Assessment of the Abbott FlexNav™ Delivery System for Portico Transcatheter Aortic Valve Implantation in High and Extreme Risk Patients With Symptomatic Severe Aortic Stenosis
Phase: NA
Conditions: Symptomatic Severe Aortic Stenosis
Sponsor: Abbott Medical Devices

 
Clinical Investigation Plan Cover Page 
 
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87173 CIP Posting Cover Page Ver B 
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Page 1 of 1 
 
NCT Number: NCT03724812 
FlexNav EU CE Mark Study 
Assessment of the Abbott FlexNav™ Delivery System for Portico Transcatheter Aortic Valve Implantation 
in High and Extreme Risk Patients with Symptomatic Severe Aortic Stenosis  
Study Document No: #ABT-CIP-10260 
Version A 
Date: 23-Oct-2018 
 
 
Sponsor  
 
 
Abbott 
        
 
 
 
5050 Nathan Lane N  
Plymouth, MN 55442 
USA 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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ABT-CIP-10260 
FlexNav EU CE Mark Study 
Assessment of the Abbott FlexNav™ Delivery System for Portico Transcatheter Aortic Valve 
Implantation in High and Extreme Risk Patients with Symptomatic Severe Aortic Stenosis 
 
Version Number 
A 
Date 
October 23, 2018 
Coordinating Clinical 
Investigator/Study Principal 
Investigator:                
Francesco Bedogni, MD 
Planned Number of Sites and Region(s) 
Up to eight (8) sites in Europe including: Switzerland, Denmark, 
Germany, Italy, United Kingdom 
Clinical Investigation Type 
Prospective, single-arm, non-randomized, multi-center, CE Mark 
investigational study 
Abbott Medical Expert 
Eric Manasse, MD eMBA 
Medical Director, Structural Heart BU 
Divisional Vice President, Global Medical Affairs 
Centro Direzionale Colleoni 
Palazzo Andromeda, 20/3 
20864 Agrate Brianza (MB) 
Italy 
 
Sponsor 
 
Abbott 
5050 Nathan Lane N  
Plymouth, MN 55442, USA  
 
 
Electronic Data Capture Software 
Oracle 
Core Laboratories 
 
Echocardiographic Core Laboratory: 
Medstar Health Research Institute 
6525 Belcrest Road, Suite 700, Hyattsville, MD 20782 
 
Computed Tomography (CT) Sizing Core Laboratory: 
Cedars-Sinai Heart Institute 
8700 Beverly Blvd, West Hollywood, CA 90048-1804 
Clinical Events Committee 
Administration 
Duke University Medical Center, Durham, NC, USA 
CIP Author of Current Version  
 
Alicia Kimber, Ph.D. 
Senior Clinical Research Scientist 
Structural Heart BU 
 
 

ABT-CIP-10260 Ver. [A] 
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements applicable 
in conducting this clinical investigation. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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express written consent of Abbott 
Template: 86357 Rev. E 
 
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STUDY PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements applicable 
in conducting this clinical investigation. 
 
 
[Study Principal Investigator] 
 
Printed name: 
Signature: 
Date: 
 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ............................................................................................................................ 10 
1.1 
Background and Rationale ....................................................................................................... 10 
 
Background ...................................................................................................................... 10 
 
Rationale for Conducting this Clinical Investigation ........................................................... 13 
2 
CLINICAL INVESTIGATION OVERVIEW ....................................................................................... 14 
2.1 
Clinical Investigation Objective ................................................................................................ 14 
 
Primary objective .............................................................................................................. 14 
2.2 
Device(s) To Be Used in the Clinical Investigation ................................................................... 14 
 
Name of the Device(s) Under Investigation ....................................................................... 14 
 
Intended Indication for Use ............................................................................................... 16 
 
Description of the Device(s) Under Investigation ............................................................... 16 
 
Summary of Preclinical Studies ........................................................................................ 19 
 
Device Handling................................................................................................................ 19 
3 
CLINICAL INVESTIGATION DESIGN ............................................................................................. 19 
3.1 
Purpose ................................................................................................................................... 19 
3.2 
Design Overview ...................................................................................................................... 19 
3.3 
Clinical Investigation Procedures and Follow-up Schedule ...................................................... 20 
3.4 
Measures Taken to Avoid and Minimize Bias ........................................................................... 21 
 
Screening by an inter-disciplinary local Heart Team ......................................................... 22 
 
Assessment of Anatomical Suitability by a Computed Tomography (CT) sizing Core 
Laboratory ...................................................................................................................................... 22 
 
Use of an Independent Subject Selection Committee ....................................................... 22 
 
Adjudication of Adverse Events by an Independent Clinical Events Committee ................ 22 
 
Review of Echocardiographic Images by an Independent Echocardiographic Core 
Laboratory ...................................................................................................................................... 22 
 
Monitoring Follow-Up Compliance .................................................................................... 23 
 
