Evaluation of the Portico™ NG (Next Generation) Transcatheter Aortic Valve in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis
Phase: NA
Conditions: Symptomatic Severe Aortic Stenosis
Sponsor: Abbott Medical Devices

 
Study Name: Portico NG Approval Study 
Clinical Investigation Plan 
 
 
Portico NG Approval Study 
Evaluation of the Navitor Transcatheter Aortic Valve in High and 
Extreme Risk Patients with Symptomatic Severe Aortic Stenosis 
 
 
Version E_US 
 
May 1, 2023 
 
 
NCT # 04011722 
 
Redaction Date: April 18, 2024 
 
 
 
 
 

 
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Clinical Investigation Plan 
 
 
 
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical study. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date (DD-MM-YYYY): 
 
 
 

 
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Clinical Investigation Plan 
 
 
 
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STUDY PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical study. 
 
 
Study Principal Investigators 
 
Printed name: 
Signature: 
Date (DD-MM-YYYY): 
 
Printed name: 
Signature: 
Date (DD-MM-YYYY): 
 
 

 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ................................................................................................................................. 10 
1.1 
Background and Rationale ........................................................................................................... 10 
 
Background ........................................................................................................................... 10 
 
Rationale for Conducting this Clinical Study ........................................................................ 12 
2 
CLINICAL Study OVERVIEW .............................................................................................................. 12 
2.1 
Clinical Study Objective................................................................................................................ 12 
 
Primary objective ................................................................................................................... 12 
2.2 
Device(s) To Be Used in the Clinical Study ................................................................................. 12 
 
Name of the Device(s) Under Investigation .......................................................................... 12 
 
Intended Indication for Use ................................................................................................... 13 
 
Description of the Device(s) Under Investigation ................................................................. 14 
 
Device Handling .................................................................................................................... 18 
3 
CLINICAL Study DESIGN ................................................................................................................... 18 
3.1 
Clinical Study Procedures and Follow-up Schedule .................................................................... 19 
3.2 
Measures Taken to Avoid and Minimize Bias .............................................................................. 20 
 
Screening by an interdisciplinary Heart Team ...................................................................... 21 
 
Assessment of Anatomical Suitability by a Computed Tomography (CT) Core Laboratory 21 
 
Use of an Independent Subject Selection Committee.......................................................... 21 
 
Adjudication of Adverse Events by an Independent Clinical Events Committee ................. 21 
 
Review of Echocardiographic Images by an Independent Echocardiographic Core 
Laboratory ............................................................................................................................................ 21 
 
Maintaining High Rates of Follow-Up Compliance ............................................................... 22 
 
Standardized Administration of Patient-Reported Outcome Measures and Stroke 
Assessment Scales (mRS and NIHSS) .............................................................................................. 22 
3.3 
Suspension or Early Termination of the Clinical Study ............................................................... 22 
4 
ENDPOINTS ........................................................................................................................................ 23 
4.1 
Primary Endpoints and Rationale ................................................................................................ 23 
4.2 
Secondary Endpoint and Rationale ............................................................................................. 23 
4.3 
Descriptive Endpoints ................................................................................................................... 24 
5 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 25 
5.1 
Subject Population ....................................................................................................................... 25 
 
High Risk Classification ........................................................................................................ 25 
 
Extreme Risk Classification .................................................................................................. 25 
5.2 
Subject Screening and Informed Consent ................................................................................... 26 
 
Subject Screening ................................................................................................................. 26 

 
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Informed Consent .................................................................................................................. 27 
5.3 
Eligibility Criteria ........................................................................................................................... 28 
 
General Eligibility Criteria ...................................................................................................... 28 
 
Inclusion Criteria ................................................................................................................... 28 
 
Exclusion Criteria .................................................................................................................. 29 
5.4 
Subject Enrollment ....................................................................................................................... 31 
 
Roll-in Cohort ........................................................................................................................ 31 
 
Enrollment of Medicare Beneficiaries ................................................................................... 31 
 
Historically Under-Represented Demographic Subgroups .................................................. 31 
5.5 
Subject Withdrawal ....................................................................................................................... 33 
 
Lost-to-Follow-up .................................................................................................................. 33 
5.6 
Number of Subjects ...................................................................................................................... 33 
5.7 
Duration of the Clinical Study ....................................................................................................... 34 
6 
TREATMENT AND EVALUATION OF ENDPOINTS ......................................................................... 34 
6.1 
Baseline ........................................................................................................................................ 34 
 
Baseline Assessments .......................................................................................................... 34 
 
Pre-procedure Antiplatelet/Anticoagulant Medications ........................................................ 35 
 
Pre-procedure Blood Tests ................................................................................................... 35 
6.2 
Index Procedure ........................................................................................................................... 35 
 
Procedures Involved in the Use of the Device Under Investigation ..................................... 35 
 
Procedural Anticoagulation ................................................................................................... 35 
 
Implant Procedure ................................................................................................................. 35 
 
Post-procedure Imaging ........................................................................................................ 36 
6.3 
Post–procedure (In-hospital) ........................................................................................................ 36 
 
Post-procedure Laboratory Tests ......................................................................................... 36 
6.4 
Discharge Assessments ............................................................................................................... 36 
6.5 
Follow-up Assessments ............................................................................................................... 37 
 
Follow-up Medications .......................................................................................................... 37 
 
Follow-up for All Subjects ..................................................................................................... 37 
 
Unscheduled Follow-up ........................................................................................................ 39 
 
Patient Reported Outcome (PRO) Measures ....................................................................... 40 
 
Schedule of Events ............................................................................................................... 42 
6.6 
Requirement for Core Laboratories ............................................................................................. 44 
7 
Adverse Events .................................................................................................................................... 44 
7.1 
Definitions ..................................................................................................................................... 44 
 
Adverse Event ....................................................................................................................... 44 

 
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Serious Adverse Event ......................................................................................................... 44 
 
Device Deficiency .................................................................................................................. 45 
7.2 
Device Relationship ...................................................................................................................... 45 
 
Unanticipated Serious Adverse Device Effect ...................................................................... 45 
 
Serious Health Threat ........................................................................................................... 45 
7.3 
Adverse Event and Device Deficiency Reporting ........................................................................ 45 
 
Adverse Event Reporting ...................................................................................................... 45 
 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB .................... 46 
 
Device Deficiency Reporting ................................................................................................. 46 
 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor ..................... 47 
8 
STATISTICAL CONSIDERATIONS .................................................................................................... 47 
8.1 
Analysis Population ...................................................................................................................... 47 
8.2 
Statistical Analyses ...................................................................................................................... 47 
 
Primary Safety Endpoint Analysis (Portico NG cohort) ........................................................ 47 
 
Primary Safety Endpoint Analysis (Titan cohort) .................................................................. 48 
 
Primary Effectiveness Endpoint Analysis (Portico NG cohort)............................................. 49 
 
Primary Effectiveness Endpoint Analysis (Titan cohort) ...................................................... 50 
 
Secondary Endpoint Analysis ............................................................................................... 50 
8.3 
Sample Size Calculation and Assumptions ................................................................................. 52 
8.4 
Timing of Analysis ........................................................................................................................ 52 
8.5 
Subgroup Analysis ....................................................................................................................... 52 
8.6 
Multiplicity ..................................................................................................................................... 52 
8.7 
Pooling Strategy ........................................................................................................................... 52 
8.8 
Procedures for Accounting for Missing Data ............................................................................... 52 
8.9 
Planned Interim Analysis .............................................................................................................. 53 
8.10 
Statistical Criteria for Termination ................................................................................................ 53 
8.11 
Success Criteria ........................................................................................................................... 53 
8.12 
Deviations from Statistical Plan.................................................................................................... 53 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................................... 53 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 53 
10.1 
Selection of Clinical Sites and Investigators ................................................................................ 53 
10.2 
Site Principal Investigator Responsibilities .................................................................................. 53 
10.3 
Clinical Study Finances and Agreements .................................................................................... 54 
10.4 
CIP Amendments ......................................................................................................................... 54 
10.5 
Training ......................................................................................................................................... 54 
 
Site Training .......................................................................................................................... 54 

 
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Training Required for the Use of the Device ........................................................................ 54 
10.6 
Monitoring ..................................................................................................................................... 54 
10.7 
Deviations from CIP ..................................................................................................................... 55 
10.8 
Quality Assurance Audit ............................................................................................................... 55 
10.9 
Sponsor Auditing .......................................................................................................................... 56 
10.10 
Committees ............................................................................................................................... 56 
 
Subject Selection Committee ............................................................................................ 56 
 
Data Monitoring Committee (DMC) ................................................................................... 56 
 
Clinical Events Committee (CEC) ..................................................................................... 57 
 
Publication and Steering Committee ................................................................................. 57 
11 
DATA HANDLING AND RECORD KEEPING ................................................................................. 57 
11.1 
Protection of Personally Identifiable Information ......................................................................... 57 
11.2 
Data Management Plan................................................................................................................ 58 
11.3 
Source Documentation ................................................................................................................. 58 
11.4 
Case Report Form Completion .................................................................................................... 59 
11.5 
Record Retention.......................................................................................................................... 59 
11.6 
Investigational Devices Accountability ......................................................................................... 59 
12 
ETHICAL CONSIDERATION ........................................................................................................... 59 
12.1 
Institutional Review Board/Medical Ethics Committee Review and Approval ............................. 59 
13 
CLINICAL STUDY CONCLUSION .................................................................................................. 60 
14 
PUBLICATION POLICY ................................................................................................................... 60 
15 
RISK ANALYSIS .............................................................................................................................. 60 
15.1 
Anticipated Clinical Benefits ......................................................................................................... 60 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ...................................... 61 
 
Potential Anticipated Adverse Events ................................................................................... 61 
15.3 
Residual Risks Associated with the Device Under Investigation, as Identified in the Risk 
Analysis Report ....................................................................................................................................... 62 
15.4 
Risks Associated with Participation in this Clinical Study ............................................................ 63 
15.5 
Steps Taken to Control or Mitigate Risks .................................................................................... 63 
15.6 
Risk to Benefit Rationale .............................................................................................................. 65 
16 
APPENDICES .................................................................................................................................. 67 
APPENDIX I: ABBREVIATIONS AND ACRONYMS .................................................................................. 67 
APPENDIX II: STUDY ENDPOINT DEFINITIONS .................................................................................... 69 
APPENDIX III: ADDITIONAL DEFINITIONS .............................................................................................. 73 
APPENDIX IV: SURGICAL RISK ASSESSMENT TOOLS ........................................................................ 75 
APPENDIX V: FRAILTY ASSESSMENT.................................................................................................... 76 

 
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APPENDIX VI: NYHA CLASSIFICATION .................................................................................................. 78 
APPENDIX VII: QUALITY OF LIFE – SF-36v2 .......................................................................................... 79 
APPENDIX VIII: MINI-MENTAL STATE EXAMINATION (MMSE-2) ......................................................... 85 
APPENDIX IX: BARTHEL INDEX............................................................................................................... 89 
APPENDIX X: STRUCTURED INTERVIEW FOR THE MODIFIED RANKIN SCORE (mRS) ................. 91 
APPENDIX XI: NIH STROKE SCALE (NIHSS) .......................................................................................... 92 
APPENDIX XII: SIX MINUTE WALK TEST .............................................................................................. 100 
APPENDIX XIII: PERI-PROCEDURAL GUIDELINES ............................................................................. 103 
APPENDIX XIV: SITE CONTACT INFORMATION .................................................................................. 104 
APPENDIX XV: RATES OF FORSEEABLE ADVERSE EVENTS .......................................................... 105 
APPENDIX XVI: LABELS ......................................................................................................................... 108 
APPENDIX XVII: CASE REPORT FORMS .............................................................................................. 110 
APPENDIX XVIII: INFORMED CONSENT FORM ................................................................................... 111 
APPENDIX XIX: MONITORING PLAN ..................................................................................................... 112 
APPENDIX XX: REVISION HISTORY ..................................................................................................... 113 
APPENDIX XXI: CIP SUMMARY ............................................................................................................. 115 
 
 

 
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COMPLIANCE STATEMENT:  
 
This clinical study will be conducted in accordance with this Clinical Investigation Plan, the Declaration of 
Helsinki, applicable Good Clinical Practices and regulations (e.g., US 21 CFR Part 50, 21 CFR Part 56, 
21 CFR Part 812, and OUS ISO14155:2020) and the appropriate local legislation(s). The most stringent 
requirements, guidelines or regulations must always be followed. The conduct of the clinical study will be 
approved by the appropriate Institutional Review Board (IRB)/Ethics Committee (EC) of the respective 
investigational site and by the applicable regulatory authorities (e.g., FDA, MHRA, etc.). 
 
 

 
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1 
INTRODUCTION 
This document is a clinical investigational plan (CIP) for a prospective, multi-center, international, single-
arm investigational study intended to support regulatory approvals of the Portico™ NG Transcatheter 
Aortic Heart Valve (Portico NG, to be named Navitor™ upon commercialization) used in combination with 
the FlexNav™ Delivery System.  As of protocol revision D, this study includes a product size extension 
(Navitor Titan™ valve) analyzed as a separate cohort.  When the product is referenced as the Navitor 
Valve in this document, this language applies to both the Navitor 23-29mm valve sizes and Navitor Titan 
Valve.  The investigational devices are intended for use in patients with symptomatic severe native aortic 
stenosis, who are considered high or extreme surgical risk.  This clinical study is sponsored by Abbott. 
The primary objective of the clinical study is to evaluate the acute safety and effectiveness of the Navitor 
Transcatheter Aortic Heart Valve based on the rates of all-cause mortality at 30 days and moderate or 
greater paravalvular leak at 30 days. 
This clinical study will be conducted in accordance with this CIP.  All investigators involved in the conduct 
of the clinical study will be qualified by education, training, or experience to perform their tasks and this 
training will be documented appropriately. 
1.1 Background and Rationale 
 Background 
Aortic stenosis (AS) remains the most common valvular disease in the Western population requiring 
intervention and its prevalence increases with age, estimated at approximately 2% of adults 70-80 years 
of age and increasing up to 9% after age 80.1  Clinical risk factors for AS have been identified as smoking, 
elevated blood pressure, obesity, dyslipidemia, and altered mineral metabolism, which collectively 
contribute to calcific degeneration of the aortic valve.2  Although symptoms may remain latent for a period 
of time, the progression of AS can lead to the narrowing of aortic valve area by up to as much as 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 more prevalent in the older population and usually coupled with coronary 
artery disease (CAD) and chronic renal insufficiency, leading to clinical symptoms and the need for 
treatment.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.  The 
AHA/ACC revised their guidelines in 2017 to indicate transcatheter aortic valve replacement (TAVR) as a 
class I indication for the treatment of aortic valve stenosis in patients at prohibitive or high surgical risk, 
and a reasonable alternative for patients deemed intermediate surgical risk based on evidence from recent 
clinical trials.4  In a recent meta-analysis, clinical studies with newer generation TAVR devices have 
demonstrated low rates of early mortality (pooled estimate:  2.2%, 95% CI: 1.6%-2.8%) and disabling 
stroke (pooled estimate:  1.1%, 95% CI: 0.7%-1.5%) along with improved valve functional outcomes in 
 
1 Iung, B, Vahanian, A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol 2011; 8:162-172. 
2 Chen HY, Engert JC, Thanassoulis G. Risk factors for valvular calcification. Curr Opin Endocrinol Diabetes Obes 
2019; 26:1-7. 
3 Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular 
heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines. Circulation 2006; 114(5): e84-231. 
4 Nishimura RA, Otto CM, Bonow RA, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the 
management of patients with valvular heart disease. J Am Coll Cardiol 2017; 70(2): 252-289. 

