Participation in Intensive Study ................................................................... 37 
16 
APPENDICES .................................................................................................................................... 38 
16.1 
APPENDIX I: ABBREVIATIONS AND ACRONYMS ...................................................................... 38 
16.2 
APPENDIX II: DEFINITIONS .......................................................................................................... 40 
16.3 
APPENDIX III: TAVI PRE-PROCEDURAL WORKUP .................................................................... 50 
16.4 
APPENDIX IV: PERI-PROCEDURAL GUIDELINES ...................................................................... 51 
16.5 
APPENDIX V: REFERENCES ........................................................................................................ 52 
 
Abbreviations and definitions used throughout this Protocol can be found in Appendix I and II.  
 
 

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INDEX OF TABLES 
Table 1: Devices Included in the Intensive Study ........................................................................................ 12 
Table 2: Matching Components in the Navitor/Navitor Vision Implantation System................................... 12 
Table 3: Patient Anatomical Specification per the Navitor/Navitor Vision Valve ........................................ 13 
Table 4: FlexNav Delivery System Models and Compatibility with Navitor/Navitor Vision Valve Sizes ..... 16 
Table 5: Follow-up and Data Collection Requirements .............................................................................. 29 
Table 6: Safety Definitions .......................................................................................................................... 31 
 
 
INDEX OF FIGURES 
Figure 1: Navitor/Navitor Vision Valve ........................................................................................................ 14 
Figure 2: FlexNav Delivery System- Handle Detail ..................................................................................... 16 
Figure 3: FlexNav Delivery System - Distal End Detail ............................................................................... 17 
Figure 4: Assessment of implant depth ....................................................................................................... 52 
 
 
 
 
 
 
 

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1 INTRODUCTION 
INTENSIVE is a prospective, single-arm, multi-center, international, investigator-initiated study of the 
Navitor/Navitor Vision Transcatheter Aortic Valve (Navitor/Navitor Vision Valve) in patients with 
symptomatic, severe native aortic stenosis to monitor the outcomes of this valve in a real-world clinical 
setting. The investigators involved in the conduct of the clinical investigation will be qualified by education, 
training, or experience to perform their tasks. 
1.1 
TAVI Evolving Indications  
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 
1.2 
TAVI Indications  
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 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 

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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%.18 
1.3 
TAVI Market Approvals 
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, 

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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.19 
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.20 
1.4 
The Navitor/Navitor Vision TAVI 
The Navitor/Navitor Vision 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/Navitor Vision Valve 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/Navitor Vision 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 120 subjects in Australia, Europe, and the U.S., 
the rate of all-cause mortality at 30 days was 0%, 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/Navitor Vision subjects had a mean 
aortic valve area of 2.0 ± 0.5 cm2 with a mean gradient of 8.1 ± 3.7 mmHg. The combination of the 
Navitor/Navitor Vision 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/Navitor Vision Transcatheter Valve System (including the FlexNav Delivery System and 
Navitor/Navitor Vision Loading System) received CE Mark in May 2021 as well as approval in Japan, India, 
and Canada in 2022 for the treatment of patients with symptomatic, severe AS that are considered high or 
extreme surgical risk, and is currently under regulatory review in other geographies. 
 
1.5 
Rationale for the Intensive Study 
 
The INTENSIVE Study will provide comprehensive real-world evidence on the safety, performance, and 
clinical outcomes of the Navitor/Navitor Vision Valve with the FlexNav Delivery System in routine clinical 
practice. By enrolling a broad, unrestricted TAVI population across multiple interventional centers, the study 
captures the diversity and complexity of patients typically encountered in daily clinical settings. This 

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comprehensive dataset will offer valuable insights into device performance, inform clinical decision-making, 
and support best practices in the evolving field of transcatheter valve therapy. 
2 
CLINICAL STUDY OVERVIEW 
2.1 
Clinical Investigation Objective 
The INTENSIVE Study aims to gather and monitor real-world outcomes of the Navitor/Navitor Vision Valve 
with the FlexNav Delivery System in a diverse population undergoing TAVR. For a detailed description of 
primary and secondary endpoints see Section 4.1 and 4.2. This comprehensive data collection across 25 
interventional centers, aligned with standard clinical care practices, seeks to provide an objective 
benchmark for current TAVR practice.  
 
2.2 
The Navitor System 
The Navitor System include the Navitor Transcatheter Aortic Valve (23 mm, 25 mm, 27 mm, 29 mm, and 
the 35 mm), FlexNav Delivery System (small and large), and Navitor Loading System (small, large, and 
LG+). The FlexNav Delivery System (small and large) is commercially available in Europe. The 23 mm, 25 
mm, 27 mm, 29 mm, and 35 mm valves and their loading systems are currently CE Marked.  
Model numbers for the Navitor Valve, FlexNav Delivery System, and Navitor Loading System and their 
regulatory status are provided below in Table 1. The matching components of the Navitor Implantation 
System are listed in Table 2. 
Table 1: Devices Included in the Intensive Study 
Device name 
Model/Type 
Navitor 23 mm Valve 
PRT-NG- 23/NVTR-23 
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 
 
FlexNav Small Delivery System 
FN-DS-SM-IDE/ FNAV-DS-SM 
 
FlexNav Large Delivery System 
FN-DS-LG-IDE/ FNAV-DS-LG 
 
Navitor Small Loading System 
PRT-NG-LS- SM/NVTR-LS-SM 
 
Navitor Large Loading System 
PRT-NG-LS- LG/NVTR-LS-LG 
 
Navitor Titan Loading System 
LG+ 
PRT-NG-LS-35 
 
 
Table 2: Matching Components in the Navitor Implantation System 
Navitor Valve Catalog Numbers 
FlexNav Delivery System 
Catalog Numbers 
Navitor Loading System 
Catalog Numbers 
PRT-NG-23/NVTR-23 (23 mm) 
FN-DS-SM-IDE/FNAV-DS-SM 
PRT-NG-LS-SM/NVTR-LS-SM 
or 