Standardized Administration of Patient-Reported Outcome Measures and Stroke  
Assessment Scales (mRS and NIHSS) ............................................................................. 23 
3.5 
Suspension or Early Termination of the Clinical Investigation .................................................. 23 
4 
ENDPOINTS ................................................................................................................................... 24 
4.1 
Primary Endpoint and Rationale .............................................................................................. 24 
4.2 
Descriptive Endpoint(s) ............................................................................................................ 25 
5 
SUBJECT SELECTION AND WITHDRAWAL ................................................................................. 26 
5.1 
Subject Population ................................................................................................................... 26 
 
High Risk Classification: ................................................................................................... 26 

ABT-CIP-10260 Ver. [A] 
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Extreme risk classification ................................................................................................. 26 
5.2 
Subject Screening and Informed Consent ................................................................................ 27 
 
Subject Screening ............................................................................................................. 27 
 
Informed Consent ............................................................................................................. 28 
5.3 
Eligibility Criteria ...................................................................................................................... 29 
 
General Eligibility Criteria .................................................................................................. 29 
 
Inclusion Criteria ............................................................................................................... 29 
 
Inclusion Criteria - High Risk Cohort .......................................................................... 29 
 
Exclusion Criteria - High and Extreme Risk Cohort ........................................................... 30 
5.4 
Subject Enrollment ................................................................................................................... 32 
5.5 
Subject Withdrawal .................................................................................................................. 32 
 
Lost-to-Follow-up .............................................................................................................. 33 
5.6 
Total Expected Duration of the Clinical Investigation ............................................................... 33 
5.7 
Expected Duration of Each Subject’s Participation ................................................................... 33 
5.8 
Number of Subjects ................................................................................................................. 34 
5.9 
Estimated Time Needed to Select Required Number of Subjects ............................................ 34 
6 
TREATMENT AND EVALUATION OF ENDPOINTS ...................................................................... 34 
6.1 
Baseline Assessments ............................................................................................................. 34 
 
Baseline Laboratory and Clinical Tests ............................................................................. 34 
 
Pre-procedure Antiplatelet/Anticoagulation Medications ................................................... 35 
 
Pre-Procedure Blood Test ................................................................................................ 35 
6.2 
Index Procedure ...................................................................................................................... 35 
 
Procedure Involved in the Use of the Investigational Devices ........................................... 35 
 
Anticoagulation Therapy ................................................................................................... 35 
 
Treatment Procedures ...................................................................................................... 35 
 
Final (Post-procedure) Imaging ......................................................................................... 37 
6.3 
Post–procedure (In-hospital) .................................................................................................... 37 
 
Post-procedure Laboratory and Clinical Tests .................................................................. 37 
6.4 
Discharge Plan ........................................................................................................................ 37 
6.5 
Follow Up Visits ....................................................................................................................... 38 
 
Follow-up Medications ...................................................................................................... 38 
 
Follow-up for All Enrolled Subjects.................................................................................... 38 
 
Unscheduled Follow-up .................................................................................................... 40 
 
Patient Reported Outcome (PRO) Measures .................................................................... 41 
 
Schedule of Events ........................................................................................................... 44 
6.6 
Requirement for Core Laboratories .......................................................................................... 46 

ABT-CIP-10260 Ver. [A] 
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7 
ADVERSE EVENTS ....................................................................................................................... 46 
7.1 
Definitions ................................................................................................................................ 46 
 
Adverse Event .................................................................................................................. 46 
 
Serious Adverse Event ..................................................................................................... 46 
 
Device Deficiency ............................................................................................................. 47 
7.2 
Device Relationship ................................................................................................................. 47 
 
Unanticipated Serious Adverse Device Effect (USADE) .................................................... 47 
7.3 
Adverse Event and Device Deficiency Reporting ..................................................................... 47 
 
Adverse Event Reporting .................................................................................................. 47 
 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC .................... 48 
 
Device Deficiency ............................................................................................................. 48 
 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .................... 49 
8 
STATISTICAL CONSIDERATIONS ................................................................................................ 49 
8.1 
Analysis Populations ................................................................................................................ 49 
8.2 
Statistical Analyses .................................................................................................................. 49 
 
Primary Safety Endpoint Analyses .................................................................................... 49 
8.3 
Sample Size Calculation and Assumptions .............................................................................. 50 
8.4 
Timing of Analysis .................................................................................................................... 50 
8.5 
Subgroup Analysis ................................................................................................................... 50 
8.6 
Multiplicity ................................................................................................................................ 50 
8.7 
Pooling Strategy ...................................................................................................................... 50 
8.8 
Procedures for Accounting for Missing Data ............................................................................ 51 
8.9 
Planned Interim Analysis ......................................................................................................... 51 
8.10 
Statistical Criteria for Termination ............................................................................................ 51 
8.11 
Success Criteria ....................................................................................................................... 51 
8.12 
Deviations from Statistical Plan ................................................................................................ 51 
9 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS................................................................... 51 
10 QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 51 
10.1 
Selection of Clinical Sites and Investigators ............................................................................. 51 
10.2 
Clinical Investigation Finances and Agreements ...................................................................... 51 
10.3 
CIP Amendments ..................................................................................................................... 52 
10.4 
Training.................................................................................................................................... 52 
 