 
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To support PMA approval of the Navitor Valve, data from a minimum of 152 subjects who undergo a Navitor 
implant attempt (excluding roll-ins) will be analyzed and at least 40 of the 152 analysis subjects will be 
implanted with a 23 mm or 25 mm Navitor valve, with at least 10 subjects receiving a 23 mm valve.   To 
ensure sufficient number of subjects for primary endpoint analysis (described in detail in section 8.3), a 
total of 169 subjects may undergo a Navitor implant attempt in the PMA cohort for the 23-29mm Navitor 
sizes (Portico NG cohort).  Furthermore, at least 50% of the subjects in the Portico NG analysis cohort 
(n=85 subjects) will be enrolled at sites in the United States.  
A separate cohort of 60 subjects (Titan cohort) will undergo an implant attempt with the Navitor Titan valve.  
Data from the Titan cohort will be analyzed separately to support submissions for regulatory approval.   At 
least 50% of the subjects in the Titan analysis cohort (n=30 subjects) will be enrolled at sites in the United 
States.  Prospective data from Titan subjects enrolled under a separate, regional OUS protocol may be 
combined with US subjects to meet the minimum required sample size for the PMA submission.  
Importantly, both protocols enroll high and extreme surgical risk subjects with severe symptomatic AS who 
undergo Navitor Titan valve implantation with the FlexNav Delivery System in a premarket setting and are 
aligned in terms of inclusion/exclusion criteria, devices being studied, training requirements and 
Instructions for Use, follow-up requirements and data collection.  Furthermore, subjects enrolled in the 
Titan cohort will undergo the same screening, baseline, procedure and follow-up assessments as the 
Portico NG cohort. 
In addition, up to a total of 20 roll-in subjects may be enrolled and undergo a Navitor implant attempt.  
While there is no pre-specified minimum number of extreme risk patients required for the study, a maximum 
of 20% of the analysis population may be classified as extreme risk (n=33 subjects for the Portico NG 
cohort and n=12 for the Titan cohort) to enroll a similar patient population as the Portico IDE and FlexNav 
studies.  No investigational site may enroll more than 20% of the total analysis population (n=33 for the 
Portico NG cohort and n=12 for the Titan cohort).   
Subjects participating in the clinical study will be followed for a total of 5 years with data collected at 
screening, baseline, procedure, prior to hospital discharge, and follow-up at 30 days, 12 months and 
annually thereafter up to 5 years.  Key assessments required at each visit are described below in Section 
6.  The expected duration of enrollment is 12 months, and the total duration of the clinical study is expected 
to be 6.5 years.  Abbott plans to submit safety and effectiveness data for Navitor when a minimum of 152 
analysis subjects (meeting the valve size requirements) have completed 30-day follow-up to support PMA 
approval in the United States; an analysis of the first 80 subjects with 30-day follow-up data will be provided 
to support the CE Mark submission. Global regulatory submissions for the Navitor Titan valve will be 
completed when 60 subjects have 30-day follow-up data.  Follow-up data through 5 years will be submitted 
as part of a final report to respective regulatory agencies. 
3.1 Clinical Study Procedures and Follow-up Schedule 
Subjects will be screened for study eligibility by the investigator as well as the site’s heart team per the 
inclusion and exclusion criteria listed in Section 5.3.  Upon submission of medical history information and 
screening exams to the sponsor and independent core laboratory, subjects will be reviewed by an 
independent Subject Selection Committee to confirm anatomical suitability and surgical risk classification 
assigned by the site’s Heart Team. 
If the Subject Selection Committee determine the subject’s anatomy precludes implantation of the Navitor 
Valve using the FlexNav Delivery System or if the Subject Selection Committee deems the assigned 
surgical risk classification outside of the study inclusion criteria, the subject will be exited from the study 
as a screen failure.  
Clinical study assessments will occur at baseline, implant procedure, discharge, 30 days, 12 months and 
annually thereafter to 5 years post-implantation (Figure 6).  It is strongly recommended the procedure be 

 
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• 
Use of an independent Subject Selection Committee 
• 
Adjudication of adverse events by an independent Clinical Events Committee 
• 
Review of echocardiographic images by an independent Echocardiographic Core Laboratory  
• 
Maintaining high rates of follow-up compliance 
• 
Standardized administration of patient-reported outcomes assessments 
These are described in further detail below.  
 Screening by an interdisciplinary Heart Team 
At each investigational site, a heart team consisting of at least of one cardiac surgeon and one 
interventional cardiologist will be responsible for screening patients for anatomical suitability and surgical 
risk classification for participation in the clinical study.  It is strongly recommended for the heart team to 
assess all available TAVR patients as potential candidates for the study. 
 Assessment of Anatomical Suitability by a Computed Tomography (CT) Core Laboratory  
An independent Computed Tomography (CT) Core Laboratory will be used for anatomical assessments of 
each patient prior to approval for implantation with the Navitor valve. Assessment results will be provided 
to the Subject Selection Committee for consideration of a subject’s eligibility to participate in the study, 
primary arterial access side and route, and valve size selection.  Use of an independent core laboratory to 
confirm anatomical criteria minimizes variability of critical measurements and provides an objective 
assessment for the SSC to review. 
 Use of an Independent Subject Selection Committee 
An independent Subject Selection Committee (SSC), consisting of cardiologists and surgeons considered 
experts in the field of aortic valve replacement with a focus on TAVR, will be responsible for ensuring all 
subjects’ clinical eligibility (i.e., risk classification and comorbidities) and anatomic suitability for implant in 
conjunction to the protocol and sizing recommendations provided in the IFU. SSC review and approval are 
required prior to implanting a subject with the Navitor Valve. 
The composition, guiding policies, and operating procedures governing the SSC in this clinical study are 
further defined in the SSC Charter.   
 Adjudication of Adverse Events by an Independent Clinical Events Committee 
An independent Clinical Events Committee (CEC), consisting of, at a minimum, an interventional 
cardiologist, cardiologist, cardiothoracic surgeon, and a neurologist will review and adjudicate pre-specified 
events reported by investigators in the clinical study as defined in the CEC Charter.  Pre-specified clinical 
events defined in the primary and descriptive endpoints will be adjudicated according to the Valve 
Academic Research Consortium 2 (VARC-2) definitions. The CEC will have final adjudication 
responsibilities for subject outcomes related to primary and descriptive outcome measures.  
 Review of Echocardiographic Images by an Independent Echocardiographic Core 
Laboratory 
An independent Echocardiographic Core Laboratory will be utilized for the analysis of the screening and 
all study visit echocardiograms according to the echocardiographic protocol.  
The screening echocardiogram will be assessed for aortic stenosis severity (including valve hemodynamic 
performance parameters; aortic valve area, mean transvalvular gradient, peak velocity).  Echocardiograms 

 
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collected post implantation will be assessed for hemodynamic performance and aortic regurgitation (total 
regurgitation and paravalvular leak (PVL) according to the Echo Core Laboratory Standard Operating 
Procedure Manual.  Each site is responsible for performing the echocardiogram according to the core 
laboratory imaging protocol, forwarding the exam to the core laboratory for analysis and providing local 
interpretation of the echocardiogram for clinical assessment.  The echocardiographic core laboratory will 
be responsible for completing the relevant case report forms and submitting these to the Sponsor. 
 Maintaining High Rates of Follow-Up Compliance  
The Sponsor will work with investigational sites to maintain a high follow-up compliance as follows: 
1. Sponsor will emphasize to the site the importance of subject follow-up during site initiation 
visits and subsequent communications. Site should communicate the importance of follow-up 
visits to each subject. 
2. Sites will be informed to promptly reschedule any missed subject visits, and to reinforce the 
necessity of a follow-up visit to the subject. 
3. Site is advised to involve Sponsor when needed.  Example:  Arrange alternate transportation 
if a scheduled visit is missed due transportation/travel issues, or due to subject illness 
4. Sites should document reasons for any subject withdrawals from the study, and request 
agreement for a follow-up call from the investigator when the last subject has completed the 
12-month visit. 
5. Sites should monitor follow-up rates closely to promptly identify and address any issues. 
Additionally, investigational sites will be educated on the importance of maintaining low rates of 
withdrawals and will be expected to make all effort to maintain low withdrawals during study conduct.  
 Standardized Administration of Patient-Reported Outcome Measures and Stroke 
Assessment Scales (mRS and NIHSS) 
A standardized script will be used when administering patient-reported outcome (PRO) measures to 
minimize bias and undue influence. All PRO measures must be completed by the subject or his/her legal 
representative (where allowed per local regulations).  In the latter case, a note to file must be completed 
to document the inability of the subject to complete the measures(s). 
The Modified Rankin Scale (mRS) and National Institute of Heath Stroke Scale (NIHSS) must be 
completed by an assessor who has a current certificate that demonstrates completion of an accredited 
training program for these stroke scales.  Standardized PRO measures and assessment scales minimize 
bias in the reporting of clinical events and perceived patient outcomes, thus allowing for a more robust 
comparison to results captured from other studies utilizing these same measures. 
3.3 Suspension or Early Termination of the Clinical Study 
The Sponsor reserves the right to discontinue the clinical 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: 
• 
Unanticipated adverse device effect (UADE) occurs and it presents an unreasonable risk to the 
participating subjects 
• 
Data monitoring committee or study principal investigator(s) makes a recommendation to stop or 
terminate the clinical study (such as higher frequency of anticipated adverse device effects) 
• 
Further product development is cancelled. 

 
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Should the clinical study be discontinued by the Sponsor, subjects will be followed per routine hospital 
practice with device-related adverse events (AEs) reported to the Sponsor as per vigilance/commercial 
reporting requirements.  Additionally, the investigator shall return all clinical study materials (including 
devices) to the Sponsor and provide a written statement to the IRB/EC (if applicable).  All applicable clinical 
study documents shall be subject to the same retention policy as detailed in Section 11.5 of the CIP.  
A Principal Investigator, IRB/EC or regulatory authority may suspend or prematurely terminate participation 
in the clinical study at the investigational site(s) for which they are responsible. The investigators will follow 
the requirements specified in the Clinical Trial Agreement.  
If the Sponsor suspends or prematurely terminates the clinical study at an individual site in the interest of 
safety, the Sponsor will inform all other Principal Investigators. 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing resources 
to fulfill the obligations from the CIP and existing agreements for following the subjects enrolled in the 
clinical investigation. Details for such subject’s follow-up will be provided. The Principal Investigator or 
authorized designee will promptly inform the enrolled subjects at his/her site, if appropriate. 
4 
ENDPOINTS 
4.1 Primary Endpoints and Rationale 
This clinical study has two (2) co-primary endpoints.  The same primary endpoints will be evaluated in both 
the Portico NG and Titan cohorts and analyzed independently for each cohort. 
The primary safety endpoint is all-cause mortality at 30 days.  The 30-day primary safety endpoint is 
established by VARC-2 as the most appropriate time period to assess the safety of the procedure.15  It is 
also consistent with the primary safety endpoint used in the Portico TAVI System CE Mark Study 
(NCT01493284) and is consistent with the timepoint of assessment of the primary safety endpoint  for 
multiple pivotal TAVR trials.8,9,21 
The primary effectiveness endpoint is moderate or greater paravalvular leak at 30 days.  The primary 
effectiveness endpoint will characterize the ability of the new fabric outer cuff that has been added to the 
exterior portion of the valve stent to optimize valve sealing and minimize paravalvular leak (PVL).  Moderate 
or greater PVL was selected as the primary effectiveness endpoint based on the clinical relevance and 
associated link to increased risk of mortality.  Hermann et al. 16 reported that moderate or greater PVL was 
associated with a statistically significant increase in the risk of mortality at 1 year as compared to none/trace 
(HR: 3.65, p<0.01) or mild PVL (HR: 3.29, p<0.01), thus supporting the relevance of moderate or greater 
PVL as the primary effectiveness endpoint. For additional details on the primary endpoints including 
analysis and success criteria, please refer to section 8.2 (Statistical Analyses). 
  
4.2 Secondary Endpoint and Rationale 
This clinical study has one secondary endpoint, a non-hierarchical composite of all-cause mortality, 
disabling stroke, life threatening bleeding, acute kidney injury (stage 3), or major vascular complications at 
 
15 Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions for transcatheter aortic 
valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol 2012; 
60(15): 1438-1454 
16 Hermann H, Thourani V, Kodali S, et al. One-year clinical outcomes with SAPIEN 3 transcatheter aortic valve 
replacement in high-risk and inoperable patients with severe aortic stenosis. Circulation 2016;134:130-140. 

 
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30 days.  The secondary endpoint is the same for the Titan cohort as the Portico NG cohort and will be 
analyzed independently for each cohort. 
The non-hierarchal composite safety endpoint is reasonably consistent with the primary safety endpoint in 
the Portico US IDE pivotal trial (NCT02000115), with minor modifications to life-threatening bleeding 
(removed ‘requiring transfusion’) and acute kidney injury (removed ‘requiring dialysis’) to better align with 
recent TAVR studies of commercially approved devices in a similar patient population.8,9   
4.3 Descriptive Endpoints 
The following key outcomes (relevant to characterizing the safety profile and outcomes based on the 
design modifications) will be assessed as descriptive endpoints for the study (for both the Portico NG 
and Titan cohorts, but analyzed independently for each cohort): 
  
• 
Technical device success defined as successful vascular access, delivery and deployment of the 
Navitor Valve; retrieval with the delivery system and correct positioning of a single valve in the 
proper anatomical location and the absence of procedural mortality 
• 
All-cause mortality at 12 months from the index procedure 
• 
Cardiovascular-related mortality at 30 days and 12 months from the index procedure 
• 
Disabling stroke at 30 days and 12 months from the index procedure 
• 
Life threatening and major bleeding at 30 days from the index procedure 
• 
Acute kidney injury at 30 days from the index procedure 
• 
Major and minor vascular complications at 30 days from the index procedure 
• 
Permanent pacemaker insertion at 30 days and 12 months from the index procedure  
• 
Changes in functional status from baseline to follow-up assessments at 30 days and 12 months 
(e.g., NYHA classification, six-minute walk test, quality of life measures) 
• 
Paravalvular leak at discharge, 30 days and 12 months from the index procedure 
• 
Changes in echocardiographic parameters from baseline to follow-up at 30 days and 12 months 
(e.g., mean effective orifice area, mean transvalvular gradient, mean peak velocity) 
• 
Symptomatic valve thrombosis at 30 days and 12 months from the index procedure 
 
Additional outcomes to be collected and assessed during the study: 
• 
Myocardial infarction at 30 days and 12 months from the index procedure 
• 
New-onset atrial fibrillation at 30 days and 12 months from the index procedure 
• 
Coronary obstruction requiring intervention at 30 days from the index procedure 
• 
Valve embolization during procedure, and at 30 days and 12 months from the index procedure 
• 
Reintervention to treat valve-related dysfunction at 30 days and 12 months from the index 
procedure 
• 
Total aortic valve regurgitation (transvalvular plus paravalvular leak) at discharge, 30 days and 
12 months from the index procedure 

 
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5 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 Subject Population 
This clinical study will enroll male and female subjects who have symptomatic, severe native AS and are 
determined to be at high or extreme surgical risk.  Subjects must sign and date the informed consent prior 
to undergoing any study-specific procedures not considered standard of care.  Any patient data transmitted 
to the independent CT and echocardiographic core laboratories, SSC or Sponsor for screening purposes 
must have prior signed and dated informed consent.   
The operative risk determination of study candidates will be based on assessment by the local heart team 
and confirmation by the SSC.  The assessment of surgical risk will include the Society of Thoracic 
Surgeons (STS) Adult Cardiac Surgery Risk Calculator score and the EuroSCORE II score, indices of 
frailty, and comorbidities not captured by the STS calculator, as described below, and based on current 
TAVR practice guidelines.17,18   
Subject case review will be conducted by the SSC to determine the patient’s anatomical eligibility to receive 
a Navitor Valve using the FlexNav Delivery System and final risk classification.  Refer to the SSC charter 
for a full description of the review process. Subjects will be assigned as high or extreme risk according to 
criteria below. 
 High Risk Classification 
High risk classification will be assigned to subjects with severe aortic stenosis symptoms for whom 
conventional aortic valve replacement surgery is associated with high risk equivalent to an STS risk score 
that is ≥7%. 
Patients with an STS risk score that is <7% will be assigned high risk if frailty indices and/or existing co-
morbidities not captured by STS are also present.  Specifically, assessments of patient’s physical 
performance including a 15-foot (5m) gait speed test, grip strength testing and Katz Index of Independence 
in Activities of Daily Living will be considered along with surgical comorbidities not addressed in the STS 
score (including porcelain aorta, pulmonary hypertension, mitral regurgitation, moderate tricuspid 
regurgitation, diabetes, chronic kidney disease, chronic and/or oxygen dependent lung disease). 
 Extreme Risk Classification 
Extreme risk classification will be assigned to subjects with severe aortic stenosis symptoms who are 
deemed unsuitable for conventional aortic valve replacement because of predicted probability of ≥50% 
mortality, or at risk for a serious irreversible complication by 30 days.  
Subjects with an STS risk score that is >7%, aged >90 years and with a frailty index ≥ 2 will automatically 
be classified as extreme risk.  No more than 20% of subjects (n=33 for the Portico NG cohort and n=12 for 
the Titan cohort) in the total analysis population or the first 80 subjects (n=16) who undergo a Navitor 
implant attempt may be classified as extreme risk. 
 