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Navitor Valve Catalog Numbers 
FlexNav Delivery System 
Catalog Numbers 
Navitor Loading System 
Catalog Numbers 
PRT-NG-25/NVTR-25 (25 mm) 
PRT-NG-27/NVTR-27 (27 mm) 
FN-DS-LG-IDE/FNAV-DS-LG 
PRT-NG-LS-LG/NVTR-LS-LG 
or 
PRT-NG-29/NVTR-29 (29 mm) 
PRT-NG-35 (35 mm) 
FN-DS-LG-IDE/FNAV-DS-LG 
PRT-NG-LS-35 
The intended Indication for Use statements for the products used in this Study 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.  
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. 
2.2.1 
Navitor System Description 
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. 
2.2.1.1 
Navitor/NavitorVision 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 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/Navitor Vision 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 

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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 
*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™ anti calcification 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. 
Figure 1a: 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. 
Figure 1b. Navitor Vision Valve 

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VALVE 
NVRO-23 
NVRO -25 
NVRO-27 
NVRO-29 
NVRO-35 
A) Inflow Diameter 
(mm)  
23 
25 
27 
29 
35 
B) Outflow Diameter 
(mm)  
23 
25 
27 
29 
35 
C) Aortic Stent 
diameter (mm)  
41 
43 
44 
46 
48 
D) Commissure Height 
(mm)  
21 
23 
24 
25 
27 
E) Half Cell Height 
(mm)  
7 
7 
8 
8 
9 
F) NaviSeal™ cuff 
height (mm)  
9 
9 
10 
10 
11 
G) Stent Height (mm)  
47 
48 
48 
48 
47 
H) Marker’s height 
(mm)  
3 
3 
3 
3 
3 
The Navitor Vision Valve differs from the Navitor Valve for the presence of the 3 markers. 
Three tantalum radiopaque markers (Vision Technology) are positioned between the inner and outer skirt, 
aligned beneath each commissure of the bioprosthesis, 3 mm above the inflow leaflet edge. These 
markers assist with fluoroscopic positioning and ensure accurate depth implantation. 
 
2.2.1.2 
   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 Portico or Navitor/Navitor Vision 
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/Navitor Vision 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 
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Table 4: FlexNav Delivery System Models and Compatibility with Navitor/Navitor Vision Valve 
Sizes 
Description 
Catalog 
Number 
Equivalent 
Integrated 
Sheath 
Diameter 
Distal 
End 
Outer 
Diameter 
Integrated 
Sheath 
Working 
Length 
Delivery 
System 
Length 
Minimum 
Vessel 
Diameter 
Compatible 
Valve Size 
FlexNav 
Delivery 
System 
(small) 
FNAV-DS-SM 
14 F 
6.0 mm 
30 cm 
107 cm 
≥ 5.0 mm 
23 mm and 
25 mm 
FlexNav 
Delivery 
System 
(large) 
FNAV-DS-LG 
15 F 
6.3 mm 
30 cm 
107 cm 
≥ 5.5 mm 
27 mm, 29 
mm, and 35 
mm 
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) 

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Figure 3: FlexNav Delivery System - Distal End Detail 
2.2.1.3 
   Navitor Loading System 
The Navitor/Navitor Vision Loading System is an accessory used to compress and load the Navitor/Navitor 
Vision Valve onto the FlexNav Delivery System. The Navitor/Navitor Vision 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/Navitor Vision Loading System components (loading 
base, loading tube, leaflet tester) are the same as the FlexNav Loading System. The method of loading the 
Navitor/Navitor Vision Valve onto the FlexNav Delivery System is also unchanged. 
The Navitor/Navitor Vision Small Loading System is used for loading the 23 or 25 mm Navitor/Navitor Vision 
Valves on the FlexNav Small Delivery System, the Navitor/Navitor Vision Large Loading System is used for 
loading the 27 or 29 mm Navitor/Navitor Vision Valves on the FlexNav Large Delivery System, and the 
Navitor/Navitor Vision Titan Loading System - LG+ is used for loading the Navitor/Navitor Vision Titan 35 
mm Valve on the FlexNav Large Delivery System. 
Please refer to the IFU for additional information regarding the device used in this Study. 
3 
INTENSIVE STUDY OVERVIEW 
The INTENSIVE Study is a prospective, single-arm, multi-center, international, investigator-initiated study 
in patients with symptomatic, severe native aortic stenosis to monitor the outcomes of Navitor/Navitor Vision 
Valve in a real-world clinical setting. The Study will collect clinical outcome data from a maximum of 1000 
subjects from qualified interventional centers in multiple countries (including Germany, Italy, Spain, UK, 
France). 
The Study will enroll subjects that, after comprehensive Heart Team evaluation, are scheduled for treatment 
with the Navitor/Navitor Vision Valve according to standard of care at up to 25 experienced TAVI implant 
centers across Europe and UK. All sites must either have prior Portico or Navitor/Navitor Vision TAVI 
system experience. Subjects who provide informed consent for the collection of their clinical data in this 
Study, will undergo Navitor/Navitor Vision Valve implantation via a transfemoral or alternative access 
(subclavian or axillary) approach using the site’s anesthesia protocol for TAVI procedures.  
In the Study, 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/Navitor Vision 
Valve) into the subject’s vasculature (the subject is considered attempted with Navitor/Navitor Vision Valve 
implantation at this point) (Figure 4). Only registered subjects will be included in the analysis. 
The endpoints of interest will be defined according to VARC-3 definitions. 