Site Training ..................................................................................................................... 52 
 
Training Required for the Use of the FlexNav™ Delivery System ..................................... 52 
10.5 
Monitoring ................................................................................................................................ 52 
10.6 
Deviations from CIP ................................................................................................................. 53 

ABT-CIP-10260 Ver. [A] 
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10.7 
Quality Assurance Audit ........................................................................................................... 54 
10.8 
Sponsor Auditing ..................................................................................................................... 54 
10.9 
Committees ............................................................................................................................. 54 
 
Subject Selection Committee ............................................................................................ 54 
 
Clinical Events Committee ................................................................................................ 55 
 
Steering and Publications Committee ............................................................................... 55 
11 DATA HANDLING AND RECORD KEEPING ................................................................................. 55 
11.1 
Protection of Personally Identifiable Information ...................................................................... 56 
11.2 
Data Management Plan ........................................................................................................... 56 
11.3 
Source Documentation ............................................................................................................ 56 
11.4 
Case Report Form Completion ................................................................................................ 56 
11.5 
Record Retention ..................................................................................................................... 57 
11.6 
Investigational Devices Accountability ..................................................................................... 57 
12 ETHICAL CONSIDERATION .......................................................................................................... 57 
12.1 
Medical Ethics Committee Review and Approval ..................................................................... 57 
13 CLINICAL INVESTIGATION CONCLUSION ................................................................................... 58 
14 PUBLICATION POLICY .................................................................................................................. 58 
15 RISK ANALYSIS ............................................................................................................................. 58 
15.1 
Anticipated Clinical Benefits ..................................................................................................... 58 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects .................................... 59 
 
Potential Anticipated Adverse Events ............................................................................... 59 
15.3 
Residual Risks Associated with the Device Under Investigation, as Identified in the Risk 
Analysis Report ........................................................................................................................ 61 
15.4 
Risks Associated with Participation in this Clinical Investigation .............................................. 61 
15.5 
Steps Taken to Control or Mitigate Risks ................................................................................. 62 
15.6 
Risk to Benefit Rationale .......................................................................................................... 63 
16 APPENDICES ................................................................................................................................ 65 
 
LIST OF TABLES  
Table 1: Identification of Devices Included in the Study.......................................................................... 14 
Table 2: FlexNav™ Delivery System Models and Compatibility with Portico™ Transcatheter Aortic Valve 
Sizes ...................................................................................................................................................... 17 
Table 3: Study-related assessments and data collection schedule ......................................................... 44 
Table 4: Examples of Potential Study Protocol Deviations ..................................................................... 54 
Table 5: Anticipated Clinical Impact of Design Modifications to FlexNav™ Delivery System .................. 59 
Table 6: Known Risks Associated with Study-Specific Assessments and Mitigation Measures .............. 61 
 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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LIST OF FIGURES 
Figure 1:Second-Generation FlexNav™ Delivery System ...................................................................... 15 
Figure 2: Second-Generation FlexNav™ Loading System Base and Insert............................................ 16 
Figure 3: Second-Generation FlexNav™ Delivery System Handle Detail ............................................... 17 
Figure 4: Second-Generation FlexNav™ Delivery System (Proximal End) ............................................. 17 
Figure 5: FlexNav™ Loading System ..................................................................................................... 18 
Figure 6: Clinical Investigation Flow Chart ............................................................................................. 21 
 
 
 
LIST OF APPENDICES 
APPENDIX I: ABBREVIATIONS AND ACRONYMS .............................................................................. 65 
APPENDIX II: VARC II ENDPOINTS ..................................................................................................... 67 
APPENDIX III: NON-STUDY SPECIFIC DEFINITIONS ......................................................................... 71 
APPENDIX IV: STUDY-SPECIFIC ASSESSMENTS ............................................................................. 73 
APPENDIX V: SITE CONTACT INFORMATION .................................................................................... 75 
APPENDIX VI: SURGICAL RISK ASSESSMENT TOOLS ..................................................................... 76 
APPENDIX VII: FRAILY ASSESSMENT ................................................................................................ 77 
APPENDIX VIII: NYHA CLASSIFICATION............................................................................................. 79 
APPENDIX IX: CANADIAN CARDIOVASCULAR SOCIETY GRADING OF ANGINA PECTORIS ......... 80 
APPENDIX X: QUALITY OF LIFE- EQ-5D 3L ........................................................................................ 81 
APPENDIX XI: QUALITY OF LIFE – SF-36v2 ........................................................................................ 83 
APPENDIX XII: QUALITY OF LIFE-KANAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) .... 89 
APPENDIX XIII: MINI-MENTAL STATE EXAMINATION (MMSE-2) ....................................................... 93 
APPENDIX XIV: BARTHEL INDEX ........................................................................................................ 97 
APPENDIX XV: STRUCTURED INTERVIEW FOR THE MODIFIED RANKIN SCORE (mRS) .............. 99 
APPENDIX XVI: NIH STROKE SCALE (NIHSS) .................................................................................. 100 
APPENDIX XVII: SIX MINUTE WALK TEST ........................................................................................ 108 
APPENDIX XVIII: PERI-PROCEDURAL GUIDELINES ........................................................................ 112 
APPENDIX XIX: EXPLANT, RETURN, AND ANALYSIS OF VALVE ................................................... 113 
APPENDIX XX: INSTRUCTIONS FOR DEVICE RETURN- LARGE AND SMALL KITS ...................... 114 
APPENDIX XXI: GERMAN HANDLING OF SERIOUS ADVERSE EVENTS ........................................ 115 
APPENDIX XXII: INDEPENDENT COMMITTEE AND CORE LABORATORY CONTACT DETAILS ... 118 
APPENDIX XXIII: RATES OF FORSEEABLE ADVERSE EVENTS ..................................................... 119 
APPENDIX XXIV: LABELS .................................................................................................................. 120 
APPENDIX XXV: CASE REPORT FORMS .......................................................................................... 124 
APPENDIX XXVI: INFORMED CONSENT FORM ............................................................................... 125 
APPENDIX XXVII: MONITORING PLAN ............................................................................................. 126 
APPENDIX XXVIII: CONTACT INFORMATION ................................................................................... 127 
APPENDIX XXIX: REVISION HISTORY .............................................................................................. 128 
APPENDIX XXX: CIP SUMMARY ........................................................................................................ 129 
 