17 Otto CM, Kumbhani DJ, Alexander KP et al. 2017 ACC Expert Consensus Decision Pathway for Transcatheter 
Aortic Valve Replacement in the Management of Adults with Aortic Stenosis: A Report of the American College of 
Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2017; 69(10): 1313-1346. 
18 Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the Management of Valvular Heart 
Disease. Eur Heart J 2017; 38(36):2739-2791. 

 
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5.2 Subject Screening and Informed Consent 
 Subject Screening 
Potential patients presenting at the study sites will be fully informed about the clinical study, following the 
established Informed Consent process (described in Section 5.2.2). Once a duly dated and signed 
Informed Consent form is obtained, the clinical study-specific screening procedures may begin.  All cardiac 
medications and all medications given for cardiovascular effect may be continued at their prescribed 
dosages for the screening assessments. 
The following assessments are performed as part of the screening process: 
1. Demographics (age on consent date, gender) 
2. Medical History (including major cardiovascular, vascular, and other coexisting medical 
conditions) 
3. Physical Exam (including weight, heart rate, blood pressure)  
4. Surgical Risk Assessment tools (STS Risk Score and EuroSCORE II) 
5. New York Heart Association (NYHA) Functional Classification 
6. Frailty Index Assessment (Katz index of Activates of Daily Living, Grip Strength, 5 meter walk test) 
7. Forced Expiratory Volume (FEV1) Test, if clinically indicated 
8. Echocardiography 
to 
include 
comprehensive 
transthoracic 
or 
transesophageal 
2D 
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) 
9. Lab Measurements (including CBC and Platelet count, BUN and creatinine, BNP or ProBNP, and 
Albumin) 
10. 12 Lead Electrocardiogram (ECG) 
11. Computed Tomography Scan with Angiography for chest, abdomen and pelvis: aortic root and 
valve annulus sizing, assessment of suitability of iliofemoral or alternate access, and determination 
of appropriate coaxial angles for optimizing the valve implantation procedure. CT scan performed 
up to 12 months prior to consent will be acceptable. 
12. 3D Transesophageal Echocardiogram (TEE) if CT is contraindicated 
13. Coronary and aortic angiogram (arteriograms of the lower abdominal aorta to the femoral arteries), 
with runoff if clinically indicated. Coronary and aortic angiogram performed up to 12 months prior 
to consent will be acceptable. 
14. Adverse Event Assessment 
 
Subjects must be screened for clinical study eligibility by a member of the site’s clinical study team 
(Principal Investigator, co-Investigator and/or Research Coordinator) previously trained to the CIP, and, if 
applicable, will be entered into a site-specific screening log. 
Data available in the patient’s medical record may be utilized to fulfill screening requirements and testing 
does not need to be repeated if performed within 90 days prior to Informed Consent.  Computed 
Tomography (CT) scan with angiography and coronary and aortic angiogram (with runoff if clinically 
indicated) may be performed within 12 months prior to Informed Consent. 

 
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In case the subject does not meet all inclusion criteria or meets any of the exclusion criteria, the subject 
is considered a screen failure.  The Principal Investigator or the delegated clinical study personnel will 
record the screen failure in the hospital records and on a screening log as required.  Patients meeting 
general inclusion criteria and no exclusion criteria will be asked to sign an Informed Consent form if they 
wish to participate in the clinical study.  These patients will also be entered into the screening log. 
Upon initial screening of eligibility of patients by the heart team, subject case reviews will be conducted by 
an independent SSC to confirm a patient’s eligibility to receive a Navitor Valve via transfemoral or alternate 
access implantation (specified per the IFU).  The SSC will also provide final determination of a subject’s 
risk classification for the study.  If a site disagrees with the committee’s final decision regarding risk 
classification the subject will not be eligible for implantation with the Navitor Valve and will be exited from 
the study as a screen failure.  If the SSC does not approve the subject for study participation, the subject 
will be exited from the study as a screen failure and will not be counted toward the sample size of 169 
analysis subjects in the Portico NG cohort or 60 analysis subjects for the Titan cohort.  
Subject data will be collected following enrollment into the clinical study. 
 Informed Consent 
The Investigator or his/her authorized designee will conduct the Informed Consent process, as required by 
applicable regulations and the center’s IRB or EC. This process will include a verbal discussion with the 
subject on all aspects of the clinical study that are relevant to the subject’s decision to participate, such as 
details of clinical study procedures, anticipated benefits, and potential risks of clinical study participation. 
Subjects must be informed about their right to withdraw from the clinical study at any time and for any 
reason without sanction, penalty or loss of benefits to which the subject is otherwise entitled. Withdrawal 
from the clinical 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 subject and will respect subject’s legal rights. Financial incentives will not be given to the 
subject. Subjects may be compensated for time and travel directly related to the participation in the clinical 
study. The subject shall be provided with the Informed Consent form written in a language that is 
understandable to the subject and has been approved by the center’s IRB or EC. The subject 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 subject understands the information provided. If 
the subject agrees to participate, the Informed Consent form must be signed and dated by the subject and 
thereafter by the person obtaining the consent prior to any clinical study-specific procedures. The signed 
original will be filed in the subject’s hospital or research charts, and a copy will be provided to the subject. 
Prior to consideration of live cases at congresses, the investigator must request Sponsor approval prior to 
performing a Live Case, which may be accepted or denied at the discretion of the Sponsor.  If approved, 
the patient needs to sign a specific Live Case Informed Consent Form (ICF), approved by the IRB/EC and 
by the Sponsor, as well as by the competent authorities (e.g., FDA), as applicable.  
Failure to obtain informed consent from a subject prior to clinical study enrollment should be reported to 
Sponsor as soon as possible and to the reviewing center’s IRB/EC according to the respective reporting 
requirements. 
If, during the clinical 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 will provide this 
information to the subject. If relevant, the subject will be asked to confirm their continuing informed consent 
in writing. 

 
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 Special Circumstances for Informed Consent 
Consistent with the study exclusion criteria listed in section 5.3.3, incapacitated individuals, defined as 
persons who are mentally ill, mentally handicapped, or individuals without legal authority, are excluded 
from the study population.  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 be in compliance with Section 5.2.2.  In addition, an 
authorization for use and disclosure of the subject’s protected health information, in accordance with the 
Health Insurance Portability and Accountability Act (HIPAA), must be obtained from the subject or their 
legally acceptable representative.  
5.3 Eligibility Criteria 
 General Eligibility Criteria 
Assessment for general eligibility criteria is based on medical records of the site and interview with a 
candidate patient.  If some of the clinical and laboratory tests are not included in site standard tests, they 
must be done but after written informed consent is obtained.  Patients must meet ALL of the inclusion 
criteria to be considered for the clinical study.  If ANY of the exclusion criteria are met, the patient is 
excluded from the clinical study and cannot be enrolled. 
 Inclusion Criteria 
 General Inclusion Criteria 
1. Subjects must have a Society of Thoracic Surgeons (STS) score of ≥7% OR documented heart 
team agreement of high or extreme risk for surgical aortic valve replacement due to frailty or co-
morbidities not captured by the STS score.  
2. Subject is of legal age or older for consent in the host country. 
3. Subject has symptomatic aortic stenosis as demonstrated by NYHA Functional Classification of II, 
III, or IV. 
4. The subject has been informed of the nature of the study, agrees to its provisions and has provided 
written informed consent as approved by the Institutional Review Board (IRB) or Ethics Committee 
(EC) of the respective clinical site. 
5. The subject and the treating physician agree that the subject will return for all required post‐
procedure follow‐up visits. 
 Imaging Inclusion Criteria 
1. Subject has senile degenerative aortic valve stenosis with echo-derived criteria, defined as: aortic 
valve area (AVA) of ≤ 1.0 cm2 (or indexed EOA ≤ 0.6 cm2/m2) AND mean gradient ≥40 mmHg or 
peak jet velocity ≥ 4.0 m/s or doppler velocity index (DVI) ≤0.25. (Qualifying AVA baseline 
measurement must be within 90 days prior to informed consent). 
2. Portico NG cohort (only): aortic annulus diameter of 19‐27mm and ascending aorta diameter of 26-
42 mm for the specified valve size listed in the IFU, as measured by CT conducted within 12 months 
prior to informed consent. (If a CT is contraindicated and/or not possible to be obtained for certain 
subjects, a 3D echocardiogram and non‐contrast CT of chest and abdomen/pelvis may be 
accepted).  

 
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3. Titan cohort (only): aortic annulus diameter of 27-30 mm and ascending aorta diameter of 27-44 
mm per the IFU, as measured by CT conducted within 12 months prior to informed consent. (If a 
CT is contraindicated and/or not possible to be obtained for certain subjects, a 3D echocardiogram 
and non‐contrast CT of chest and abdomen/pelvis may be accepted).  
 Exclusion Criteria 
 General Exclusion Criteria 
1. Pregnant or breastfeeding subjects and those who plan pregnancy during the clinical study follow-
up period.  
2. Need for emergency surgery for any reason. 
3. Life expectancy < 12 months from the time of informed consent due to non-cardiac co-morbid 
conditions. 
4. In the judgment of the investigator, subject presents with a medical, social or psychological 
condition that could limit the ability or willingness to participate in the study, comply with study 
required testing and/or follow-up visits or that could impact scientific integrity of the study 
5. Incapacitated individuals, defined as persons who are mentally ill, mentally handicapped, or 
individuals without legal authority 
6. Individuals who are unable to read or write 
7. Currently participating in an investigational drug or device study that has not reached the primary 
endpoint or may confound the results of this study 
 Medical Exclusion Criteria 
8. Evidence of an acute myocardial infarction (defined as: ST Segment Elevation as evidenced on 12 
Lead ECG) within 30 days prior to index procedure. 
9. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior 
to index procedure. 
10. Blood dyscrasias as defined: leukopenia (WBC<3000 mm3), acute anemia (Hb < 9 g/dL), 
thrombocytopenia (platelet count <50,000 cells/mm³). History of bleeding diathesis or 
coagulopathy. 
11. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support. 
12. Untreated clinically significant coronary artery disease requiring revascularization 
13. Hemodynamic instability requiring inotropic support or mechanical heart assistance 
14. Hypertrophic cardiomyopathy with obstruction. 
15. Active peptic ulcer or upper GI bleeding within 3 months prior to index procedure that would 
preclude anticoagulation 
16. A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), bivalirudin or 
clopidogrel (Plavix), sensitivity to contrast media which cannot be adequately premedicated, or 
clinical condition that precludes contrast CT or TEE imaging. 
17. Recent (within 6 months prior to index procedure date) cerebrovascular accident (CVA) or a 
transient ischemic attack (TIA). 

 
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18. Renal insufficiency (creatinine > 3.0 mg/dL) and/or end stage renal disease requiring chronic 
dialysis. 
19. Sepsis or active bacterial endocarditis within 6 months prior to the index procedure. 
20. Liver failure (Child-Pugh class C) 
21. Untreated atrial fibrillation (e.g., patients with atrial fibrillation not on anticoagulants) 
22. Severe pulmonary hypertension with pulmonary systolic pressure greater than two-thirds of 
systemic pressure 
 Imaging Exclusion Criteria 
23. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic 
regurgitation 3-4+). 
24. Aortic valve is a congenital unicuspid or congenital bicuspid valve or is non-calcified as verified by 
echocardiography.  
25. Severe ventricular dysfunction with LVEF <25% as measured by resting echocardiogram. 
26. Pre-existing prosthetic heart valve or other implant in any valve position, prosthetic ring, severe 
circumferential mitral annular calcification (MAC) which is continuous with calcium in the left 
ventricular outflow tract (LVOT), severe (greater than or equal to 3+) mitral insufficiency, or severe 
mitral stenosis with pulmonary compromise.  
27. Echocardiographic or multi-slice computed tomography (MSCT) evidence of intracardiac mass, 
thrombus or vegetation. 
28. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal 
luminal diameter 5cm or greater; marked tortuosity (hyperacute bend), aortic arch atheroma 
(especially if thick [> 5 mm], protruding or ulcerated) or narrowing (especially with calcification and 
surface irregularities) of the abdominal or thoracic aorta, severe “unfolding” and tortuosity of the 
thoracic aorta (applicable for transfemoral access only) 
29. Native aortic annulus size < 19 mm or > 27 mm per the baseline diagnostic imaging. 
30. Aortic root angulation > 70°  
31. Undue risk of coronary obstruction (e.g., bulky aortic valve leaflets in close proximity to coronary 
ostia) 
32. Non-calcified aortic annulus 
33. Iliofemoral vessel characteristics that would preclude safe insertion of the FlexNav™ Delivery 
System with or without an arterial introducer sheath such as severe obstructive calcification, 
protruding thrombus or severe tortuosity (applicable for transfemoral access only) 
34. Severe tricuspid regurgitation or severe right ventricle dysfunction 
35. Minimum access vessel diameter of <5.0mm for small FlexNav™ Delivery System and <5.5 mm 
for large FlexNav™ Delivery System 
36. Ascending aorta anatomy that would preclude safe delivery of the valve to the native aortic annulus 
37. Sinus of Valsalva anatomy that would prevent adequate coronary perfusion  
38. Annulus eccentricity ratio <0.73 

 
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5.4 Subject Enrollment 
The point of a subject’s enrollment in the clinical study is completion of signing the informed consent. 
Consented subjects who undergo study-specific testing and are found to have met exclusion criteria or not 
all inclusion criteria (or if a site disagrees with the Subject Selection Committee’s decision regarding risk 
classification) will be considered screen failures; these subjects will not be counted toward the sample size 
of 169 analysis subjects and will be exited from the study without further follow-up.   
In addition, consented subjects who undergo study-specific testing and meet study criteria but do not 
undergo a Navitor implant attempt (defined as insertion of the delivery system into the vasculature) will not 
be counted toward the sample size of 169 analysis subjects and will be exited from the study without further 
follow up.   
All subjects who undergo a Navitor implant attempt will be included in the analysis population or designated 
as roll-in as described in Section 5.4.1.  Subjects who undergo a Navitor implant attempt but are not 
implanted with the Navitor Valve will be followed for 30 days and then exited from the study; similarly, any 
subject who undergoes explant of the Navitor Valve during the study follow-up period will be exited from 
the study 30 days following the explant procedure. 
 Roll-in Cohort 
The requirement for roll-in cases will be determined based on experience of the implanting physicians.  If 
neither of the implanting physicians have previous Portico with FlexNav clinical experience, a minimum of 
one roll-in subject will be required.  Data from roll-in subjects will be analyzed separately as the “roll-in 
arm” and will not be included in the analysis population.  A maximum of 20 roll-in subjects will be permitted 
in the study.  Designation of roll-in or analysis subject will be made by the Sponsor in advance of the 
procedure.  The combined Portico NG and Titan cohorts will not exceed a total of 20 roll-in subjects. 
The total number of roll-in subjects required per site will be at the discretion of the Sponsor and will be 
based on the primary implanting physician’s recent Portico implant experience.  
 Enrollment of Medicare Beneficiaries 
This clinical study will enroll subjects with Medicare benefits and therefore conforms to all standards of 
Medicare coverage requirements. The Risks and Benefits section describes how all enrolled subjects, 
including Medicare beneficiaries, may be affected by the device under investigation. 
Subjects enrolled in the clinical study are expected to be consistent with the Medicare population based 
on age and as such, the clinical study results are expected to be generalizable to the Medicare population. 
 Historically Under-Represented Demographic Subgroups 
The Sponsor intends to ensure adequate representation of women and other traditionally under-
represented demographic subgroups in this clinical study.  Some barriers to participation of women and 
ethnic minorities in clinical studies have traditionally been: 
• 
Lack of understanding about main obstacles to participation of such subgroups in clinical 
research  
• 
Inclusion/exclusion criteria potentially not needed to define the clinical study population may 
unintentionally exclude specific subgroups  
• 
Under diagnosis of disease etiologies and pathophysiology leading to lower referral rates of 
demographic subgroups  