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Subjects participating in the Study will be followed for a total of 5 years with data collected at, baseline, 
procedure, prior to hospital discharge, and follow-up at 30 days, 12 months and annually thereafter up to 5 
years.  
Key clinical outcome assessments at each follow-up visit are described in Section 6.0.  
The expected duration of enrollment is 12 months, and the total duration of the Study including final 
data cleaning, reporting, and site close-out is expected to be approximately 6.5 years.  
For a discussion of the risks and benefit of participation in this Study, Refer to the Risks Analysis (Section 
15.0) of this protocol for details. 
4 
ENDPOINTS 
4.1 
Primary Endpoint 
The primary endpoint is all-cause mortality at 12 months post index Navitor/Navitor Vision implantation 
procedure  
4.2 
Secondary (Descriptive) Endpoints 
The rate of the following key outcomes for the Study will be assessed as descriptive endpoints per the 
Valve Academic Research Consortium (VARC) 3 event definitions21,22: 
1. 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. Composite of all-cause mortality or all stroke at 12 months 
3. Procedural success defined as successful vascular access, delivery and deployment of 
the Navitor/Navitor Vision Valve; retrieval of the delivery system and correct positioning of 
a single Navitor/Navitor Vision 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. Difference in Coronary arteries’ cannulation time pre vs post Navitor/Navitor Vision implant  
16. Differences in outcome of PVL, embolization / migration based on: 
a. no-predilation, 
b. pre-dilation with balloon not exceeding minimum diameter on CT scan 
c. pre-dilation with balloon exceeding the minor axis but not exceeding perimeter derived 
diameter on CT scan 

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Suggested to acquire a short cine during final release to visualize (or at least measure) any valve 
migration 
17. Assessment of PM dependency at 3 months post implant 
a. Suggested methodology: 
i. PM will be set with  
1. baseline frequency equal to the one recorded by the ECG performed at 
rest at admission - 10 bpm 
2. all diagnostics ON 
3. rate-responsiveness OFF 
4. AV autosensing ON 
5. Spontaneous AV conduction favoring algorithm ON 
ii. at 3 months, based on the PM diagnostics, following data will be collected: 
1. % of total stimulation (stimulated beats vs total beats) 
2.  weekly (if available) % stimulation evolution 
iii. True permanent PM is being defined by San Donato consensus and EP expertise 
– Prof. Pappone 
iv. Download diagnostic – if possible – at follow-up to be stored in the eCRF 
18. Vascular access complication rate according to the “Hostile Score” (JACC Cardiovasc Interv 2023 
Feb 27;16(4):396-411) 
19. 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, quality of life measure: Kansas 
City Cardiomyopathy Questionnaire (KCCQ)) 
20. Rehospitalization (procedure-related or valve-related hospitalization, and other cardiovascular 
hospitalization) at 30 days and 12 months 
21. Paravalvular leak (none/trace, mild, moderate or severe) at discharge, 30 days, 12 months and 
annually (when collected) through 5 years 
22. Changes in echocardiographic parameters from baseline to follow-up at 30 days, 12 months and 
annually (when collected) through 5 years (e.g., mean effective orifice area, mean transvalvular 
gradient) 
23. Aortic valve reintervention at 30 days, 12 months, and annually through 5 years 
24. Prosthetic valve endocarditis at 12 months and annually through 5 years 
25. Structural valve deterioration at 12 months and annually through 5 years 
26. Non-structural valve dysfunction at 12 months and annually through 5 years 
27. Successful coronary access as needed at 12 months and annually through 5 years 
28. Clinically significant prosthetic valve thrombosis at 12 months and annually through 5 years 
 
All endpoints will be assessed from the index procedure unless otherwise noted. 

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5 
SUBJECT SELECTION AND WITHDRAWAL 
5.1 
Subject Population 
This Study will enroll subjects of all genders who have symptomatic, severe AS, either in native or in a 
surgical bioprosthetic valve and are indicated for TAVI implantation. The latter can also be predominantly 
regurgitant to be suitable for enrolment. Complete clinical investigation eligibility criteria are described in 
Section 5.3. Subjects must meet all general eligibility criteria for the TAVI procedure and provide written 
informed consent prior to sites collecting any clinical data for this Study. 
The operative risk determination of study candidates will be done by the local heart team. 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.23 
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 protocol must evaluate patients 
for the general 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 Study. 
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 Study. 
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 Ethics Committee. This process will include a verbal 
discussion with the patient on all aspects of the Study. As this is a investigator initiated Study where the 
Navitor/Navitor Vision Valve is used according to the approved indications, the subject consent will be 
focused on the agreement to allow his/her clinical data collection and participation in the Study follow-up 
visits that will allow the evaluation of the relevant clinical outcomes.  
None of the Study follow-up examinations expose the subject to potential risk or burden, therefore the risk 
of participation in the Study is limited to potential breach of confidentiality, which is mitigated through 
pseudonymization of all data collected in the Study.  Sites must inform patients about their right to withdraw 
from the study at any time and for any reason without sanction, penalty, or loss of benefits to which the 
patient is otherwise entitled. Withdrawal from the study 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.  
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 Ethics Commission. 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 data collection. The site will file the signed original in the 
patient’s hospital or research charts and provide a copy to the patient.  
If, during the Study, 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 

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information to the subject. If relevant, sites will ask the subject to confirm their continuing informed consent 
in writing. 
5.2.2.1 
  Vulnerable Subjects Exclusion 
Consistent with the Study exclusion criteria listed in Section 5.3.3, this Study excludes individuals unable 
to make the decision to participate in the study on their own or who are unable to fully understand all aspects 
of the study 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.  
5.2.3 
Subject Pre-Procedure Workup 
Once a duly dated and signed Informed Consent form is obtained, sites will collect the following data that 
are routinely obtained in all patients scheduled for TAVI as part of the standard pre-procedural workup: 
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 plus Independence in Ambulation 
Index)) 
7. 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) 
8. 12 Lead Electrocardiogram (ECG) 
9. 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 
(brachial approach or transcaval approach), and determination of appropriate coaxial angles for 
optimizing the valve implantation procedure. CT covering at least systole is required for valve sizing. 
CT scan performed up to 12 months prior to consent will be acceptable. 
 