 

ABT-CIP-10260 Ver. [A] 
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COMPLIANCE STATEMENT:  
 
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, the 
Declaration of Helsinki, ISO 14155:2011 standards and the appropriate local legislation(s). The most 
stringent requirements, guidelines or regulations must always be followed. The conduct of the clinical 
investigation will be approved by the appropriate Ethics Committee (EC) of the respective clinical site and 
as specified by local regulations. 
 
 
 
 

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1 
INTRODUCTION 
This document is a clinical investigational plan (CIP) for a prospective, multi-center, single-arm 
investigational study intended to support CE Mark of the latest design iteration of the St Jude Medical 
Portico Delivery System (“second-generation FlexNav™ Delivery System”). The investigational device is 
intended for use with the CE Marked Portico™ Transcatheter Aortic Heart Valve (Portico™ valve) for the 
treatment of symptomatic, severe aortic stenosis in high and extreme surgical risk patients.  
The primary focus of the clinical investigation is to characterize the safety profile of the FlexNav™ Delivery 
System with respect to rate of major vascular complications, which is expected to be directly impacted by 
the recent design modifications to the FlexNav™ Delivery System. This clinical study is sponsored by 
Abbott.     
This clinical investigation will be conducted in accordance with this CIP. All investigators involved in the 
conduct of the clinical investigation will be qualified by education, training, or experience to perform their 
tasks and this training will be documented appropriately. 
1.1 Background and Rationale 
 Background 
 TAVR in the Treatment of Aortic Stenosis 
Aortic stenosis (AS) is a clinically important degenerative valvular heart disease that is associated with 
poor prognosis following the onset of cardiac symptoms. In the elderly patient population, the prevalence 
of AS and severe AS is estimated at 12.4%, and 3.4%, respectively.1 Historically, surgical aortic valve 
replacement (SAVR) has been the primary treatment option for severe AS until seminal findings from the 
Placement of Aortic Transcatheter Valves (PARTNER) Cohort A and B Trials revealed transcatheter aortic 
valve replacement (TAVR), a less invasive treatment option, to be non-inferior to SAVR2 and superior to 
conventional medical therapy3 with respect to survival rates at 1 year. 
Investment in the TAVR platform has seen the technology emerge as the new standard of care for 
symptomatic patients with advanced disease at extreme surgical risk for whom no effective definitive 
therapy is available. In 2017, the AHA/ACC revised their guidelines in a focused update to make TAVR a 
class I indication (previously a class IIa indication) for the treatment of AS in patients at both high and 
prohibitive surgical risk.4 Most recently, TAVR has been shown to be a safe alternative to SAVR in patients 
in whom surgery is feasible but who are considered to be intermediate risk5 with new trials in low surgical 
risk patients currently underway.  
                                               
1 Osnabrugge RLJ, Mylotte D, Head SJ et al. Disease Prevalence and Number of Candidates for Transcatheter Aortic Valve Replacement: A 
Meta-Analysis and Modeling Study. Journal of the American College of Cardiology 2013;62:1002-1012 
2 Smith C, Leon M, Mack M et al. Transcatheter versus Surgial Aortic-Valve Replacement in High-Risk Patients. N Engl J Med 2011;364:2187-
2198. 
3 Leon M, Smith C, Mack M et al. Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery. N Engl J 
Med 2010;363:1597-1607. 
4 Nishimura RA, Otto CM, Bonow RO et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients 
With Valvular Heart Disease. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. 2017;70:252-289. 
5 Leon M, Smith C, Mack M et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med 
2016;374:1609-20. 