 
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• 
Avoidance of specific subgroups by investigators and Sponsors due to the perception that it takes 
more time and resources to recruit them  
• 
Family responsibilities limiting women's ability to commit time for follow-up requirements 
 
Historically, TAVR clinical studies performed in a similar patient population have shown the treatment 
population to be approximately 50% or higher female.8,9,11 Furthermore, the traditional barriers to 
enrollment of women (such as fear of fetal consequences, family responsibilities that may limit the ability 
for time commitment to trial follow-up) are not applicable in this study due to the expected average age of 
the patient population (> 80 years).  Additionally, aortic stenosis is prevalent in traditionally 
underrepresented non-white subgroups based on data collected from over 18.9 million patients treated in 
the U.S. from 2002 to 2012 (74.8% White, 12.6% Black, 7.3% Hispanic, 1.9% Asian or Pacific Islander, 
0.6% Native American, 2.8% other ethnicity).19   
In the Portico IDE randomized cohort, which enrolled subjects at sites in the United States and Australia, 
the study population was approximately 50% female and nearly 8% of non-white ethnicity.  As the Portico 
NG study will also enroll subjects in the U.S., which has a diverse population, the proportion of females 
and the proportion of non-white subjects are expected to be comparable to that enrolled in the Portico IDE 
which had nearly identical inclusion/exclusion criteria.  Therefore, there is no expected impact of the 
inclusion/exclusion criteria on the enrollment of females and ethnic minorities for the Portico NG study; 
specifically, the anatomical parameters required and devices sizes available allow for inclusion of female 
subjects and ethnicities with smaller anatomical measurements (i.e., small annulus diameters), and 
medical exclusion criteria are translatable to a general TAVR patient population deemed high or extreme 
risk for surgical valve replacement without any gender or racial bias.  For the Titan cohort, the same 
principles apply, with the exception that due to the large annulus use range, it is anticipated there will be a 
larger proportion of male subjects as observed in clinical studies for FDA approved large valve devices 
(i.e., Evolut R 34mm).20 
 
The Sponsor will take the following steps to ensure adequate representation of women and racial or 
ethnic minorities in this clinical study:  
• 
The Sponsor will provide training to investigational site personnel to ensure adequate 
representation of these demographic subgroups  
• 
The Sponsor will regularly review enrollment data to investigate whether there is under-
representation of these demographic subgroups  
• 
The Sponsor will regularly review withdrawal rates for under-represented subgroups and compare 
these rates with that in the overall clinical study population 
• 
As appropriate and necessary, the Sponsor will retrain sites on the importance of recruiting and 
retaining subjects in the clinical study 
• 
The Sponsor will approach sites without bias or consideration for specific demographic subgroups  
 
19 Beydoun HA, Beydoun MA, Liung H, et al. Sex, Race, and Socioeconomic Disparities in Patients With Aortic 
Stenosis (from a Nationwide Inpatient Sample). Am J Cardiol 118 (6): 860-865. 
20 Tang GHL, Reardon MJ, Kodali SK, et al. Comparison of Clinical and Echocardiographic Outcomes After 
Transcatheter Aortic Valve Implantation with 31-mm CoreValve versus 34-mm Evolut R Bioprostheses from the 
STS/ACC TVT Registry. Am J Cardiol 2019;124:1091-1098. 

 
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• 
The Sponsor will have informed consent materials in alternative languages and will work with 
sites and IRBs/ECs on recruitment materials  
5.5 Subject Withdrawal 
Each enrolled subject shall remain in the clinical study until completion of the required 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 voluntary withdrawal  
• 
Subject lost-to follow-up as described below  
• 
Subject’s follow-up is terminated according to Section 3.3. 
 
The Sponsor must be notified by the site of subject’s discontinuation as well as the reason(s) for subject 
discontinuation. Investigators must also report subject discontinuations to their respective IRB/EC as 
defined by their institution’s procedure(s).  
No additional follow-up will be required or data recorded from subjects once withdrawn from the clinical 
study.  However, if a subject withdraws from the study due to problems related to the safety or performance 
of the device under investigation, the investigator shall ask for the subject's permission to follow his/her 
status/condition outside of the clinical study.   
 Lost-to-Follow-up 
If the subject misses two consecutive scheduled follow-up visits 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, a certified or registered letter should be sent 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 study cardiologist or relative will be 
considered as subject contact for the purpose of collecting vital status information. The center shall retain 
records of the contact. 
5.6 Number of Subjects  
A total of 169 analysis subjects (up to a total of 189 subjects including roll-ins) will undergo an attempted 
Navitor implant in order to analyze the primary endpoints for the Portico NG cohort.  Furthermore, a total 
of 60 analysis subjects will undergo an attempted Navitor Titan implant for the PMA submission.  To ensure 

 
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enrollment balance across study sites, no site may enroll more than 20% of the analysis population (n=33 
for the Portico NG cohort and n=12 for the Titan cohort).   
5.7 Duration of the Clinical Study 
The expected duration of each subject’s participation in the clinical study is 5 years, including the 
scheduled visits and data collection as listed in Section 6.5.5. All enrolled subjects will be followed until 
their 5-year visit, subject withdrawal, or study closure, whichever occurs first. Subjects that are exited 
from the study after providing Informed Consent but prior to enrollment in the study will not require any 
additional follow-up. 
Overall, the total duration of the clinical study is expected to be approximately 
years, based on an 
expected enrollment period of 12 months, 5 years of follow-up for each subject, and approximately 6 
months for study closure activities and results reporting. 
6 
TREATMENT AND EVALUATION OF ENDPOINTS 
6.1 Baseline 
For subjects that have successfully completed screening, scheduled visits will be performed in the following 
order: Baseline, Index Procedure, Discharge, 30 days,12 months, and annual follow-up assessments to 5 
years.   
 Baseline Assessments 
Subjects who are deemed eligible for implantation of a Navitor Valve using the FlexNav Delivery System 
will undergo a baseline visit prior to the procedure (may occur on the day of, procedure prior to the implant 
procedure). 
The following baseline assessments will be performed for all subjects prior to the index procedure. 
1. Chest X-ray (if standard of care) 
 
2. Cardiovascular medications documentation (including dosage) 
 
3. Modified Rankin Scale (mRS) 
 
4. NIH Stroke Scale (NIHSS) 
 
5. Barthel Index 
 
6. Quality of Life Measures (SF-36) 
 
7. Mini Mental State Exam (MMSE-2:SV) 
 
8. Six Minute Walk Test (6MWT)  
 
9. Lab Measurements (Troponin or CK/CK-MB, INR if subject is on Coumadin or Warfarin or other 
anticoagulants/vitamin K antagonists in lieu of warfarin) 
 
10. Adverse events assessment 
 
Excluding the chest X-ray scan which is standard of care and will be conducted per hospital guidelines, all 
baseline assessments are considered study-related assessments.  

 
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 Pre-procedure Antiplatelet/Anticoagulant Medications 
Antiplatelet/Anticoagulation and other medications should be administered pre-procedure per the standard 
of care at the investigational site. 
 Pre-procedure Blood Tests 
The following blood tests will be performed at the investigational site within 72 hours prior to the index 
procedure: 
1. Cardiac enzymes (Troponin or CK/CK-MB)  
2. BUN and Creatinine  
6.2 Index Procedure 
 Procedures Involved in the Use of the Device Under Investigation  
Please refer to IFU for instructions on handling and preparation of the Navitor Valve, FlexNav Delivery 
System, Navitor Loading System. All Investigators must read and understand the IFU and Investigator 
Brochure, as applicable. 
 Procedural Anticoagulation 
Anticoagulation use during the procedure is left to the physician’s discretion or should be established as 
with any other transcatheter valve implantation, considering risks and benefits for the patient.  The 
activated clotting time (ACT) should be monitored and recorded on source documentation during the 
procedure and medications should be adjusted to attempt to keep the subject’s ACT>250 seconds. 
 Implant Procedure 
It is recommended (required for US sites per the Medicare National Coverage Decision) that the heart 
team's interventional cardiologist(s) and cardiac surgeon(s) jointly participate in the intra-operative 
technical aspects of the TAVR procedure. 
It is strongly recommended that the index procedure occur within 14 calendar days following SSC approval. 
A Navitor Valve may be implanted in a subject who has signed the ICF and Data Protection Form (if 
applicable) and approved by the SSC.  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.  
The following data will be collected during the implant procedure: 
1. Device access, deployment and final valve placement data collection  
2. Aortic systolic/diastolic pressure, mean aortic pressure, mean aortic valve gradient, peak aortic 
valve gradient and aortic regurgitation (post-implant only) immediately pre- and post implant,  
3. If performed, right atrial pressure, pulmonary artery systolic/diastolic pressure, mean pulmonary 
artery pressure, pulmonary capillary wedge pressure (PCWP) immediately pre- and post implant 
4. Cardiac rhythm monitoring and rhythm changes throughout the duration of the procedure 

 
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5. Procedural information and imaging (angiogram, cine, intra-procedure echocardiography to be 
available to the Sponsor and provided upon request by the site) 
 
Investigational sites should follow study-specific guidelines for the assessment of aortic regurgitation and 
implant depth.  Refer to APPENDIX XIII for a description of standardized methods for measuring aortic 
regurgitation according to VARC-2 criteria and instructions for assessing implant depth in the LVOT.  
During the procedure, the implanting physician may determine implantation of the Navitor valve is either 
not feasible or not in the best interest of the patient. 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.  If the implant procedure was not attempted (i.e., the FlexNav Delivery System was never 
introduced into the subject’s vasculature), the subject will be considered a procedural exclusion. 
If the implant procedure was attempted (i.e. the FlexNav Delivery System was introduced into subject’s 
vasculature) but the Navitor Valve could not be implanted (e.g. Navitor attempted but other valve ultimately 
placed in the annulus), the subject will be withdrawn from the study after a 30-day adverse event collection 
period. 
All the required information must be recorded on the applicable CRF.  Following the procedure, the FlexNav 
Delivery System and Navitor Loading System should be securely disposed as per hospital requirements 
for hazardous materials. If there are any concerns noted with the Navitor Valve, FlexNav Delivery System, 
or the Navitor Loading System during the procedure, these products should be returned to the Sponsor for 
evaluation.  
 Post-procedure Imaging 
Subjects implanted with a Navitor Valve will be required to undergo an echocardiogram between 24 and 
48 hours after the procedure.  
6.3  Post–procedure (In-hospital) 
 Post-procedure Laboratory Tests 
The following laboratory tests should be performed in-hospital post-implant procedure:  
1. Troponin, or CK / CK-MB should be collected between approximately 12 and 24 hours after 
procedure, between approximately 36 and 48 hours after the procedure, and at approximately 72 
hours after the procedure (or at discharge, if patient is discharged prior to 72 hours post procedure).  
2. BUN and Creatinine to be collected within 72 hours after index procedure 
6.4 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 week day prior to discharge.  
 
The discharge assessment will include: 
1. Physical exam (weight, heart rate, blood pressure) 
2. Modified Rankin Scale (mRS) 
3. NIH Stroke Scale (NIHSS) 

 
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4. Barthel Index 
5. Echocardiogram (if not performed during the post procedure testing within 48 hours after 
procedure) 
6. 12 lead ECG (for subjects receiving a new permanent pacemaker, ECG should be completed 
showing the underlying rhythm as well as the current pacing programming) 
7. Cardiovascular medications documentation 
8. Adverse events assessment 
9. Lab Measurements (CBC and Platelet count, BUN and Creatinine, and Troponin or CK/CK-MB if 
patient is discharged prior to 72 hours post-procedure) 
6.5  Follow-up Assessments  
 Follow-up Medications 
Medications administered to subjects during the follow-up period will be at the physician’s discretion.  
 Follow-up for All Subjects 
Required clinical follow-up will be performed at the following intervals for all subjects who were implanted 
with a Navitor valve: 
 • 30 days (+21 days) follow-up site visit (visit must be conducted even if subject is in hospital) 
• 12 months (365 days -30/+45 days) follow up site visit 
• 
Annual follow-up at 2, 3, 4 and 5 years (±60 days) 
Subjects with a Navitor implant attempt that did not have a Navitor Valve implanted will only be required to 
complete the 30-day follow-up visit prior to exiting the study.   
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.  If, despite all efforts, the subject is unable to return to the study site during a follow-up 
window, subjects may undergo a remote follow-up assessment to collect applicable data.  Remote 
assessments should include telephone contact with the subject and/or a visit to a medical facility with all 
data that can be reasonably and legally collected remotely on the study subject.  If necessary, in-home 
assessment by an authorized health care representative (e.g. Hawthorne Effect) may be conducted. 
Follow-up visits occurring at non-study sites will be limited to standard of care data collection only.  
Authorization for the release of medical records from non-study facility is the responsibility of the 
investigational site.  Any missed testing will be considered a protocol deviation.  
An enrolled subject may only be followed at another investigational site with prior agreement from that 
site’s Investigator and from the Sponsor. 
Each site will be responsible for performing and interpreting the follow-up echocardiograms using the 
VARC-2 definitions.  Echocardiograms will be sent to an independent Echocardiographic Core Laboratory 
for further analysis.  Exams should be recorded in DICOM format and should be de-identified prior to 
sending to the Sponsor. If medically indicated, a subject may undergo additional imaging per standard of 

 
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care (e.g., contrast CT scan or TEE) to evaluate device specific findings (e.g., valve thrombosis); if 
performed, this additional imaging will be sent to the Sponsor for analysis. 
 30-day Follow-Up 
The 30-day follow-up visit will occur 30 days (+21 days) post-index procedure, and will include the following 
assessments: 
1. Physical exam (weight, heart rate, blood pressure) 
2. Modified Rankin Scale (mRS) 
3. NIH Stroke Scale (NIHSS) 
4. Barthel Index 
5. Echocardiography  
6. 12 lead ECG (for subjects receiving a new permanent pacemaker, ECG should be completed 
showing the underlying rhythm as well as the current pacing programming) 
7. Lab Measurements (including CBC and Platelet count, BUN and creatinine, BNP or ProBNP, 
INR if subject is on coumadin, warfarin or other anticoagulants/vitamin K antagonists in lieu of 
warfarin, Troponin or CK/CK-MB and Albumin) 
8. NYHA Functional Classification 
9. Frailty Index Assessment (Katz Index of Activities of Daily Living, Grip Strength, 5 meter walk 
test) 
10. Quality of Life Assessment (SF-36) 
11. MMSE-2:SV 
12. Six Minute Walk Test (6MWT)  
13. Cardiovascular medications documentation 
14. Adverse events assessment 
 12-Month Follow-Up 
The 12-month follow-up visit will take place at 12 months (365 days -30 /+45 days) post-index procedure, 
and will include the following assessments: 
1. Physical exam (weight, heart rate, blood pressure) 
2. Modified Rankin Scale (mRS) 
3. NIH Stroke Scale (NIHSS) 
4. Barthel Index 
5. Echocardiography  
6. 12 lead ECG (for subjects receiving a new permanent pacemaker, ECG should be completed 
showing the underlying rhythm as well as the current pacing programming) 
7. Lab measurements (including CBC and Platelet count, BUN and creatinine, BNP or ProBNP, 
INR if subject is on coumadin, warfarin or other anticoagulants/vitamin K antagonists in lieu of 
warfarin, Troponin or CK/CK-MB and Albumin) 