All cardiac medications and all medications given for cardiovascular effect may be continued at their 
prescribed dosages for the screening assessments. 
Further details regarding Pre-Procedure Workup can be found in Appendix III. 
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. 

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5.3.2 
Inclusion Criteria 
5.3.2.1 
  General Inclusion Criteria 
1. Subject is referred to receive a Navitor/Navitor Vision TAVI according to the local Heart Team. The 
Heart Team determines the indication to TAVI with Navitor/Navitor Vision before the possible 
enrolment and independently from the study. 
2. Subject is of legal age for consent in the host country. 
3. Subject has been informed of the nature of the study, agrees to its provisions and has provided 
written informed consent as approved by the Ethics Committee (EC) of the respective clinical site. 
5.3.3 
  Exclusion Criteria 
5.3.3.1 
  General Exclusion Criteria 
1. Pregnant or nursing subjects 
2. Need for emergency surgery for any reason 
3. Contraindications to Navitor/Navitor Vision TAVI according to the IFU: 
a.  Any sepsis, including active endocarditis 
b.  Any evidence of left ventricular or atrial thrombus 
c. Vascular conditions (i.e., stenosis, tortuosity, or severe calcification) that make insertion 
and endovascular access to the aortic valve impossible 
d. Non-calcified aortic annulus 
e. Any leaflet configuration other than tricuspid 
f. 
Inability to tolerate antiplatelet/anticoagulant therapy 
 
4. Incapacitated individuals, defined as persons who are mentally ill, mentally handicapped, 
individuals with severe dementia or individuals without legal authority 
5. Individuals who are unable to read or write 
5.4 
Subject Enrollment Point 
A patient is considered enrolled in the Intensive Study from the moment the patient provides written 
informed consent. 
5.5 
Subject Discontinuation 
Each subject meeting all general eligibility criteria who is enrolled and receives the Navitor valveshall be 
followed up until completion of the recommended 5 year follow-up period; however, a subject’s participation 
in any clinical study 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 undergoes the interventional procedure but exits the operating room without an implanted 
Navitor Valve; in this case, follow-up is limited to 30 days post-procedure for safety assessment 
• 
After Navitor implantation, subject receives another aortic valve intervention during follow-up (eg, 
valve in valve intervention, surgical AVR, etc): in this case, follow-up is limited to 30 days after the 
additional procedure for safety assessment 
• 
Subject voluntary withdrawal 

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• 
Subject lost-to follow-up as described below 
• 
Subject’s follow-up is terminated according to Section 13.1 
Sites must collect and document 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 Study, except 
for the status (deceased/alive). 
In case of subject withdrawal of consent, the site should make attempts to schedule the subject for a final 
follow-up visit. At this final follow-up visit, the subject will undergo the following assessments (routine 
assessments during follow-up visit) and related data will be collected when available: 
• 
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 
Lost-to-Follow-up 
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 1000 subjects will be included. 
5.7 
Total Expected Duration of the Clinical Investigation 
The expected duration of enrollment is 12 months. The expected duration of each subject’s participation is 
5 years, including the scheduled visits and data collection for this Study. Subjects will be exited from the 
Study at the conclusion of their 5-year follow-up visit. 

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6 
TREATMENT AND EVALUATION OF ENDPOINTS 
Scheduled visits will be performed in the following order, which constitutes the routine clinical practice: 
Baseline, Index Procedure, Discharge, 30 days,12 months, and annual follow-up assessments to 5 years. 
6.1 
Baseline  
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  
• 
Quality of Life Assessment: KCCQ  
• 
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 standard of care. 
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, as per standard of care, 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  
Please refer to IFU for instructions on handling and preparation of the Navitor/Navitor Vision Valve, FlexNav 
Delivery System, Navitor/Navitor Vision Loading System. If the devices were not used according to the IFU, 
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. 
6.2.3 
Implant Procedure 
Navitor/Navitor Vision implants will be performed by experienced TAVI implanters that are board certified 
interventional cardiologist(s) and/or cardiac surgeon(s) and study investigators. 
Operators are encouraged to utilize the Navitor/Navitor Vision Cusp Overlap technique (COT) to facilitate 
an accurate valve deployment. As per usual practice the COT will follow the following steps: 
 
1. 
Perform pre-BAV sizing the balloon according to local practice 

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2. 
Initial positioning of the Navitor/Navitor Vision valve: 
a. 
Position the inflow edge of the constrained valve frame at the base of the NCC in the cus
p overlap view 
3. 
Valve deployment: 
a. 
Proceed with slow, steady deployment to allow the inflow edge of the valve to attain the t
arget implant depth of 3mm. 
4. 
At 80% deployment 
a. 
Confirm implant depth and proper valve position in both cusp overlap and an alternative v
iew with frame parallax removed. 
5. 
Final deployment 
a. 
Withdraw the guidewire to a mid-ventricular position and ensure neutral position of the Fl
exNav Delivery system. 
b. 
Release the valve slowly and confirm all 3 retainer tabs have been released before withdr
awing the FlexNav delivery system into the descending aorta. 
If needed but not mandatory, an Echocardiographer or Echocardiographic Technician should be available 
and may perform a post t implantation on-table TTE to assess for both transvalvular gradient and PAR and 
complications, prior to leaving the procedure room. All patients will also undergo standardized invasive 
hemodynamics to determine invasive transvalvular gradients after TAVR. 
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 (angiography, intra-procedure echocardiography to be stored 
and provided) 
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 specific guidelines for the assessment of aortic regurgitation and implant 
depth. Refer to Appendix IV 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/Navitor Vision 
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/Navitor Vision 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/Navitor Vision Valve, FlexNav Delivery System, or the 
Navitor/Navitor Vision Loading System during the procedure, these need to be notified to the Manufacturer 
and return these products for evaluation, if possible, as usually done via the regular channels for CE-marked 
products. See Section 7.3.3 for Incident/Device 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/Navitor Vision 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 5 years (± 60 days) 
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. 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. 
Each site will be responsible for performing and interpreting the follow-up echocardiograms for potential 
adverse events. Echocardiograms will be submitted to the Study Steering Committee for further analysis. 
Examinations should be recorded in DICOM format and should be de- identified prior to submitting for 
analysis. If medically indicated, a subject may undergo additional imaging per standard of care (e.g., 