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Page 11 of 132 
 TAVR and Major Vascular Complications  
Transfemoral access is recognized as the safest and thus preferred approach for TAVR with proven 
superiority over a transapical approach and conventional surgery in high and intermediate risk patients.6,7 
Vascular access (defined by vessel calcification, tortuosity and vessel narrowing) continues to be the main 
limiting factor for transfemoral TAVR with a minimum vessel access diameter of ≥ 6mm required.  As the 
use of TAVR expands to lower risk populations, minimizing vascular complications which are amongst the 
most frequent and serious complications of transfemoral TAVR is of paramount importance as studies 
show vascular and bleeding complications during the procedure are associated with increased morbidity 
and mortality risk.8,3   
The incidence of major vascular complications via transfemoral access has reduced with the introduction 
of next-generation TAVR systems. In a meta-analysis of 1,232 match-controlled patients, the rate of major 
vascular complications was shown to decline from 7.2%  with early-generation TAVR systems to 2.5% with 
next-generation TAVR systems.9   Studies show arterial sheath size is an important determinant of major 
vascular complications and life-threatening/disabling bleeding during TAVR.10 Vascular complications 
occur when the minimal artery diameter is smaller than the sheath external diameter.i Specifically, a sheath 
to femoral artery ratio (SFAR) > 1.05 is shown to be associated with increased risk of major vascular 
complications and mortality at 30 days.11  
 Competitor TAVR Delivery Systems 
Edwards LifeSciences and Medtronic are the current TAVR market leaders accounting for 95% of the 
global TAVI market share. Two key design elements of the latest-generation,  commercially-available 
balloon-expandable Edwards Sapien 3™ valve and self-expanding Medtronic CoreValve™ Evolut™ PRO 
valve systems that help mitigate the frequency of vascular and bleeding complications are: 1) a low 
insertion profile due to the use of a custom expandable sheath (Sapien 3™) and integrated sheath 
(Evolut™ PRO™); and 2) the ability to achieve precise valve placement without repositioning or with 
minimal need to re-sheath and reposition. 
The Medtronic Evolut™ PRO transcatheter heart valve is delivered through the EnVeo™ R Delivery 
Catheter System without the use of a separate arterial sheath and is indicated for vessels down to 5.0 mm. 
The EnVeo R system features a dedicated InLine Sheath that retains the outer diameter size as the system 
enters the vessel and advances to the annulus. The addition of the InLine sheath makes the EnVeo™ R 
Delivery Catheter System the lowest delivery platform currently on the market and provides a greater 
opportunity to treat patients with smaller vessels through the preferred transfemoral access route. 
The Edwards Commander™ Delivery System is used for transfemoral delivery of the Edwards Sapien 3™ 
transcatheter heart valve. The delivery system uses a low-profile 14F expandable sheath (eSheath) that 
is intended to reduce the potential for arterial injury during introduction of the delivery system and valve. 
The expandable sheath transiently expands to accommodate safe passage of the compressed valve and 
                                               
6 Arnold SV, Reynolds MR, Lei Y et al. Predictors of Poor Outcomes After Transcatheter Aortic Valve Replacement: Results From the 
PARTNER (Placement of Aortic Transcatheter Valve) Trial. Circulation. 2014;129:2682-2690. 
7 Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk 
patients: a propensity score analysis. The Lancet. 387:2218-2225. 
8 Généreux P, Webb JG, Svensson LG,et al. Vascular Complications After Transcatheter Aortic Valve Replacement: Insights From the 
PARTNER (Placement of AoRTic TraNscathetER Valve) Trial. J Am Coll Cardiol. 2012;60:1043-1052. 
9 Ando T, Takagi H, Telila T and Afonso L. Comparison of outcomes in new-generation versus early-generation 
heart valve in transcatheter aortic valve implantation: A systematic review and meta-analysis. Cardiovascular Revascularization Medicine. 2018; 
19: 186-191 
10 Mieghem N, Tchetche D, Chieffo A, et al. Incidence, Predictors, and Implications of Access Site Complications With Transfemoral 
Transcatheter Aortic Valve Implantation. Am J Cardiol 2012;110:1361–1367 
11 Hayashida K, Lefèvre T, Chevalier B, et al. Transfemoral Aortic Valve Implantation: New Criteria to Predict Vascular Complications. J Am Coll 
Cardiol Intv. 2011;4:851-858. 