 
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8. NYHA Functional Classification 
9. Frailty Index Assessment (Katz Index of Activities of Daily Living, Grip Strength, 5 meter walk 
test) 
10. Quality of Life Assessment (SF-36) 
11. MMSE-2:SV 
12. Six Minute Walk Test (6MWT)  
13. Cardiovascular medications documentation 
14. Adverse events assessment 
 Annual Follow-up  
The following data should be collected at years 2, 3, 4 and 5 years (± 60 days) post index procedure 
(note: remote follow-up either in-home or by phone may be conducted): 
1. Physical exam (if an in-person office visit is conducted) 
2. NYHA Functional Classification (if an in-person office visit is conducted) 
3. Cardiovascular medications  
4. Adverse event assessment 
5. Modified Rankin Stroke Scale (if an in-person office visit is conducted) 
6. Echocardiography (required at 2-year, 4-year, and 5-year follow-up visits) 
 
Note: if the 12-month or annual follow-up visits are conducted prior to the nominal due date (e.g., before 
day 365 for the 12-month visit), it may be requested to conduct a vitality status check to document the 
subject’s status prior to the next follow-up visit. 
 Unscheduled Follow-up  
 Unscheduled Follow-Up Visits for Evaluation of Suspected Neurological Event 
If the subject experiences a neurological event (e.g., trans-ischemic attack (TIA), stroke, or 
encephalopathy) within 2 years post implantation, the event should be documented on an adverse event 
form and further evaluation should be performed at an unscheduled visit 90 days (±14 days) from the date 
of the neurological event.  The unscheduled visit will include the following assessments: 
• 
Neurological Assessment conducted by a neurologist or a neurology fellow 
• 
Modified Rankin Score (mRS) 
• 
NIH Stroke Scale 
Refer to Appendix X for a copy of the Modified Rankin Score and APPENDIX XI for a copy of the NIH 
Stroke Scale.  
 Unscheduled Follow-Up Visits Including an Echocardiographic Assessment 
All echocardiograms performed as part of an unscheduled visit will be analyzed by the echocardiographic 
core laboratory. See Section 3.2.5 for detailed information on site responsibility. 

 
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 Patient Reported Outcome (PRO) Measures 
The following PRO measures will be collected according to the CIP requirements to assess whether the 
health of subjects has improved since enrollment in the clinical study: 
• 
SF-36 
• 
Mini-Mental State Examination (MMSE-2) 
• 
New York Heart Association Functional Classification  
 
• 
Barthel Index 
The Principal Investigator, research coordinator or study designee will administer the patient-reported 
outcome (PRO) measures.  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. 
 SF-36 
The Medical Outcomes Study Questionnaire Short Form 36 Health Survey version 2 (SF-36 v2) is a widely 
used, validated questionnaire that provides an indicator of overall health status. The self-administered 
questionnaire consists of 10 items across eight separate domains (Vitality, Physical functioning, Bodily 
pain, General health perceptions, Physical role functioning, Emotional role functioning, Social role 
functioning, Mental health). The questionnaire takes approximately five to 10 minutes to complete; elderly 
subjects may require 15 minutes.  
Two sets of scores are derived from the SF-36; eight individual domain scores, and two summary scores, 
one for the physical component (PCS) and one for the mental component (MCS) summary scores.  For 
each set of scores, two alternative approaches may be used in calculating scores: a normal, additive 
approach that produces 0-to-100 scores for the eight scales (with a lower score indicating more disability 
and higher scores less disability), and a norm-based approach that adjusts these raw scores to have a 
mean of 50 and a standard deviation of 10.  Refer to Appendix VII for the sample questionnaire. 
 Mini-Mental State Examination-2 
The Mini Mental State Examination-2 (MMSE-2) is a validated, 11-question tool used to assess mental 
status. The MMSE-2 tests five areas of cognitive function: orientation, registration, attention and 
calculation, recall, and language. It takes 5-10 minutes to complete and must be administered using a 
script to the study subject.  
The MMSE-2 begins with a graded assessment of orientation to place and time, followed by testing two 
aspects of memory (immediate recall for three objects presented orally, followed by a serial sevens task 
which is interposed to assess attention, concentration, calculation, and to prevent the individual from 
rehearsing the three objects previously learned).  The third and final section surveys aphasia by testing 
functions of naming, repetition, understanding a three-stage command, reading, writing and copying a 
drawing. A maximum score of 30 is possible with a score of 23 or lower indicative of cognitive impairment. 
Refer to Appendix VIII for the sample questionnaire. 
 New York Heart Association Functional Classification 
The New York Heart Association (NYHA) Functional Classification is a validated tool used to classify the 
extent of heart failure in patients.  It places patients in one of four categories based on how much they are 
limited during physical activity; the limitations/symptoms are in regard to normal breathing and varying 

 
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degrees in shortness of breath and/or angina.  The NYHA function classification remains the most 
important  prognostic marker for heart failure in routine clinical use.  The current version includes two 
sections: functional capacity NYHA Classification based on patient symptoms and an objective 
assessment based on physical exam and diagnostic tools. Refer to Appendix VI for the sample 
questionnaire. 
 Barthel Index 
The Barthel Index for Activities of Daily Living (Barthel Index) is used to measure functional independence 
in activities of daily living (ADL). The validated tool takes approximately 5 minutes to complete and 
assesses 10 performance items describing ADL and mobility including: feeding, bathing, grooming, 
dressing, bowel control, bladder control, toilet use, transfers (bed to chair to back), mobility on level 
surfaces, stair use). Each performance item is rated on a scale with a given number of points assigned to 
each level or ranking with a higher number associated with a greater likelihood of being able to live at 
home with a degree of independence following discharge from the hospital.  Total possible scores range 
from 0 – 100, with lower scores indicating increased disability. If used to measure improvement after 
treatment, changes of more than two points in the total score reflect a probable genuine change, and 
change on one item from fully dependent to independent is also likely to be reliable.  Refer to Appendix IX 
for the sample questionnaire. 

 
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6.6 Requirement for Core Laboratories 
Independent core laboratories will be utilized for evaluating CT scans and echocardiograms collected in 
the clinical study. Each investigational site will submit CT scans and echocardiograms to the respective 
core laboratories for evaluation.  The core laboratories will provide the study required interpretation and 
documentation of each data submission according to their Standard Operating Procedures and study 
specific charter.  
Data obtained from the core laboratory readings will be used for study purposes only and not for clinical 
treatment of the subject.  The Sponsor will use the data provided by the core laboratories in data analyses, 
where measurements were collected by the core laboratory.  If the core laboratory determines that the 
imaging exam is unreadable, the site will be responsible for having the subject return for another 
assessment. 
7 
ADVERSE EVENTS 
To comply with worldwide standards and guidelines on clinical study adverse event reporting, the 
Sponsor has adopted uniform and worldwide applicable standard definitions and reporting timelines to be 
used and adhered to by the investigators.  
7.1 Definitions 
 Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, in the context 
of a clinical investigation, whether or not related to the investigational medical device. 
 
As part of ISO14155 Section 3.2, the adverse event definition has the following notes: 
 
Note 1: This definition includes events related to the investigational medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices or comparators. 
 Serious Adverse Event 
Serious adverse event is an AE that led to any of the following:  
a) Death, 
b) Serious deterioration in the health of the subject, that resulted in any of the following: 
1. Life-threatening illness or injury, 
2. Permanent impairment of a body structure or a body function, 
3. Hospitalization or prolongation of patient hospitalization, 
4. Medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function, 
5. Chronic disease  

 
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c) Fetal distress, fetal death or a congenital physical or mental impairment or birth defect. 
 
Note: A planned hospitalization for pre-existing condition, or a procedure required by the CIP, without a 
serious deterioration in health, is not considered a SAE. 
 Device Deficiency 
Device deficiency is defined as any inadequacy in the identity, quality, durability, reliability, usability, 
safety or performance of an investigational device, including malfunction, use errors or inadequacy in the 
information supplied by the manufacturer including labeling. 
 
Note 1: The definition includes device deficiencies related to investigational medical device or the 
comparator. 
 
Note 2: Cyber-security incidents related to the investigational product shall be reported as device 
deficiencies. 
 
A device malfunction is the failure of an investigational medical device to perform in accordance with its 
intended purpose when used in accordance with the instructions for use or CIP, or IB. 
7.2 Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or device under 
investigation caused or contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate CRF form. Determination should be based on assessment of temporal relationships, 
evidence of alternative etiology, medical/biologic plausibility, and patient condition (pre-existing 
condition). 
 Unanticipated Serious Adverse Device Effect 
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 Serious Health Threat 
Serious Health Threat is a signal from any adverse event or device deficiency that indicates an imminent 
risk of death or a serious deterioration in the health in subjects, users or other persons, and that requires 
prompt remedial action for other subjects, users or other persons 
Note: This would include events that are of significant and unexpected nature such that they become 
alarming as a potential serious health hazard or possibility of multiple deaths occurring at short intervals. 
7.3 Adverse Event and Device Deficiency Reporting 
 Adverse Event Reporting 
Safety surveillance and reporting starts as soon as the subject is enrolled in the clinical study. Safety 
surveillance and reporting will continue until the last follow-up visit has been performed, the subject is 
deceased, the subject concludes participation in the clinical study or the subject withdraws from the 

 
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clinical study. Adverse event data, including deaths and device deficiency data, will be collected 
throughout the time period defined above and will be reported to the Sponsor on a CRF. Additional 
information with regard to an adverse event should be updated within the appropriate CRF. 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be reported. 
For the purposes of this study, the following event types will be reported: 
1. All Adverse Events 
 
2. All Adverse Device Effects 
3. All Serious Adverse Events (whether or not the event is considered device or procedure related) 
4. Unanticipated Serious Adverse Device Effects 
5. All Device Deficiencies 
 
Cardiac and non-cardiac related abnormal laboratory values will not be considered AEs unless:  
1. the investigator determined that the value is clinically significant,  
2. the abnormal lab value required intervention, or  
3. the abnormal lab value required subject withdrawal from the clinical study. 
 
An offline form will be made available to allow the investigator to report SAEs in the event the entry 
cannot be made in the Electronic Data Capture (EDC). This does not replace the EDC reporting system. 
All information must still be entered in the EDC system as soon as feasible. 
 
SAE Reporting 
The investigator should report all SAEs to the Sponsor as soon as possible but no later than outlined 
below.  
 
Clinical Site 
Reporting timelines 
All Sites 
SAEs must be reported to the Sponsor no later than 3 calendar days from the 
day the site personnel became aware of the event or as per the investigative 
site’s local requirements, if the requirement is more stringent than those outlined 
above. 
 
The date the site staff became aware the event met the criteria of an SAE must be recorded in the 
source document. The Investigator will further report the SAE to the local IRB/EC according to the 
institution’s IRB/EC reporting requirements. 
 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB 
The Sponsor requires the Investigator to report any USADE to the Sponsor within 3 calendar days of the 
investigator’s knowledge of the event, unless local requirements are more stringent, and to the IRB/EC 
per IRB/EC requirements.  
 Device Deficiency Reporting 
All device deficiencies should be reported on the appropriate CRF form. 

 
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The investigator should report all device deficiencies to the Sponsor as soon as possible but no later 
than outlined below. 
Clinical Sites 
Reporting timelines 
All Sites 
Device deficiencies must be reported to the Sponsor no later than 3 calendar 
days from the day the site personnel became aware of the event or as per 
the investigative site’s local requirements, if the requirement is more 
stringent than those outlined above. 
 
The device, if not implanted or not remaining in the subject, should be returned to the Sponsor. 
Device deficiencies should be reported to the IRB/EC per the investigative site’s local requirements. 
An offline form will be made available to allow the investigator to report device deficiencies in the event 
that the entry cannot be made in the EDC system. This does not replace the EDC reporting system. All 
information must still be entered in the EDC system as soon as feasible.  
In case a device deficiency occurred before the patient ID has been assigned, the device deficiency 
should be reported to the Sponsor via the offline reporting form.  
 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
The Sponsor will report SAEs and reportable device deficiencies to the country regulatory authority per 
local requirements.  
 
Note: Reportable device deficiencies include device deficiencies that might have led to an SAE if a) 
suitable action had not been taken or b) intervention had not been made or c) if circumstances had been 
less fortunate. These are handled under the SAE reporting system. 
8 
STATISTICAL CONSIDERATIONS 
The following section describes the statistical methods for the clinical study. Additional details on 
statistical analyses, including justification of clinical study design, poolability analyses, subgroup analysis, 
and analysis of descriptive endpoints will be maintained in a separate Statistical Analysis Plan (SAP). 
8.1 Analysis Population 
The analysis population will include all subjects in whom a Navitor implant is attempted, excluding roll-in 
cases.  A Navitor implant attempt is defined as insertion of the FlexNav Delivery System (loaded with a 
Navitor Valve) into the subject’s vasculature. 
8.2 Statistical Analyses  
 Primary Safety Endpoint Analysis (Portico NG cohort) 
The primary safety endpoint for the Portico NG cohort is all-cause mortality at 30 days post index 
procedure. 
 
The proportion of Portico NG subjects experiencing a primary safety endpoint will be estimated from the 
binomial model.  The 95% confidence intervals will be calculated using the exact Clopper–Pearson 
method.  The estimated primary safety endpoint rate at 30 days will be descriptively compared with the all-
cause mortality rates (and 95% confidence intervals) of FDA approved TAVR devices studied in the same 

 
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8.9 Planned Interim Analysis 
No interim analyses are planned for this clinical study. 
8.10 Statistical Criteria for Termination 
There are no statistical criteria for termination of this clinical study. 
8.11 Success Criteria 
Study success will be determined independently for the Portico NG and Titan cohorts.  The Portico NG 
cohort will be considered successful if the rate for the primary safety endpoint (all-cause mortality within 
30 days) is within expected ranges as compared to previous commercially approved devices studied in the 
same patient population (e.g., high and extreme surgical risk) and the null hypothesis is rejected for the 
primary effectiveness endpoint (moderate or greater PVL at 30 days). 
 
The Titan cohort will be considered successful if three (3) or fewer deaths occur within 30 days of the index 
procedure in 60 analysis subjects. 
8.12 Deviations from Statistical Plan 
Any major changes to the statistical plan will be documented in an amendment to the statistical plan.  
Less significant changes to the planned analyses will be documented in the final report.   
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents for the purpose of 
performing clinical study-related monitoring, audits, IRB/EC review and regulatory inspections. 
Subjects providing informed consent are agreeing to allow clinical study monitors or regulatory 
authorities including foreign countries to review, in confidence, any records identifying the subjects in this 
clinical study. This information may be shared with regulatory agencies; however, Sponsor undertakes 
not to otherwise release the subject's personal and private information. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Selection of Clinical Sites and Investigators 
The Sponsor will select investigators qualified by training and experience to participate in the clinical 
study. Sites will be selected based upon review of a recent site assessment, if applicable, and the 
qualifications of the investigators who will participate in the clinical study. A list of the participating sites 
will be provided upon request. 
10.2 Site Principal Investigator Responsibilities 
The role of the Site Principal Investigator is to implement, oversee the management of the day-to-day 
conduct of the clinical investigation as well as ensure data integrity and the rights, safety and well-being 
of the subjects involved in the clinical investigation. The principal investigator shall support monitoring 
and reporting to IRB/EC and local competent authorities as necessary, throughout the conduct of the 
clinical investigation. 