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contrast CT scan or TEE) to evaluate device specific findings (e.g., valve thrombosis); if performed, this 
additional imaging will be submitted to the Study Steering Committee for analysis. For details, see 10.7. 
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. 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) 
5. Echocardiography (TTE) 
6. Quality of Life Assessment (KCCQ) 
7. Lab Measurements (INR if subject is on warfarin or other anticoagulants/vitamin K antagonists in 
lieu of warfarin) 
8. Adverse events assessment 
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. Neurological assessment and Modified Rankin Scale (mRS)  
5. 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) 
6. Echocardiogram (TTE) 
7. Quality of Life Assessment (KCCQ) 
8. Lab measurements (INR if subject is on warfarin or other anticoagulants/vitamin K antagonists in 
lieu of warfarin) 
9. Adverse events assessment 
6.4.2.3 
  Annual Follow-Up 
The following data should be collected at years 2 through 5 years (± 60 days) post index procedure: 
1. Physical Examination (including weight, resting heart rate, and blood pressure) 
2. Cardiovascular medications documentation 
3. NYHA Functional Classification 
4. Modified Rankin Scale (mRS) (optional for patients with neurological events) 
5. Echocardiography (TTE) 
6. Quality of Life Assessment (KCCQ) 
7. Adverse event assessment 

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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 should 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 may be performed in accordance to routine clinical practice for 
neurological events at an unscheduled visit 90 days from the date of the neurological event. The 
unscheduled visit will include the following assessments: 
• 
Neurological Assessment conducted by a neurologist or a neurology fellow 
• 
Modified Rankin Score (mRS) 
6.4.3.2 
  Survival Status Check 
The Study Steering Committee 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 to 
assess whether the health of subjects has improved since enrollment in the Intensive 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.  
6.4.5 
Schedule of Assessments (SoA) 
The study-required activities and standard of care data collection in the INTENSIVE Study are summarized 
in Table 5. 
 

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Table 5: Follow-up and Data Collection Requirements 
Clinical Assessments 
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 
X 
Surgical Risk Assessment 
(STS & EuroSCORE II) 
X 
  
  
  
  
  
NYHA Classification 
X 
  
  
X 
X 
X 
Frailty Index (Appendix III) 
X 
  
  
  
  
  
Cardiovascular 
Medications 
documentation 
 X 
  
X 
X 
X 
X 
CT Angiography 
 (upload) 
X 
  
  
  
  
  
Modified Rankin Scale 
(mRS)  
 X 
  
X 
 
X 
(X) 
Neurological Assessment 
 
 
 
 
(X)H 
(X)H 
12 lead Electrocardiogram 
(ECG) A,B 
X 
XB 
XA,B 
XA 
XA 
  
Cardiac Rhythm 
  
X 
  
  
  
  
2D Transthoracic 
Echocardiogram 
 (TTE-upload) 
X 
XC 
X 
X 
X 
X 
Angiogram (upload) 
  
X 
  
  
  
  
CT scan with Angiography 
of chest, abdomen and 
pelvis (upload) 
XD 
  
  
  
  
  
KCCQ  
 X 
  
  
X 
X 
X 
CBC and Platelet Count 
X 
  
  
  
  
  
Creatinine 
XE 
XF 
X 
  
  
  
INR (if subject is on 
Warfarin) 
 X 
  
  
X 
X 
  
Troponin or CK-MB 
  
XF 
X 
  
  
  

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Clinical Assessments 
Screening/Baseline 
Procedure 
Discharge 
30 
days 
[-
7/+21 
days] 
12 
months 
[+45 
days] 
Annual 
visits [±60 
days] 
Adverse Event 
Assessment G 
X 
X 
X 
X 
X 
X 
Deviation 
(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) 
A For subjects receiving a new permanent pacemaker, ECG should be completed showing the underlying 
rhythm as well as the current pacing programming. 
B Record a 12-lead ECG following the implant of the valve and daily until day of discharge 
C Copy of echocardiographic examination to be stored at the site and available to the Steering Committee 
upon request. 
D To be done within 12 months prior to consent; CT covering at least systole is required for valve sizing. 
E Includes eGFR 
F To be collected within 72 hours before index procedure 
G Transesophageal echocardiogram (TEE) is also recommended after adverse events of ischemic stroke 
and myocardial infarction 
H In case of a suspected neurological event, a neurological assessment will be conducted as per standard 
clinical practice, usually at 90 days (±14 days) from the date of the suspected neurological event 
(X) indicates if applicable 
7 
ADVERSE EVENTS AND INCIDENTS REPORTING 
7.1 
Requirements and definitions 
To comply with worldwide standards and guidelines on adverse event /incident reporting for CE marked 
devices, the Promoter has adopted uniform and worldwide applicable standard definitions and reporting 
timelines to be used and adhered to by the investigators. As such, safety reporting will follow the applicable 
requirements for the Vigilance System as outlined in Medical Device Regulation No. 2017/745, Article 87, 
Reporting of serious incidents and field safety corrective actions. 
The device manufacturer is responsible to reporting to the relevant competent authorities, in accordance 
with Articles 92(5) and (7), the following: 
(a) any serious incident, except expected side-effects which are clearly documented in the product 
information and quantified in the technical documentation and are subject to trend reporting pursuant to 
Article 88; 
(b) any field safety corrective action. 
As such, Principal Investigators must inform the manufacturer of any incidents or serios incidents, as 
defined the table below. 