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subsequently recoils to its lower profile diameter as the Sapien 3™ valve passes. The transient expansion 
of the eSheath minimizes the force required to insert and pass the delivery system and valve through the 
sheath, while maintaining a reduced profile compared to other standard arterial sheaths.   
The reduced profile of these next-generation devices has increased the proportion of patients who are now 
eligible for transfemoral TAVR in Europe without compromising the risk of vascular injuries and access site 
complications.  
 Commercial Portico Experience in Europe 
Abbott’s (formerly St Jude Medical) first-generation, self-expanding Portico™ transcatheter aortic heart 
valve (THV) system has been in commercial use in Europe since 2012 when the 23mm Portico™ valve 
and transfemoral Portico™ Delivery System first received Conformité Européenne (CE) mark approval.  
Data from the PORTICO TAVI System CE Mark study (PORTICO CE Mark study) was used to support 
device approval.  The PORTICO CE Mark study was the first prospective, European, non-randomized, 
multi-center clinical study to assess safety and performance of the full family of Portico™ valve sizes at 30 
days and through 1 year.  As part of the study, 222 patients with symptomatic, severe AS at high surgical 
risk were recruited between December 2011 and September 2015 across 12 centers in Europe (n=11) and 
Australia (n=1). Due to the sequential release of valve sizes in Europe, subjects were enrolled in three 
separate cohorts commencing with the Portico™ 23mm valve cohort on 6 December 2011; 25mm valve 
cohort on 14 January 2013; and 27/29mm valve cohort on 13 February 2014.). A minimum of 50 patients 
were implanted with each available Portico™ THV size (23, 25, 27, 29 mm) in the study.  Initial 30-day 
results of patients implanted with the 23mm and 25mm valves (n=100) were published in 201612; with 30-
day and 1-year outcomes data for all 220 patients successfully implanted with the full-family of Portico™ 
valve published shortly thereafter13, 14. Overall, results through to12 months demonstrated the full family of 
Portico™ valves are safe when implanted via transfemoral access and have good clinical, functional and 
hemodynamic outcomes. 
One of the key anatomical requirements for transfemoral valve implantation in the PORTICO CE Mark 
study was a minimum vessel access diameter of ≥6mm to safety accommodate the use of a separate 
arterial sheath with the first-generation Portico™ Delivery System. Since CE Mark of the Portico™ THV 
system in Europe, approximately 8000 commercial procedures have been performed using the full family 
of THV sizes (23, 25, 27 and 29mm) via a transfemoral access approach. Despite growing adoption of the 
Portico THV system in Europe, the introduction of optimized delivery catheter systems with lower profile 
sheaths has prompted some physicians to begin implanting the Portico™ valve via a ‘sheathless’ approach 
(insertion of the delivery system without a separate introducer). Results from single-center experiences 
that have implanted the Portico™ valve without the use of a separate introducer suggest the reduced 
insertion profile of the delivery system associated with a “sheathless” approach leads to improved rates of 
major vascular complications, life-threatening or disabling bleeding and major bleeding events15,16. In 
support of the data, the Portico™ Delivery System received CE Mark in May 2018 to be used ‘sheathless’.   
                                               
12 Manoharan G, Linke A, Moellmann H, et al. Multicentre clinical study evaluating a novel resheathableannular functioning self-expanding 
transcatheter aortic valve system: safety and performance results at 30 days with the Portico system. EuroIntervention 2016;12:768-74. 
13 Möllmann H, Linke A, Holzhey DM, et al. Implantation and 30-Day Follow-Up on All 4 Valve Sizes Within the Portico Transcatheter Aortic 
Bioprosthetic Family. JACC: Cardiovascular Interventions 2017;10:1538-47. 
14 Linke A, Holzhey D, Möllmann H, Manoharan G, Schäfer U, Frerker C et al. Treatment of Aortic Stenosis With a Self-Expanding, 
Resheathable Transcatheter Valve. One-Year Results of the International Multicenter Portico Transcatheter Aortic Valve Implantation System 
Study 2018;11 
15 Taramasso M, Denegri A, Kuwata S, et al. Feasibility and safety of transfemoral sheathless portico aortic valve implantation: Preliminary 
results in a single center experience. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & 
Interventions. 2018 91.3:533-539 
16 Denegri A, Nietlispach F, Kottwitz J et al. Real-world procedural and 30-day outcome using the Portico transcatheter aortic valve prosthesis: A 
large single center cohort. International Journal of Cardiology. 2018 253:40-44 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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 Customer Need for Second-Generation Portico Delivery System 
Based on customer feedback, the first-generation Portico Delivery System used in the PORTICO CE Mark 
study has undergone several design modifications to better compete against the current market-leading 
TAVR devices and to allow for future movement into expanded patient indications (i.e. intermediate risk, 
low risk, valve-in-valve, alternate access).  
The second-generation FlexNav™ Delivery System (“FlexNav™ Delivery System”) builds on the strength 
of the existing Portico platform and technology (i.e. maintains the ‘best in class’ trackability of the first-
generation Portico™ Delivery System) while incorporating design features that improve overall 
performance and provide one of the lowest insertion profiles. Specifically, the FlexNav™ Delivery System 
features a redesigned handle with improved ergonomic design to provide a more intuitive operation during 
valve deployment, a hydrophilic stability layer to minimize system manipulations and support precise valve 
placement and an integrated sheath to reduce the delivery profile diameter to minimize vessel trauma at 
the access site.  
While these new design modifications do not alter the procedure to load or deploy the Portico™ valve, the 
safety profile of the FlexNav™ Delivery System is expected to be comparatively better to the first-
generation Portico™ Delivery System with respect to access-site complications and vascular injury. It is 
also anticipated to allow physicians the ability to treat more patients via the preferred transfemoral access 
approach.  
Abbott is proposing to undertake a prospective, single-arm study (“FlexNav EU study”) to collect safety 
outcomes data on the FlexNav™ Delivery System, which will be submitted as part of the CE Mark 
submission to support commercial use of the Portico™ Transcatheter Heart Valve with the FlexNav™ 
Delivery System in Europe. The proposed FlexNav EU study will include a minimum of 73 analysis patients. 
To achieve the minimum required sample size, prospective data from subjects enrolled in the FlexNav 
study of the Portico US IDE pivotal trial (“US IDE FlexNav study”) may be combined with FlexNav EU study 
subjects.  The US IDE FlexNav study is a prospective, multicenter single-arm study of high or extreme risk 
subjects with severe symptomatic AS who undergo Portico™ valve implantation with the FlexNav™ 
Delivery System in the Portico US IDE pivotal trial. Abbott plans to submit safety results when a total of 73 
subjects from this clinical investigation and the US FlexNav IDE study have reached 30 days of follow-up 
in the CE Mark submission. 
 Rationale for Conducting this Clinical Investigation 
The rationale for conducting the FlexNav EU study is to collect safety data in a high or extreme surgical 
risk patient population to support CE Mark of the second-generation FlexNav™ Delivery System and 
Loading System in Europe. 
A minimum of 73 high or extreme risk patients with symptomatic, severe native AS who meet eligibility 
criteria for transfemoral implantation of the Portico™ valve will be enrolled in the clinical investigation study 
to ensure sufficient precision to assess the clinical impact of the FlexNav™ Delivery System on rate of 
major vascular complications at 30 days. 
It is expected the rate of major vascular complications at 30 days will be numerically lower than the rate 
reported in published literature using the first-generation Portico™ Delivery System due to design 
modifications that (1) enhance valve deliverability, (2) reduce the system’s profile and (3) minimize vessel 
trauma at the vascular-access site. 