 
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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 investigation site team but retains responsibility for the clinical 
investigation. This also applies when activities are outsourced to an external organization by the principal 
investigator in which case he/she shall exercise oversight to ensure the integrity of all tasks performed 
and any data generated by this external organization. 
10.3 Clinical Study Finances and Agreements 
The clinical study will be financed by Abbott.  Investigational sites will be compensated by Abbott for 
participation in the clinical study per the conditions of agreement between the Sponsor and the 
Investigational site. 
10.4 CIP Amendments  
Approved CIP amendments will be provided to the Investigators by the Sponsor prior to implementing the 
amendment. The Principal Investigator is responsible for notifying the IRB/EC or equivalent committee of 
the CIP amendment (administrative changes) or obtaining IRB’s/EC’s approval of the CIP amendment 
(changes in subject care or safety), according to the instructions provided by the Sponsor with the CIP 
amendment.   
The Sponsor will submit the CIP Amendment to regulatory bodies per applicable regulation and await 
regulatory approval before implementing the CIP amendment. 
 
Acknowledgement/approval by the IRB/EC of the CIP amendment must be documented in writing prior to 
implementation of the CIP amendment. Copies of this documentation must also be provided to the 
Sponsor. 
10.5 Training 
 Site Training 
Investigators and clinical study personnel are required to attend Sponsor training sessions, which may be 
conducted at an Investigator's meeting, a site initiation visit, or other appropriate training sessions.  Over-
the-phone or self-training may take place as required.  Training of Investigators and clinical study 
personnel will include, but is not limited to, the CIP requirements, investigational device usage, electronic 
case report form completion and clinical study personnel responsibilities. All Investigators and clinical 
study personnel that are trained must sign a training log (or an equivalent) upon completion of the 
training.  Prior to signing the training log, Investigators and clinical study personnel must not perform any 
CIP-related activities that are not considered standard of care at the site.  
 Training Required for the Use of the Device 
 
Training on the Navitor TAVI System will be conducted with implanting physicians prior to their first case 
in accordance with the appropriate training plan(s).  Proof of training records will be controlled documents 
managed by the Sponsor in an appropriate archiving system. If updates are made to the training plan, 
physicians will be required to complete the revised training plan prior to their next case.  
10.6 Monitoring  
Sponsor and/or designee will monitor the clinical study over its duration according to the CIP-specific 
monitoring plan which will include the planned extent of source data verification.  

 
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Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following criteria 
are met:  
• 
The investigator understands and accepts the obligation to conduct the clinical study according to 
the CIP and applicable regulations, and has signed the Investigator Agreement or Clinical Trial 
Agreement  
• 
The Investigator and his/her staff should have sufficient time and facilities to conduct the clinical 
study and should have access to an adequate number of appropriate subjects to conduct the 
clinical study.  
• 
Source documentation (including original medical records) must be available to substantiate proper 
informed consent procedures, adherence to CIP procedures, adequate reporting and follow-up of 
adverse events, accuracy of data collected on case report forms, and device information.  
• 
The Investigator/site will permit access to such records. A monitoring visit sign-in log will be 
maintained at the site. The Investigator will agree to dedicate an adequate amount of time to the 
monitoring process. The Investigator and/or research coordinator will be available for monitoring 
visits. It is expected that the Investigator will provide the monitor with a suitable working 
environment for review of clinical study-related documents. 
10.7 Deviations from CIP 
The Investigator should not deviate from the CIP for any reason except in cases of medical emergencies 
when the deviation is necessary to protect the rights, safety and well-being of the subject or eliminate an 
apparent immediate hazard to the subject. In that event, the Investigator will notify Sponsor immediately 
by phone or in writing.  
No waivers for CIP deviations will be granted by the Sponsor.  All deviations must be reported to the 
Sponsor using the Deviation CRF. The occurrence of CIP deviations will be monitored by the Sponsor for 
evaluation of investigator compliance to the CIP and regulatory requirements and dealt with according to 
written procedures. Investigators will determine the cause of deviations, implement corrective actions and 
inform their IRB or EC of all CIP deviations in accordance with their specific IRB or EC reporting policies 
and procedures.  
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or company 
representative will attempt to secure compliance by one or more of the following (and not limited to):  
• Visiting the investigator and/or delegate 
• Telephoning the investigator and/or delegate 
• Corresponding with the investigator and/or delegate 
Repeated non-compliance with the signed agreement, the CIP or any other conditions of the clinical study 
may result in further escalation in accordance with the Sponsor’s written procedures, including securing 
compliance or, at its sole discretion, Sponsor may terminate the investigator's participation in the clinical 
study.   
10.8 Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical study records, including source 
documentation, for inspection during a Quality Assurance audit.  
In the event that an investigator is contacted by a Regulatory Agency in relation to this clinical study, the 
Investigator will notify Sponsor immediately. The Investigator and Research Coordinator must be available 

 
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to respond to reasonable requests and audit queries made during the audit process. The Investigator must 
provide Sponsor with copies of all correspondence that may affect the review of the current clinical study 
(e.g., Form FDA 483, Inspectional Observations, Warning Letters, Inspection Reports, etc.). Sponsor may 
provide any needed assistance in responding to regulatory audits. 
10.9 Sponsor Auditing 
Sponsor audits may be conducted for the clinical study in accordance with the below requirements: 
1. The Sponsor shall prepare an audit plan as well as the operating procedures for the related duties 
and conduct audits in accordance with the audit plan and the operating procedures. 
2. Individual engaged in auditing (hereinafter referred to as "auditor") shall be different than those in 
charge of medical device development or monitoring. 
3. The auditor shall prepare an audit report documenting the matters confirmed in the audit to certify 
and verify that the audit has been conducted and submit them to the Sponsor. 
10.10 
Committees 
The clinical study will utilize the following separate committees: 
• 
Subject Selection Committee (SSC) 
• 
Data Monitoring Committee (DMC) 
• 
Clinical Events Committee (CEC) 
• 
Steering and Publication Committee 
 
Subject Selection Committee 
 
The Subject Selection Committee (SSC) will consist of cardiac surgeons and cardiac interventionalists who 
will be responsible for ensuring subject eligibility in the clinical study according to the CIP. After Informed 
Consent is obtained and study eligibility is confirmed by the local heart team, subject data will be reviewed 
by the SSC to confirm anatomic suitability for the Navitor implant procedure based on echocardiographic 
and pre-implant CT measurements and appropriate risk classification of the patient as defined in the SSC 
Charter.  
The Committee’s decision on whether to include the subject in the study must be documented and 
communicated to the enrolling investigational site by the Sponsor. If the SSC considers the subject 
ineligible for participation in the study, the subject will be exited from the study and the reason for exclusion 
will be documented in the reviewers’ feedback form.  If a site disagrees with the Committee’s final decision 
regarding risk classification the subject will not be eligible for a Navitor implant attempt in the study. 
 
Data Monitoring Committee (DMC) 
The Data Monitoring Committee (DMC) is an independent multidisciplinary group restricted to individuals 
free of apparent significant conflicts of interest. The source of these conflicts may be financial, scientific, 
or regulatory in nature. The DMC will be composed of at least two physicians with experience relevant to 
the clinical study (e.g., cardiologist, cardiac surgeon, neurologist) and a biostatistician.   
The DMC will serve in an advisory role to the Sponsor to ensure safety by reviewing cumulative data from 
the clinical study at prescribed intervals for the purpose of safeguarding the interests of enrolled subjects 
and those patients yet to be enrolled, as well as the continuing validity and scientific merit of the clinical 

 
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study. The composition, frequency of the meetings and the statistical monitoring guidelines are described 
in detail in the DMC charter. 
The DMC may consider a recommendation for modifications or termination of the clinical study based on 
any perceived safety concerns regardless of statistical significance. The recommendations of the DMC are 
not binding, and all final decisions related to clinical study modifications rest with the Sponsor.  
 
Clinical Events Committee (CEC) 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of qualified 
physicians (e.g., an interventional cardiologist, cardiothoracic surgeon, and a neurologist) who are not 
participants in the clinical study. The CEC will review and have final adjudication responsibilities for pre-
specified adverse events reported by investigators or identified by Safety personnel for the clinical study 
as defined in the CEC Standards of Operation Charter and according to definitions provided in this CIP.   
 
Publication and Steering Committee 
 
A Steering and Publication Committee may be established to oversee the clinical study and its publications, 
including publication planning and authorship determinations as applicable. Committee membership may 
include members of the Principal Investigators, a representative of the Sponsor and a statistician. The 
Committee will determine policy and strategies regarding individual presentations and/or publications 
arising from clinical study generated data. The committee will also review all external requests for 
accessing clinical study-related data and strategies aligning with the Sponsor’s presentation and 
publication team expectations. The Committee will also follow the Sponsor’s applicable policies and 
Standard Operating Procedures. 
11 DATA HANDLING AND RECORD KEEPING 
 
Sponsor and/or its affiliates will maintain documentation of the systems and procedures used in data 
collection for the duration of the clinical study.  
CRF data collection will be performed through a secure web portal and only authorized personnel will 
access the Electronic Data Capture (EDC) system using a unique username and password to enter, 
review or correct data. Passwords and electronic signatures will be strictly confidential.   
The data will be subjected to consistency and validation checks within the EDC system and 
supplemental review by the Sponsor. 
At the conclusion of the clinical 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.  
For the duration of the clinical study, the Investigator will maintain complete and accurate documentation 
including, but not limited to, medical records, clinical study progress records, laboratory reports, CRFs, 
signed ICFs, device accountability records (if applicable), correspondence with the IRB/EC and clinical 
study monitor/Sponsor, adverse event reports, and information regarding subject discontinuation or 
completion of the clinical study. 
11.1 Protection of Personally Identifiable Information 
The Sponsor respects and protects personally identifiable information collected or maintained for this 
clinical study.  

 
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The Sponsor implements technical and physical access controls to ensure that Personal Information is 
accessible only to and processed only on a ‘need to know’ basis, including periodic review of access rights, 
and revocation of access when an individual’s employment is terminated or the individual transitions to a 
role that does not require access to Personal Information, and appropriate restrictions on physical access 
to premises, facilities, equipment, and records containing Personal Information. 
The Sponsor requires the investigational sites to transfer into Sponsor’s data management systems only 
pseudonymous Personal Information (key-coded) necessary to conduct the clinical study, such as the 
patient’s medical condition, treatment, dates of treatment, etc.  The Sponsor discloses as part of the clinical 
study informed consent process that some Sponsor representatives still may see Personal Information at 
the participating sites for technical support of the participating physicians on the device implant or 
procedures, monitoring and quality control purposes.  Confidentiality of Personal Information will be 
observed by all parties involved at all times throughout the clinical study. The privacy of each subject and 
confidentiality of his/her information will be preserved in reports and when publishing any data. 
The Sponsor data management systems and processes were designed, developed, and tested according 
to industry standards to appropriately safeguard Confidential Information (including any Personal 
Information) against unauthorized access and/or interference by third parties, intrusion, theft, destruction, 
loss or alteration.  Clinical study data are encrypted in transit and at rest.  
The Sponsor maintains a Privacy Incident procedure that complies in all respects with Applicable Law and 
industry best practices. 
11.2 Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, data cleaning, issuing and 
resolving data discrepancies, and database locking. If appropriate, the DMP may be updated throughout 
the duration of the clinical study. All revisions will be tracked and document controlled. 
11.3 Source Documentation  
Regulations and GCP require the Investigator to maintain information in the subject’s original medical 
records that corroborates data collected on the CRFs. In order to comply with these regulatory 
requirements/GCP, the following information should be included in the subject record at a minimum and 
if applicable to the clinical study: 
• 
Medical history/physical condition of the subject before involvement in the clinical study sufficient 
to verify CIP entry criteria 
• 
Dated and signed notes on the day of entry into the clinical study referencing the Sponsor, CIP 
number, subject ID number and a statement that informed consent was obtained 
• 
Dated and signed notes from each subject visit (for specific results of procedures and exams) 
• 
Adverse events reported and their resolution, including supporting documents, such as discharge 
summaries, catheterization laboratory reports, ECGs, and lab results including documentation of 
site awareness of SAEs and of investigator assessment of device relationship for SAEs. 
• 
CIP-required laboratory reports and 12-lead ECGs, reviewed and annotated for clinical 
significance of out of range results (if applicable).  
• 
Notes regarding CIP-required and prescription medications taken during the clinical study 
(including start and stop dates) 
• 
Subject’s condition upon completion of or withdrawal from the clinical study 

 
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• 
Any other data required to substantiate data entered into the CRF 
• 
Patient reported outcome measures may be completed using CRF worksheets. These serve as 
the source documentation. 
11.4 Case Report Form Completion  
Primary data collection based on source-documented hospital and/or clinic chart reviews will be performed 
clearly and accurately by site personnel trained on the CIP and CRF completion.  The investigator will 
ensure accuracy, completeness, legibility and timeliness of the data reported to the Sponsor on the CRFs 
and in all required reports. 
Data on CRFs will be collected for all subjects who sign an informed consent form, including subjects who 
may not meet all inclusion/exclusion criteria during screening at the index procedure. 
Only authorized site personnel will be permitted to enter the CRF data through the EDC system deployed 
by the Sponsor.  An electronic audit trail will be used to track any subsequent changes of the entered data. 
11.5 Record Retention 
The Sponsor and Investigator/Site will archive and retain all documents pertaining to the clinical study as 
per the applicable regulatory record retention requirements. The Investigator must obtain permission 
from Sponsor in writing before destroying or transferring control of any clinical study records. 
11.6 Investigational Devices Accountability 
The Sponsor ships investigational products only to the Principal Investigator (the responsible leader of 
the investigational site) or his/her legal designee of each site, after sites receive documentation of site 
activation and shipping authorization is complete.   
The Investigator or an authorized designee must maintain adequate records of the receipt and 
disposition of each investigational device, including part number, batch number, and serial number (if 
applicable), date used, subject identification, and treating physician. 
Storage locations for the devices at investigational sites must be locked with access restricted only to 
investigators and authorized personnel.  
Inventory Accountability Log supplied by the Sponsor will be used. The Inventory Accountability Log 
must document the disposition of all investigational devices including those that have been returned to 
Sponsor. 
All investigational devices that are associated with a device failure or device deficiency must be returned 
immediately to the Sponsor.  
12 ETHICAL CONSIDERATION  
12.1 Institutional Review Board/Medical Ethics Committee Review and Approval 
Institutional Review Board (IRB) or Ethics Committee (EC) approval for the CIP and ICF/other written 
information provided to the patient will be obtained by the Principal Investigator at each investigational site 
prior to consenting and enrolling patients in this clinical study. The approval letter must be received prior 
to the start of this clinical study and a copy must be provided to the Sponsor.  
Any amendments to the CIP as well as associated ICF changes will be submitted to the IRB/EC and written 
approval obtained prior to implementation, according to each institution’s IRB/EC requirements.  

 
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No changes will be made to the CIP or ICF or other written information provided to the patient without 
appropriate approvals, including IRB/EC, the Sponsor, and the regulatory agencies (if applicable).  
Until the clinical study is completed, the Investigator will advise his/her IRB/EC of the progress of this 
clinical study, per IRB/EC requirements. Written approval must be obtained from the IRB/EC yearly to 
continue the clinical study, or according to each institution’s IRB/EC requirements.  
No investigative procedures other than those defined in this CIP will be undertaken on the enrolled subjects 
without the written agreement of the IRB/EC and the Sponsor. 
13 CLINICAL STUDY CONCLUSION 
Upon completion of the study, a final report will be generated and submitted to all sites, competent 
authorities, reviewing IRBs and all ECs within one year of the end of the study.  For sites in the United 
States, the final report will be submitted to the FDA and reviewing IRBs within 6 months of study 
completion per 21 CFR 812.150. 
 