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Table 6: Safety Definitions 
7.2 
Reporting  
As it is a post CE-mark Study, only endpoints related events and serious adverse events should be reported 
in the EDC (Electronic Data Capture) system, Catchtrial EDC (www.catchtrial.com). Endpoints related 
events and serious adverse events will be monitored. All events must be documented in the patient’s 
medical file and on an "Adverse event" form of the EDC. 
Adverse Event (AE) information will be collected throughout the study from the point of enrollment until the 
patient’s study participation has ended (i.e. completion of study or withdrawal of consent). 
It is the responsibility of the Investigator to report all product complaints and malfunctions immediately via 
the regular channels for CE-marked products. Safety Reports should be created and notified to Ethics 
Committee and Regulatory Authority according to local requirements. 
8 
STATISTICAL CONSIDERATIONS 
The following section describes the statistical methods for the primary analysis. 
8.1 
Statistical Analyses 
Sample Size Calculation and Assumptions 
According to the FRANCE-2 registry (N Engl J Med 2012;366:1705-1715), the rate of overall mortality at 1 
year is 24%. This national registry enrolled patients with minimal exclusion criteria and using current 
transcatheter bioprostheses according to the inherent IFU. We assume that at 1 year the results of our 
study, in terms of overall mortality (the primary endpoint) will be the same. Sample size was determined 
according to the method proposed by Nagashima et al. 2012 [Nagashima K, Noma H, Sato Y, Gosho M. 
Term 
Definition 
Incident / Device 
Malfunction 
Any malfunction or alteration in the characteristics or performance of a device made 
available on the market, including use-error due to ergonomic features, as well as any 
inadequacy in the information supplied by the manufacturer and any undesirable side-
effects (adverse events). 
Serious Incident or 
Serious Adverse 
Event 
Any incident that directly or indirectly led, might have led or might lead to any of the 
following (serious adverse event): 
(a) 
the death of a patient, user or other person, 
(b) 
the temporary or permanent serious deterioration of a patient’s, 
user’s or other person’s state of health, 
(c) 
a serious public health threat; 
Serious Public 
Health Threat 
An event which could result in imminent risk of death, serious deterioration in a 
person’s state of health, or serious illness, that may require prompt remedial action, 
and that may cause significant morbidity or mortality in humans, or that is unusual or 
unexpected for the given place and time 

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Sample size calculations for single-arm survival studies using transformations of the Kaplan–Meier 
estimator. Pharmaceutical Statistics 2021;20(3):499–511], implemented in an online calculator available at: 
https://nshi.jp/en/js/onesurvyr/. 
Setting the null hypothesis to 76% survival at 1 year, the accrual time at 1 year and the follow up time at 5 
years, there will be 80% power to detect an alternative hypothesis that the Survival at 1 year is lower, at a 
level of 72%, with a sample size equal to 943 patients. The type I error was fixed at 5% with a two-sided 
test. The arcsine transformation of the survival function was used. Considering a 5% dropout, the final 
sample size is rounded up to 1000 patients.  
 
 
8.2 
Timing of Analysis 
The analysis for the primary endpoint will be done at the completion of 1 year FU of the last patient enrolled. 
8.3 
Subgroup Analysis 
Subgroup analysis will be performed to evaluate specific conditions. 
8.4 
Planned Interim Analysis 
No interim analyses are planned for this Study. 
8.5 
Statistical Criteria for Termination 
There are no statistical criteria for termination of this clinical investigation. 
9 
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 
Study. This information may be shared with regulatory agencies. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Selection of Clinical Sites and Investigators 
A list of the participating sites will be provided. 
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 study, as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the study. The principal investigator shall support monitoring and reporting to EC and local 
Competent Authorities as necessary, throughout the conduct of the study. 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 delegate tasks to members of the 

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investigation site team but retains responsibility for the study. 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 Protocol Amendments 
The Coordinating Investigator in agreement with the Study Steering Committee will provide approved 
protocol amendments to the Investigators prior to implementing the amendment. The site’s Principal 
Investigator is responsible for notifying the EC or equivalent committee of the protocol amendment 
(administrative changes) or obtaining EC’s approval of the protocol amendment (changes in subject care 
or safety). 
Sites must document in writing acknowledgement/approval of the protocol amendment by the EC prior to 
implementation of the protocol amendment. Sites must also provide copies of this documentation to the 
Study Steering Committee. 
10.4 Site Training 
All Investigators and study personnel are required to attend training sessions, which may be conducted at 
an Investigator's meeting, site initiation visit, or other training sessions. Remote (e.g., telephone, on-line, 
etc.) or self-training may take place as necessary. Training of Investigators and study personnel will include, 
but is not limited to, the protocol requirements, electronic case report form completion, and clinical study 
personnel responsibilities. All Investigators and study personnel that are trained must sign a training log (or 
an equivalent) upon completion of the training.  
10.5 Monitoring 
The designated CRU, Clinical Research Unit, IRCCS Policlinico S. Donato, San Donato M.se, Milan, Italy, 
will monitor the clinical investigation over its duration according to the monitoring plan. 
10.6 Protocol Deviations  
The Investigator should not deviate from the protocol 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 the 
Coordinating Investigator. 
Sites must report all deviations in a timely manner using the Protocol Deviation form within the CRF. The 
occurrence of protocol deviations will be monitored in accordance with 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 protocol deviations in accordance with their specific 
EC or equivalent committee reporting policies and procedures. 
Repeated non-compliance with the signed agreement, the protocol, or any other conditions of the clinical 
investigation may result in further escalation and consultation with the Study Steering Committee, including 
securing compliance or, at its sole discretion, the Coordinating Investigator may terminate the investigator’s 
participation in the clinical investigation. 
10.7 Study Steering Committee 
The Study 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 Protocol at individual centers, to review operational issues that may arise and warrant 
a Protocol amendment or other corrective action, and to determine policy regarding the primary results 
publication arising from data generated from the performance of the Study. 