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2 
CLINICAL INVESTIGATION OVERVIEW 
2.1 Clinical Investigation Objective 
 Primary objective  
The primary objective of the FlexNav EU study is to characterize the safety of the second-generation 
Portico FlexNav Delivery System (referred herein as the FlexNav™ Delivery System).  
The FlexNav EU study will be conducted as a prospective, multi-center, European, single-arm 
investigational study and will include up to 200 high or extreme risk patients with symptomatic, severe 
native aortic stenosis who meet eligibility criteria for Portico™ Transcatheter Aortic Heart Valve 
implantation via a transfemoral access approach. Thirty-day safety outcomes data for the first 73 subjects 
to undergo an attempted Portico™ valve implant using the FlexNav™ Delivery System will be summarized 
to support CE Mark of the FlexNav™ Delivery System and Loading System in Europe. 
2.2 Device(s) To Be Used in the Clinical Investigation 
 Name of the Device(s) Under Investigation 
Devices under investigation in this clinical investigation include the FlexNav™ Delivery System(s) (18 F 
and 19 F) and FlexNav™ Loading System(s) (Small and Large), which are both approved for 
investigational use only. Other devices to be used in the clinical investigation include all four (4) market- 
released St. Jude Medical (SJM) Portico™ valve sizes (23mm, 25mm, 27mm and 29mm) 
Model numbers for the FlexNav™ Delivery Systems, FlexNav™ Loading Systems and Portico™ valves 
are provided in Table 1. 
 
Table 1: Identification of Devices Included in the Study 
Device name 
Model/Type 
Serial/Lot 
Controlled 
Manufacturer 
Region/ 
Country 
Investigational 
or 
Market Released 
FlexNav™ Small 
Delivery System 
FN-DS-SM-IDE Serial numbered St. Jude Medical 
Europe 
Investigational 
FlexNav™ Large 
Delivery System 
FN-DS-LG-IDE 
Serial numbered St. Jude Medical 
Europe 
Investigational 
FlexNav™ Small 
Loading System 
FN-LS-SM-IDE 
Serial numbered St. Jude Medical 
Europe 
Investigational 
FlexNav™ Large 
Loading System 
FN-LS-LG-IDE 
Serial numbered St. Jude Medical 
Europe 
Investigational 
Portico™ 23mm 
Valve 
PRT-23 
Serial numbered St. Jude Medical 
Europe 
Market Released 
Portico™ 25mm 
Valve 
PRT-25 
Serial numbered St. Jude Medical 
Europe 
Market Released 
Portico™ 27mm 
Valve 
PRT-27 
Serial numbered St. Jude Medical 
Europe 
Market Released 
Portico™ 29mm 
Valve 
PRT-29 
Serial numbered St. Jude Medical 
Europe 
Market Released 

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Detailed information regarding the investigational FlexNav™ Delivery System and FlexNav™ Loading 
System can be found in the Investigator Brochure.  
There is no change in the intended use of the FlexNav™ Delivery System and FlexNav™ Loading System 
compared to the first-generation Portico™ Delivery System and Loading System.  
Key design modifications that have been made to the FlexNav™ Delivery System are intended to reduce 
the profile of the catheter, improve deliverability, enhance deployment accuracy and promote overall ease 
of use.  
Key design features of the FlexNav™ Delivery System include:  
• 
Addition of an integrated sheath 
• 
Addition of a stability layer 
• 
Minor changes to the nosecone, inner/outer membrane assembly, retainer 
• 
Addition of a hydrophilic coating  
• 
Minor changes to the control handle 
 
These design modifications do not alter the procedure to load or deploy the Portico valve.  
 