The clinical study will be concluded following completion when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators or the Sponsor has provided formal 
documentation of clinical study closure.  
14 PUBLICATION POLICY 
The data and results from the clinical study are the sole property of the Sponsor.  The Sponsor shall have 
the right to access and use all data and results generated during the clinical study.  The Investigators will 
not use this clinical study-related data without the written consent of the Sponsor for any purpose other 
than for clinical study completion or for generation of publication materials, as referenced in the Clinical 
Trial Agreement.  Single-center results are not allowed to be published or presented before the multi-center 
results.  Any proposals for publications or presentations by the investigators must be reviewed and 
approved by the Sponsor in a timely manner to enable Sponsor review in compliance with the Sponsor’s 
publication policy set forth in the Clinical Trial Agreement. 
 
Upon receiving IDE approval from the FDA, this clinical study will be registered on ClinicalTrials.gov. 
Sponsor shall be responsible for any such registration and results posting as required by the 
ClinicalTrials.gov website. Institution and/or Principal Investigator(s) shall not take any action to register 
the clinical study. A full report of the pre-specified outcomes, regardless of the results, will be made public 
through the ClinicalTrials.gov website no later than 12 months after clinical study completion. If this clinical 
study is terminated early, the Sponsor will make every effort to hasten the release of the pre-specified 
outcomes through the ClinicalTrials.gov website. 
15 RISK ANALYSIS 
 
15.1 Anticipated Clinical Benefits 
While there are no guaranteed clinical benefits associated with participation in this clinical study, it is 
expected that patients implanted with a Navitor valve with the FlexNav delivery system will experience 
similar improvements in symptoms related to severe aortic stenosis as patients implanted with other 

 
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commercially available transcatheter valves.  This includes improvements in chest pain, fatigue, shortness 
of breath, dizziness and fainting. 
Although the Navitor Valve and FlexNav Delivery System is not anticipated to add new clinical benefits, 
the design modifications to the Navitor valve may result in reduced risk for paravalvular leak, minimize 
vessel trauma, and improved valve expansion, stability and sealing as compared to the first-generation 
Portico valve.  
Similarly, the design features of the FlexNav Delivery System are intended to improve deliverability and 
deployment accuracy and enhance overall ease of use. Additionally, the Navitor Loading system is 
designed to accommodate the newly scaled stent aortic heights of the Navitor Valve and a new stent guard 
component is added to accommodate the atraumatic aortic cells. 
15.2 Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Risks associated with the specified device and procedure, together with their likely incidence, are 
described in Appendix XV.  There may be risks related to the devices under investigation that are 
unknown at present. Likewise, the exact frequency of the risk may be unknown. 
 Potential Anticipated Adverse Events 
The Navitor TAVI System is not intended or anticipated to introduce any new risks beyond that observed 
for the current (first-generation) Portico system. For that reason, the potential anticipated adverse events 
associated with use of the Navitor TAVI System are similar to those associated with any routine TAVR 
procedure and related follow-up. 
 
As outlined in the IFU, potential anticipated adverse events associated with the use of transcatheter 
bioprosthetic heart valves include but are not limited to, the following: 
• 
access site complications (e.g., pain, bleeding, infection, hematoma, pseudoaneurysm, etc.)  
• 
acute coronary obstruction  
• 
acute myocardial infarction  
• 
allergic reaction to antiplatelet agents, contrast medium, or valve components  
• 
aortic rupture  
• 
ascending aorta trauma  
• 
atrio-ventricular node block  
• 
cardiac arrhythmias  
• 
conduction system injury  
• 
dissection  
• 
embolism  
• 
endocarditis  
• 
heart failure  
• 
hemodynamic compromise  
• 
hemolysis  
• 
hemolytic anemia  
• 
hemorrhage (bleeding) 
• 
hypotension or hypertension  
• 
infection  
• 
myocardial ischemia  
• 
mitral valve insufficiency  

 
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• 
multi-organ failure  
• 
non-structural dysfunction (i.e., entrapment by pannus, paravalvular leak, inappropriate sizing or 
positioning)  
• 
pericardial effusion  
• 
perforation of the myocardium, ventricle, or a blood vessel  
• 
pannus  
• 
regurgitation  
• 
renal insufficiency or renal failure (acute kidney injury) 
• 
respiratory failure  
• 
sepsis  
• 
stroke  
• 
structural deterioration (i.e., calcification, leaflet tear)  
• 
thrombosis  
• 
tamponade  
• 
valve embolization or migration  
• 
vessel dissection or spasm.  
 
It is possible these complications could lead to:  
• 
transfusion  
• 
conversion to open surgical procedure  
• 
reoperation  
• 
emergent balloon valvuloplasty  
• 
emergent percutaneous coronary intervention (PCI)  
• 
emergent surgery (i.e., coronary artery bypass, heart valve replacement)  
• 
explantation  
• 
permanent disability  
• 
death  
• 
permanent pacemaker  
 
Subjects experiencing an adverse event shall be treated per the standard of care at the investigational 
site. 
15.3 Residual Risks Associated with the Device Under Investigation, as Identified in the 
Risk Analysis Report 
Risk analysis for the Navitor Transcatheter Aortic Heart Valve, FlexNav Delivery System, and Navitor 
Loading System will be performed in accordance with the Risk Analysis Plan (internal ref: 90163677).  The 
risk analysis utilizes Hazard Analysis (internal ref: 90163681) and Failure Mode Effect Analysis (FMEA) 
tools to systematically identify potential hazards associated with the design (internal refs: 90336360, 
90163680) and use (internal ref: 90078354) of the devices.  All potential harms and hazards associated 
with Navitor Valve and the FlexNav Delivery System were identified and documented in risk management 
report.  All risks will be reduced as far as possible. Information of residual risks and safety will be provided 
in the Instruction for Use. 

 
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15.4 Risks Associated with Participation in this Clinical Study 
Protocol-required assessments are summarized in Table 5.  Possible risks and discomforts associated 
with participation in the study will be similar to those associated with any routine transcatheter aortic valve 
implantation procedure and related follow-up procedures. 
Study-specific assessments that are not considered standard of care include the six-minute walk test, 
blood collection for laboratory tests, and echocardiogram exam during scheduled follow-up visits 
(excluding at discharge).  Risk associated with blood collection is similar to any routine blood collection 
and is minimal (e.g., temporary pain and small risk of infection, bleeding, or bruising/swelling at the 
puncture site), which are mitigate by appropriate cleansing and adherence to standard blood collection 
procedures.  There are no know clinical risks associated with echocardiogram; however a subject may 
experience mild discomfort from the pressure of the transducer during the exam.  A subject may experience 
fatigue, shortness of breath, chest pain and/or leg cramps during six minute walk test; this is mitigated by 
performing this test under the supervision of a trained professional and in a testing area where medical 
care is immediately available.   
15.5 Steps Taken to Control or Mitigate Risks 
In-depth recommendations, special precautions and instructions regarding patient anatomical evaluation, 
vessel sizing, pre-implantation, implantation and post-implantation precautions are included in the IFU.  
Furthermore, the IFU also states that the devices can only be used by physicians who have received 
appropriate training on how to use the device.  This statement is interpreted to mean that the physician 
users are expected to be aware of the known and foreseeable safety risks associated with the use of the 
devices including the surgical and/or non-surgical treatment of these conditions. 
 
Risks associated with the use of the device under investigation are minimized through device design, 
investigator selection and training, pre-specified patient eligibility requirements, study monitoring by the 
sponsor to ensure adherence to the protocol as well as to assess ongoing patient safety.  
 
Device Design: Specific features of the device design that to minimize potential risk to subjects are 
described below. 
 
Navitor Valve:  
The Navitor transcatheter heart valve is a pericardial tri-leaflet valve in a self-expanding stent designed for 
intra-annular placement using minimally invasive techniques.   
 
The Navitor Valve maintains several design features of the first-generation Portico Valve including: same 
valve sizes and use range, open stent cell design to provide easy coronary access and blood flow, 
repositionable with full ability to re-sheath and retrieve, leaflets derived from pericardial bovine tissue, and 
low placement of leaflets/cuff within the stent frame for early valve function to maintain hemodynamic 
stability during implant.   
 
The Navitor Valve incorporates the following key design enhancements to improve upon the first-
generation Portico™ valve: 
• 
Addition of a fabric outer cuff to the exterior portion of the stent to optimize valve sealing and 
improve paravalvular leak performance.  

 
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• 
Replacement of the inner porcine tissue cuff with the same fabric used for the new exterior cuff to 
maintain delivery system profile. 
• 
Addition of a slight inward curvature to the aortic end of the stent to minimize vessel trauma and 
aid retainer release from the FlexNav™ Delivery System 
• 
Adjusted scaling of the stent across all valve sizes to normalize the aortic/annular to stent height 
ratio. 
• 
Minor stent modifications to the 23 mm and 25mm Navitor Valves to deliver uniform minimum 
stent/valve chronic outward radial (COR) force across the Portico family to improve valve 
expansion, stability and sealing. 
Similarly, the Navitor Titan Valve maintains those same design features of the first-generation Portico valve 
and includes the outer fabric cuff and slight inward curvature of the aortic end of the stent.  The Navitor 
Titan valve is designed to provide comparable COR forces as the other Navitor sizes in patients with larger 
annulus diameters (27-30mm). 
 
FlexNav Delivery System:  
The Navitor valve is loaded onto the FlexNav™ Delivery System which has an equivalent integrated 
sheath diameter of 14 French for 23 and 25 mm valves and 15 French for 27 and 29 mm valves. The 
FlexNav Delivery System offers several key features to mitigate risks to patients:  
• 
The delivery system features an integrated sheath with hydrophilic coating on the exterior, which 
serves as an introducer sheath to decrease the insertion profile into the vasculature.  
• 
Added stability layer on outer membrane shaft acts as a stabilizing layer during deployment by 
isolating motion between the introducer/vasculature and delivery system to minimize the number 
of manipulations required during valve deployment 
• 
Stainless steel multifilar shaft increases delivery system tensile strength and flexibility to aid in 
valve alignment and improve re-sheath closure 
• 
Proximal end of nose cone tip has been modified to be more tapered to minimize potential 
dislodging of the valve during removal of the delivery system.  
• 
Nose cone profile has been lengthened to facilitate sheathless introduction.  
• 
Handle features an automatically engaged partial deployment release button to retract the outer 
sheath, releasing the valve.   
• 
The delivery system deploys the valve annulus first to allow gradual deployment of the annular 
cells. A partially deployed valve’s position can be evaluated, and the valve can be re-sheathed 
and re-deployed (if needed) provided the valve has not been released past the aortic cells. 
Complete re-sheathing of the partially deployed valve at the implant site is possible by reversing 
the deployment mechanism. 
 
Navitor Loading System:  
The Navitor Loading System facilitates valve preparation/loading onto the FlexNav Delivery System; the 
small Navitor loading system is used for loading the 23 or 25mm valves on the small delivery system (14 
F equivalent integrated sheath), and the large Navitor loading system is used for loading the 27 or 29mm 

 
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valves on the large delivery system (15 F equivalent integrated sheath).  The Navitor Loading System – 
LG+ is used for loading the Navitor Titan valve on the large delivery system. 
 
• 
The loading base has been modified to include an integrated guide tune to eliminate the potential 
for the tip of the delivery system to interact with valve leaflets during loading of the vale onto the 
delivery system.  
• 
The loading base insert has been modified to fit the new integrated guide tube 
 
Investigator Selection and Training: The following risk control measures will be implemented at the 
investigational site level to minimize potential clinical risks to subjects participating in this clinical study:  
• 
Investigators will be carefully selected based on their knowledge of, and experience implanting and 
managing, TAVR devices, including Portico TAVI system.  
• 
Interventional cardiologists and cardiovascular surgeons performing procedures must be board 
certified and experienced with TAVR implantation procedures. 
• 
The local Heart Team's interventional cardiologist(s) and cardiac surgeon(s) jointly participate in 
the intra-operative technical aspects of TAVR (required for US sites per Medicare NCD).  
• 
Investigators will be extensively trained with regards to implantation technique of the Navitor Valve 
using the FlexNav Delivery System.  
• 
Investigators will be provided with a Clinical Instructions for Use (IFU) as a reference. 
• 
Procedure setting to include either a hybrid catheterization/operating room suite and/or a fixed C-
arm angiography imaging capability in the operative suite for quality imaging. 
 
Adherence to the Clinical Investigational Protocol:  The clinical study will be monitored by the Sponsor 
to ensure adherence to the CIP.  Subjects will be carefully selected through rigorous screening by both the 
site’s heart team and independent SSC using pre-specified inclusion and exclusion criteria as stated in 
section 5.3. Additionally, as stated in section 10.9.2, an independent DMC will monitor cumulative data at 
prescribed intervals and may consider a recommendation for modifications or termination of the study 
based on any safety concerns.  Adverse events and device deficiencies will be reported to Abbott and will 
be monitored internally for safety surveillance purposes and reported to regulatory authorities as 
applicable.  
15.6 Risk to Benefit Rationale 
Current medical management guidelines have established TAVR as first-line treatment (Class I indication) 
for symptomatic severe aortic stenosis in patients considered to be high or extreme risk for surgical aortic 
valve replacement.  Risks associated with the Portico family of valves are the same as other transcatheter 
heart valves. The anticipated risks are stated in Section 15.2 Foreseeable Adverse Events and Anticipated 
Adverse Device Effects.   
Protocol-required clinical assessments are primarily standard of care assessments for cardiac/structural 
heart interventional procedures and will be administered per Hospital guidelines.  Risks to the subject 
undergoing study-specific assessments (not considered standard of care) have been addressed in the 
clinical investigational protocol with appropriate mitigation for each risk to the lowest level possible. 
The benefits of the Navitor valve are anticipated to be similar to other transcatheter aortic valves, which 
may include improvements in chest pain, fatigue, shortness of breath, dizziness and fainting.  Clinical 
evaluation of the Portico valve and first-generation Portico Delivery System in the Portico TAVI System CE 

 
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Mark study and Portico I study support the safety and performance of these devices.  While the clinical 
benefit of the Navitor valve used with the FlexNav delivery system has not been established, the design 
modifications are not intended to or anticipated to introduce new risks.  Collectively, the prior clinical 
experience with the Portico TAVI system and bench data support that the benefits outweigh the risks 
associated with the evaluation of this device in a clinical study. 
 
 

 
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APPENDIX III: ADDITIONAL DEFINITIONS 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, in the context 
of a clinical investigation, whether or not related to the investigational medical device. 
 
As part of ISO14155 Section 3.2, the adverse event definition has the following notes: 
 
Note 1: This definition includes events related to the investigational medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices or comparators. 
 
Serious Adverse Event (SAE) 
Serious adverse event is an AE that led to any of the following:  
d) Death, 
e) Serious deterioration in the health of the subject, that resulted in any of the following: 
1. Life-threatening illness or injury, 
2. Permanent impairment of a body structure or a body function, 
3. Hospitalization or prolongation of patient hospitalization, 
4. Medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or a body function, 
5. Chronic disease  
f) Fetal distress, fetal death or a congenital physical or mental impairment or birth defect. 
 
Note: A planned hospitalization for pre-existing condition, or a procedure required by the CIP, without a 
serious deterioration in health, is not considered a SAE. 
 
Adverse Device Effect (ADE) 
An adverse event related to the use of an investigational medical device. 
 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device. 
 
This definition includes any event resulting from the use error or from intentional misuse of the 
investigational medical device. 
 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event. 
 
Unanticipated Adverse Device Effect (UADE) 

 
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As defined in 21 CFR §812.3, unanticipated adverse device effects (UADE) are defined as any serious 
adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, 
a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the CIP or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.   
 