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11 DATA HANDLING AND RECORD KEEPING 
The Study Steering Committee and/or its affiliates will maintain documentation of the systems and 
procedures used in data collection for the duration of the study. 
CRF data collection will be performed through a secure web portal (www.catchtrial.com) 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 Coordinating Investigator and the Study Steering Committee. 
At the end of the study, 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 study, the Investigator will maintain complete and accurate documentation including, 
but not limited to, medical records, clinical investigation progress records, laboratory reports, CRFs, signed 
ICFs, correspondence with the EC,CRO and Coordinating Investigator/Steering Committee, adverse event 
reports, and information regarding subject discontinuation or completion of the study. 
11.1 Protection of Personally Identifiable Information 
Confidentiality of data shall be observed by all parties involved at all times throughout the study. 
Technical and physical access controls will be implemented 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. 
Only pseudonymous Personal Information (key-coded) necessary to conduct the clinical investigation, such 
as the patient’s medical condition, treatment, dates of treatment, etc., will be entered into study data 
management systems. All subject data will be identified with the unique patient identifier number. As part 
of the study informed consent process, only authorized investigators or designated personnel will have 
access to confidential records for technical support of the participating physicians on the device implant or 
procedures, monitoring and quality control purposes. The EC and other regulatory authorities also have the 
right to inspect and copy records pertinent to the study. 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 data management systems and processes designed, developed, and tested against unauthorized 
access and/or interference by third parties, intrusion, theft, destruction, loss or alteration will be used. Study 
data will be encrypted in transit and at rest. 
All subject data will always be treated with strict adherence to professional standards of confidentiality and 
according to European General Data Protection Regulation (EU GDPR) guidelines and other applicable 
local regulations. 
11.2 Case Report Form Completion 
Site research personnel trained on the Protocol 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 on the CRFs and in all 
required reports. 
Sites will collect data on all subjects who sign an informed consent form. 

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Only authorized site personnel will be permitted to enter the CRF data through the EDC system an 
electronic audit trail to track any subsequent changes of the entered data will be used. 
11.3 Record Retention 
Investigator/Site will archive and retain all documents pertaining to the study as per the applicable 
regulatory record retention requirements. The Investigator must obtain permission from Coordinating 
Investigator in writing before destroying or transferring control of any study records. 
12 ETHICAL CONSIDERATION 
12.1 Ethics Committee Review and Approval 
The Principal Investigator at each investigational site will obtain EC approval for the protocol 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 delegated CRO. 
Sites will submit any amendments to the Protocol 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 Protocol or ICF or other written information provided to the patient without 
appropriate approvals, including EC, the Study Steering Committee, and the regulatory agencies (if 
applicable). 
Until the Study is completed, the Investigator will advise his/her EC of the progress of this Study, per EC 
requirements. Written approval must be obtained from the EC to continue the study, or according to each 
institution’s EC requirements. 
13 CLINICAL INVESTIGATION CONCLUSION 
The clinical investigation will be concluded when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators or it has been provided formal documentation 
of clinical investigation closure. 
The Coordinating Investigator will submit the clinical investigation report within one year of the end of the 
investigation to the investigational sites, Competent Authorities (if applicable), and reviewing ECs. 
13.1 Suspension or Early Termination of the Clinical Investigation 
While no formal statistical rule for early termination of the Study, the Coordinating Investigator and Study 
Steering Committee reserves the right to discontinue the Study 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: 
• 
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 Coordinating Investigator 
• 
Navitor/Navitor Vision is withdrawn from market for any reason 
• 
Further data collection is cancelled 

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13.1.1 Subject Follow-up for Early Termination or Suspension of Study 
If the Study Steering Committee suspends or prematurely terminates the clinical investigation at an 
individual site in the interest of safety, the Coordinating Investigator will inform all other Principal 
Investigators. 
If suspension or premature termination occurs, the Principal Investigators will remain responsible for 
providing resources to fulfill the obligations from the Protocol and existing agreements for following the 
subjects enrolled in the Study. Details for such subjects follow up will be provided. The Principal Investigator 
or authorized site designee will promptly inform the enrolled subjects at his/her site, if appropriate. 
All applicable clinical investigation document shall be subject to the same retention policy as detailed in 
Section 11.0 of the protocol. 
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 PUBLICATION POLICY 
The Coordinating Investigator will be responsible for registering this Study on ClinicalTrials.gov website, in 
accordance with the International Committee of Medical Journal Editors guidelines, or any other applicable 
guidelines. The Coordinating Investigator shall be responsible for any such registration and results posting 
as required by the ClinicalTrials.gov website. A full report of the outcomes, will be made public through the 
ClinicalTrials.gov website no later than 12 months after the study completion. If this Study is terminated 
early, the Coordinating Investigator will make every effort to hasten the release of the outcomes through 
the ClinicalTrials.gov website. The results of the study will be published in the major cardiological 
congresses and journals. 
15 STUDY RISK BENEFIT ANALYSIS 
15.1 Anticipated Clinical Benefits 
The objective of the Study is to monitor outcomes in an all-comers population based on the routine clinical 
use of the Navitor/Navitor Vision Valve, according to the approved commercial indications.  
The benefits of the Navitor/Navitor Vision valve are proven and the product has been CE marked in 2021. 
The Navitor/Navitor Vision Valve's performance was evaluated in the Portico NG trial, detailed in Section 
1.4. Across 120 subjects in Australia, Europe, and the U.S., there were no instances of all-cause mortality 
or moderate to severe paravalvular leakage (PVL) at the 30-day mark, as confirmed by an independent 
core laboratory. Additionally, echocardiographic assessments at 30 days revealed Navitor/Navitor Vision 
subjects had a mean aortic valve area of 2.0 ± 0.5 cm2 and a mean gradient of 8.1 ± 3.7 mmHg. The 
Navitor/Navitor Vision Valve, when delivered via the FlexNav Delivery System, demonstrates a promising 
safety profile, strong hemodynamic performance, and reduced risk of PVL. 
While there are no guaranteed clinical benefits associated with participation in this study, subjects will be 
closely followed up and may receive more timely medical care and medication adjustments.  

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15.2 Potential procedure risks 
Risks associated with the specified device and procedure, together with their likely incidence, are described 
in the consent form that will be provided to you as a part of the standard of care procedure for Navitor 
implantation. These risks are part of the routine use of the transcatheter valve replacement intervention, 
and not related to this Study, which focuses on collection of clinical outcomes. 
Residual risks are likewise disclosed in the IFU in the form of clear instructions of what actions to take or 
to avoid, in order to avoid a hazardous situation of harm from occurring (contra-indications, warnings, and 
precautions). The anticipated AEs disclosed in the IFU  provide further information to enable the user, and 
potentially the patient, to make an informed decision that weighs the residual risk against the benefit of 
using the device. 
15.3 Risks Associated with Participation in Intensive Study 
Protocol-required assessments are summarized in Table 5. All these tests are part of routine care, with the 
exception of the Quality of Life Questionnaire (KCCQ) which provides no additional burden to the patients. 
Possible risks and discomforts associated with participation in the Study are the same to those associated 
with any routine transcatheter aortic valve implantation procedure and related follow-up procedures. 
Participation in the study requires patient data collection that may include protected heath information. This 
information will be kept confidential, and all data will be pseudonymized, but there is a marginal risk that 
some of the information could be unintentionally made non-confidential. The risk of this happening for this 
study is no greater than the risk of loss of confidentiality in any study.  

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16 APPENDICES  
16.1 APPENDIX I: ABBREVIATIONS AND ACRONYMS 
The following is a list of abbreviations and acronyms used in the Protocol. 
Abbreviation 
Term 
ACT 
Activated Clotting Time 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AHA 
American Heart Association 
AMI 
Acute Myocardial Infarction 
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) 
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 
Hypo Attenuated Leaflet Thickening 
HVD 
Hemodynamic Valve Deterioration 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 

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Abbreviation 
Term 
IDC 
Implantable Cardioverter Defibrillator 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
INR 
International Normalized Ratio 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
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 
SAVR 
Surgical Aortic Valve Replacement 
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) 
TIA 
Transient Ischemia Attack 
TTE 
Transthoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Effect 
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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16.2 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 Protocol 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 
 
BLEEDING AND TRANSFUSION21, 30 
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) 
 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) 

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 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 
• 
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 

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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) 
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) 

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• 
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 
• 
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) 
• 
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) 

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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. 
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) 
• 
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: 
New pathologic Q-waves in ≥2 contiguous leads 
New persistent LBBB 
Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm diameter branch 
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 

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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 criteria31 
• 
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 CRITERIA22 
  
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in 
the descending aorta 
PW Doppler 
Absent or brief 
early diastolic 
Intermediate 
Prominent, holodiastolic 

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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) 
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) 

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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 dayse 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 
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. 

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StageA 
Description 
Definition 
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) 
Time 
• 
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 

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• 
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 
• 
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: 

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• 
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 
16.3 APPENDIX III: TAVI PRE-PROCEDURAL WORKUP 
1. SURGICAL RISK ASSESSMENT 
This Study requires the use of two surgical risk assessment tools: 
1) The Society of Thoracic Surgeons’ (STS) risk calculation tools, Version 4.2 
(http://riskcalc.sts.org/stswebriskcalc/calculate) 
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. 
Katz Index of Independence in Activities of Daily Living Activities plus Independence in Ambulation Index 
will be used within this Study. 
I. 
Katz Index of Independence in Activities of Daily Living plus Independence in 
Ambulation Index 
 
Independence (1 point) 
Dependence (0 points) 
Bathing   
Bathes himself/herself completely or needs 
partial help while cleaning her back or genital 
region 
Needs help while getting in or out of the tub 
or shower, and while cleaning more than 
one part of the body 
Dressing 
Dress 
himself/herself 
completely. 
May 
sometimes need help when tying shoes 
Completely needs help while dressing 
Toileting 
Goes to toilet, gets on and off, clean genital 
area and puts on his/her clothing without help 
Needs help while going to the toilet, 
cleaning self, and dressing 
Mobilization 
Gets up from the bed and chair on his/ her 
own. May need help for carrying loads 
Needs help while getting up from bed to the 
chair 

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Incontinence 
May control himself/ herself while urinating 
and defecating 
Partially or completely incontinent of bowel 
or bladder 
Feeding 
Gets foods from plate into mouth without 
help. May need help while preparing food 
Needs complete or partial help with feeding 
or requires parenteral nutrition 
Ambulation 
No walking aid or assistance required, or 
completion of a 5-m walk in <6 s 
Walking aid or assistance required, or 
completion of a 5-m walk in >6 s 
 
3. NYHA FUNCTIONAL CLASSIFICATION 
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. 
16.4 APPENDIX IV: 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). 

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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 4 blow). 
Figure 4: Assessment of implant depth 
 
 
 
 
 
 
 
 
 
 
 
 
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