Anticipated Serious Adverse Device Effect (ASADE) 
Anticipated serious adverse device effect (ASADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem or death was previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
anticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
 
Device Deficiency (DD) 
Device deficiency is defined as any inadequacy in the identity, quality, durability, reliability, usability, 
safety or performance of an investigational device, including malfunction, use errors or inadequacy in the 
information supplied by the manufacturer including labeling.  
 
Note 1: The definition includes device deficiencies related to investigational medical device or the 
comparator. 
 
Note 2: Cyber-security incidents related to the investigational product, shall be reported as device 
deficiencies 
 
A device malfunction is the failure of an investigational device to perform in accordance with its intended 
purpose when used in accordance with the instructions for use or CIP, or IB. 

 
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APPENDIX IV: SURGICAL RISK ASSESSMENT TOOLS 
This clinical study requires the use of two surgical risk assessment tools: 
1. The Society of Thoracic Surgeons’ (STS) risk calculation tools 
(http://riskcalc.sts.org/STSWebRiskCalc273/de.aspx) 
 
2. Euro SCORE II (http://euroscore.org/calc.html) 

 
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APPENDIX VI: NYHA 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. 
 
 
 

 
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APPENDIX VII: QUALITY OF LIFE – SF-36v2 
 

 
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APPENDIX VIII: MINI-MENTAL STATE EXAMINATION (MMSE-2) 
 
 

 
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APPENDIX IX: BARTHEL INDEX 
 
 
 
 

 
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APPENDIX X: STRUCTURED INTERVIEW FOR THE MODIFIED RANKIN SCORE (mRS) 
 
After the NIHSS has been completed, the mRS (by a certified rater) is to be determined and graded by 
the same certified rater. 
The determination of the scale should be made from 5 to 0. 
The purpose of the mRS is to record whether the subject is severely, moderately, or slightly disabled and 
whether the subject is performing all usual activities without symptoms or not. Because subjects and 
family members may understate the severity of disability, it is important for the rating clinician to 
understand that the mRS is a clinical scale and not a patient-reported outcome. The assessor may ask 
questions but must assess the disability whether or not in agreement with the subject or family. 
“Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the 
Modified Rankin Scale” (Stroke; 33:2243-2246) 
 
Score 
Description 
5 
• 
Severe disability 
• 
Someone needs to be available at all times;  
• 
Care may be provided by either a trained or an untrained caregiver 
Question: Does the person require constant care?  
4 
• 
Moderately severe disability 
• 
Need for assistance with some basic activities of daily living, but does not require 
constant care 
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking?  
3 
• 
Moderate disability 
• 
Need for assistance with some instrumental activities of daily living but not basic 
activities of daily living.  
Question: Is assistance essential for preparing a simple meal, doing household chores, 
looking after money, shopping, or traveling locally?  
2 
• 
Slight disability;  
• 
Limitations in participation in usual social roles 
• 
Independent for activities of daily living.  
Questions: Has there been a change in the person’s ability to work or look after others if 
these were roles before stroke? Has there been a change in the person’s ability to 
participate in previous social and leisure activities? Has the person had problems with 
relationships or become isolated?  
1 
• 
No significant disability 
• 
Symptoms present but no other limitations.  
Question: Does the person have difficulty reading or writing, difficulty speaking or finding 
the right word, problems with balance or coordination, visual problems, numbness (face, 
arms, legs, hands, feet), loss of movement (face, arms, legs, hands, feet), difficulty with 
swallowing, or other symptom resulting from stroke?  
0 
• 
No symptoms at all 
• 
No limitations and no symptoms 
 
 
 
 
 

 
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APPENDIX XI: NIH STROKE SCALE (NIHSS) 
 

 
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APPENDIX XII: SIX MINUTE WALK TEST 
This Six Minute Walk (6MWT) Test measures the distance that a patient can quickly walk on a flat, hard 
surface in a period of 6 minutes. It evaluates the global and integrated responses of all the systems 
involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, 
peripheral circulation, blood, neuromuscular units, and muscle metabolism. It does not provide specific 
information on the function of each of the different organs and systems involved in exercise or the 
mechanism of exercise limitation, as is possible with maximal cardiopulmonary exercise testing.  
SAFETY ISSUES  
1. Testing should be performed in a location where a rapid, appropriate response to an emergency is 
possible. The appropriate location of a crash cart should be determined by the physician supervising 
the facility.  
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and albuterol 
(metered dose inhaler or nebulizer). A telephone or other means should be in place to enable a call 
for help.  
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of Basic Life 
Support by an American Health Association–approved cardiopulmonary resuscitation course. 
Advanced cardiac life support certification is desirable. Training, experience, and certification in 
related health care fields (registered nurse, registered respiratory therapist, certified pulmonary 
function technician, etc.) are also desirable. A certified individual should be readily available to 
respond if needed.  
4. Physicians are not required to be present during all tests. The physician ordering the test or a 
supervising laboratory physician may decide whether physician attendance at a specific test is 
required.  
5. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or as 
directed by a physician or a protocol. 
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable dyspnea, 
(3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
Technicians must be trained to recognize these problems and the appropriate responses. If a test is 
stopped for any of these reasons, the patient should sit or lie supine as appropriate depending on the 
severity or the event and the technician's assessment of the severity of the event and the risk of syncope. 
The following should be obtained based on the judgment of the technician: blood pressure, pulse rate, 
oxygen saturation, and a physician evaluation. Oxygen should be administered as appropriate.  
 
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the previous 
month and myocardial infarction during the previous month. Relative contraindications include a resting 
heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, and a diastolic blood 
pressure of more than 100 mm Hg.  
Patients with any of these findings should be referred to the physician ordering or supervising the test for 
individual clinical assessment and a decision about the conduct of the test. The results from a resting 
electrocardiogram done during the previous 6 months should also be reviewed before testing. Stable 
exertional angina is not an absolute contraindication for a 6MWT, but patients with these symptoms 
should perform the test after using their antiangina medication, and rescue nitrate medication should be 
readily available. A deviation from the Clinical Investigation Plan will need to be collected if the subject is 
unable to complete this test. 

 
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LOCATION 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a hard 
surface that is seldom traveled. If the weather is comfortable, the test may be performed outdoors. The 
walking course must be 30 m in length. A 100-ft hallway is, therefore, required. The length of the corridor 
should be marked every 3 m. The turnaround points should be marked with a cone (such as an orange 
traffic cone). A starting line, which marks the beginning and end of each 60-m lap, should be marked on 
the floor using brightly colored tape.  
 
PROCEDURE 
REQUIRED EQUIPMENT  
• 
Countdown timer (or stopwatch)  
• 
Mechanical lap counter  
• 
Two small cones to mark the turnaround points  
• 
A chair that can be easily moved along the walking course  
• 
Worksheets on a clipboard  
• 
A source of oxygen  
• 
Sphygmomanometer  
• 
Telephone  
• 
Automated electronic defibrillator  
PATIENT PREPARATION  
• 
Comfortable clothing should be worn.  
• 
Appropriate shoes for walking should be worn.  
• 
Patients should use their usual walking aids during the test (cane, walker, etc.).  
• 
The patient's usual medical regimen should be continued.  
• 
A light meal is acceptable before early morning or early afternoon tests.  
• 
Patients should not have exercised vigorously within 2 hours of beginning the test.  
• 
This test should be performed about the same time of day for each interval to minimize intraday 
variability.  
• 
A "warm-up" period before the test should not be performed.  
• 
The patient should sit at rest in a chair, located near the starting position, for at least 10 minutes 
before the test starts. During this time, check for contraindications, measure pulse and blood 
pressure, and make sure that clothing and shoes are appropriate. Complete the first portion of the 
worksheet. 
Baseline Measurements 
1. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary equipment (lap 
counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point.  
Instruct the patient as follows:  
“The object of this test is to walk as far as possible for 6 minutes. You will walk 
back and forth in this hallway. Six minutes is a long time to walk, so you will be 
exerting yourself. You will probably get out of breath or become exhausted. You 
are permitted to slow down, to stop, and to rest as necessary. You may lean 
against the wall while resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly 
around the cones and continue back the other way without hesitation. Now I'm 
going to show you. Please watch the way I turn without hesitation." 

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

 
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APPENDIX XIII: 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 - often shallow LAO or RAO and some cranial tilt. 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 at 10 mL/sec, 15 frames/sec and at least 5 heart cycles.  
 
Echocardiography: Use color-Doppler in the short-axis view of the ventricular part of the valve frame. 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 (within 5 to 10 min after valve deployment). The gradient between diastolic blood pressure 
(DBP) in the aorta and left ventricular end diastolic pressure (LVEDP) should be calculated over several 
cardiac cycles to evaluate the severity of paraprosthetic aortic regurgitation (PAR). 
 
To adjust the gradient for the respective systolic blood pressure (SBP) of the patient, the dimensionless 
AR index should 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).  
 
 
 
 
 
 

 
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APPENDIX XIV: SITE CONTACT INFORMATION 
Contact information for each participating clinical site is available under separate cover by contacting the 
Sponsor at: 
 
  
 
 
 
 
 
 

 
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APPENDIX XVII: CASE REPORT FORMS 
The case report forms will be kept under a separate cover and are available upon request from the 
Sponsor Clinical Project Manager for the clinical investigation. 
 
 

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

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

 
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APPENDIX XX: REVISION HISTORY 
This CIP may be amended as appropriate by the Sponsor. Rationale will be included with each amended 
version in the revision history table below. The version number and date of amendments will be 
documented. 
 
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APPENDIX XXI: CIP SUMMARY 
Clinical 
Investigation 
Name and 
Number 
Portico NG Approval Study 
 
Title 
Evaluation of the Navitor Transcatheter Aortic Valve in High and Extreme Risk 
Patients with Symptomatic Severe Aortic Stenosis 
Objective(s) 
The primary objective of this clinical study is to evaluate the acute safety and 
effectiveness of the Navitor Transcatheter Aortic Heart Valve as assessed by 
the rate of all-cause mortality at 30 days and the rate of moderate or greater 
paravalvular leak at 30 days.   
Device Under 
Investigation 
Portico NG (Navitor) Valve (23mm, 25mm, 27mm and 29mm) 
Navitor Titan Valve (35mm) 
FlexNav Delivery System (small and large) 
Portico NG (Navitor) Loading System (small and large) 
Navitor Loading System – LG+ 
Number of 
Subjects Required 
for Inclusion in 
Clinical 
Investigation 
169 analysis subjects (up to a total of 189 subjects including roll-ins) with an 
attempted Navitor implant will be enrolled in order to analyze the primary 
endpoints for the PMA submission of the Navitor 23-29mm valve sizes.  To 
ensure enrollment balance across study sites, no site may enroll more than 20% 
of the analysis population (n=33). 
A separate cohort of 60 analysis subjects will undergo a Navitor Titan valve 
implant attempt to analyze the primary endpoints for the PMA submission. 
Clinical 
Investigation 
Design 
Prospective, multi-center, international, single-arm, investigational study 
Primary 
Endpoint(s) 
The primary safety endpoint is all-cause mortality at 30 days.  The primary 
effectiveness endpoint is moderate or greater paravalvular leak at 30 days. 
Secondary 
Endpoint 
The secondary endpoint is the non-hierarchical composite of all-cause mortality, 
disabling stroke, life threatening bleeding, acute kidney injury (stage 3), or 
major vascular complications at 30 days. 
Subject Follow-up 
Subject data will be collected at baseline, procedure, discharge, 30 days, 12 
months, and annually thereafter to 5 years post implant procedure.  
 
Echocardiographic data will be collected at screening, procedure (optional), and 
discharge as well as 30 days, 12 months, and at 2, 4, and 5 years post implant 
procedure. 
Inclusion Criteria 
Key inclusion criteria, refer to the complete inclusion criteria in the body of the 
CIP (section 5.3.2): 
1. Subjects must have a Society of Thoracic Surgeons (STS) score of ≥7% 
OR documented heart team agreement of high or extreme risk for surgical 
aortic valve replacement due to frailty or co-morbidities not captured by 
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2. Subject has symptomatic aortic stenosis as demonstrated by NYHA 
Functional Classification of II, III, or IV. 
3. Subject has senile degenerative aortic valve stenosis with echo-derived 
criteria, defined as: aortic valve area (AVA) of ≤ 1.0 cm2 (or indexed EOA 
≤ 0.6 cm2/m2) AND mean gradient ≥40 mmHg or peak jet velocity ≥ 4.0 
m/s or doppler velocity index (DVI) ≤0.25. (Qualifying AVA baseline 
measurement must be within 90 days prior to informed consent). 
4. Portico NG cohort (only): aortic annulus diameter of 19‐27mm and 
ascending aorta diameter of 26-42 mm for the specified valve size listed 
in the IFU, as measured by CT conducted within 12 months prior to 
informed consent. (If a CT is contraindicated and/or not possible to be 
obtained for certain subjects, a 3D echocardiogram and non‐contrast CT 
of chest and abdomen/pelvis may be accepted).  
5. Titan cohort (only): aortic annulus diameter of 27-30mm and ascending 
aorta diameter of 27-44mm per the IFU, as measured by CT conducted 
within 12 months prior to informed consent. (If a CT is contraindicated 
and/or not possible to be obtained for certain subjects, a 3D 
echocardiogram and non‐contrast CT of chest and abdomen/pelvis may 
be accepted). 
Exclusion Criteria 
Key exclusion criteria, refer to the complete inclusion criteria in the body of the 
CIP (section 5.3.3): 
1. Evidence of an acute myocardial infarction (defined as: ST Segment 
Elevation as evidenced on 12 Lead ECG) within 30 days prior to index 
procedure. 
2. Any percutaneous coronary or peripheral interventional procedure 
performed within 30 days prior to index procedure. 
3. Active peptic ulcer or upper GI bleeding within 3 months prior to index 
procedure that would preclude anticoagulation 
4. Recent (within 6 months prior to index procedure date) cerebrovascular 
accident (CVA) or a transient ischemic attack (TIA). 
5. Renal insufficiency (creatinine > 3.0 mg/dL) and/or end stage renal 
disease requiring chronic dialysis. 
6. Sepsis or active bacterial endocarditis within 6 months prior to the index 
procedure. 
7. Liver failure (Child-Pugh class C) 
8. Untreated atrial fibrillation (e.g., patients with atrial fibrillation not on 
anticoagulants) 
9. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with 
predominant aortic regurgitation 3-4+) 
10. Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is 
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11. Severe ventricular dysfunction with LVEF <25% as measured by resting 
echocardiogram 
12.  Pre-existing prosthetic heart valve or other implant in any valve position, 
prosthetic ring, severe circumferential mitral annular calcification (MAC) 
which is continuous with calcium in the left ventricular outflow tract 
(LVOT), severe (greater than or equal to 3+) mitral insufficiency, or severe 
mitral stenosis with pulmonary compromise  
13. Echocardiographic or multi-slice computed tomography (MSCT) evidence 
of intracardiac mass, thrombus or vegetation 
14. Significant aortic disease, including abdominal aortic or thoracic 
aneurysm defined as maximal luminal diameter 5cm or greater; marked 
tortuosity (hyperacute bend), aortic arch atheroma (especially if thick 
[> 5  mm], protruding or ulcerated) or narrowing (especially with 
calcification and surface irregularities) of the abdominal or thoracic aorta, 
severe “unfolding” and tortuosity of the thoracic aorta (applicable for 
transfemoral access only) 
15. Aortic root angulation > 70°  
16. Undue risk of coronary obstruction (e.g., bulky aortic valve leaflets in close 
proximity to coronary ostia) 
17. Non-calcified aortic annulus 
18. Iliofemoral vessel characteristics that would preclude safe insertion of the 
FlexNav™ Delivery System with or without an arterial introducer sheath 
such as severe obstructive calcification, protruding thrombus or severe 
tortuosity (applicable for transfemoral access only) 
19. Severe tricuspid regurgitation or severe right ventricle dysfunction 
20. Minimum access vessel diameter of <5.0mm for small FlexNav Delivery 
System and <5.5 mm for large FlexNav Delivery System