Figure 1:Second-Generation FlexNav™ Delivery System 
Inner Member Assembly 
Outer Member Assembly 
Integrated Sheath 
Stability Layer 
Control Handle 

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Key design modifications that have been made to the FlexNav™ Loading System include: 
• 
Changes to the loading base (integrated guide tube) 
 
• 
Modified loading base insert (modified for inner ring diameter to fit the integrated guide tube).  
 
Figure 2 (below) shows the modified loading base and insert. These design modifications do not alter the 
procedure to compress and load the Portico™ valve onto the FlexNav™ Delivery System.  
 
 
 
 
Figure 2: Second-Generation FlexNav™ Loading System Base and Insert 
 Intended Indication for Use 
The FlexNav™ Delivery System is indicated for transcatheter delivery of the Portico™ valve. The delivery 
system is indicated for insertion into the vessel with or without an arterial introducer sheath.  
The FlexNav™ loading system is indicated for loading the Portico™ valve in the FlexNav™ delivery 
system. 
The Portico™ Transcatheter Heart Valve is indicated for transcatheter delivery in patients with 
symptomatic severe native aortic stenosis who are considered high or extreme surgical risk.  
The Portico™ Valve, FlexNav™ Delivery System and the FlexNav™ Loading System will be used in 
accordance with the Instructions for Use (IFU). Please refer to the SJM FlexNav™ Portico Transcatheter 
Aortic Valve Implantation System IFU (Number 600035013) for further details.  
 Description of the Device(s) Under Investigation 
Devices under investigational use in this clinical investigation include the FlexNav™ Delivery System(s) 
and the FlexNav™ Loading System(s).  
 
Second-Generation FlexNav™ Delivery System  
The second-generation FlexNav™ Delivery System (“FlexNav Delivery System”) is an over-the-wire, 
0.035”- compatible system that includes a hydrophilic-coated, integrated sheath to facilitate gradual, 
controlled deployment of the Portico™ valve in patients with a minimum vessel diameter of ≥5mm.  
The FlexNav™ Delivery System allows for transfemoral, subclavian/axillary or transaortic access methods 
with the current range of CE Marked Portico™ valves size (23, 25, 27 and 29mm) (Table 2). The FlexNav™ 
Delivery System has a working length of 107cm and is composed of a handle at the proximal end, 
connected to a shaft that is 13 French (F) at the proximal end and 18 F or 19 F at the distal end.  
Integrated guide tube 
Loading base insert 

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Table 2: FlexNav™ Delivery System Models and Compatibility with Portico™ Transcatheter Aortic Valve 
Sizes 
FlexNav 
Models  
Description 
Functional 
Length (CM) 
Minimum 
access vessel 
size 
French 
Size 
Compatible Portico 
Valve Size 
FN-DS-SM-IDE 
18 F Portico FlexNav 
Delivery System  
110 cm 
5mm 
18 F 
23mm - 25mm 
FN-DS-LG-IDE 
19 F Portico FlexNav 
Delivery System 
110 cm 
5.5mm 
19 F 
27mm - 29mm 
 
The FlexNav™ Delivery System shaft includes a stability layer over the outer member to improve control 
during positioning and deployment of the valve. The FlexNav™ Delivery System handle functions in a 
similar manner as the first-generation Portico™ Delivery system with modifications and added labeling. 
The macro slide that facilitates opening and closure of the delivery system has been moved and 
incorporated into the proximal end of the handle with two release buttons (Figure 3).   
 
 
Figure 3: Second-Generation FlexNav™ Delivery System Handle Detail 
 
The distal end of the FlexNav™ Delivery System features an atraumatic, radiopaque tip with hydrophilic 
coating and a radiopaque inner member marker band to aid in visualizing. The FlexNav™ Delivery System 
includes the same retainer design as the first-generation Portico™ Delivery System (Figure 4).  
 
 
Figure 4: Second-Generation FlexNav™ Delivery System (Proximal End) 
Deployment Indicator 
Valve Capsule Flush Port 
Deployment Lock Button 
Deployment/Re-sheath Wheel 
Macro Slide Release Buttons 
Micro-adjustment Wheel 
Stability Layer Flush Port 
Guidewire/Flush Port 

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As with the first-generation Portico™ Delivery system, the FlexNav™ Delivery Systems deploys the 
annulus end of the valve first to allow gradual deployment of the valve. The position of a partially deployed 
valve can be evaluated, and if needed, the valve can be re-sheathed and re-deployed, provided the valve 
has not been fully deployed from the delivery system. The partially deployed valve may be re-sheathed a 
maximum of two times. 
 
Summary of key design improvements to the FlexNav™ Delivery System: 
• 
Integrated sheath to allow sheathless insertion 
• 
Hydrophilic coating for smoother insertion and tracking to the target area  
• 
Stability Layer to improve valve handling and improve placement accuracy during deployment 
• 
Improved handle design to provide easier user operation 
 
 FlexNav Loading System  
The Portico FlexNav™ Loading System, like the current (first-generation) Portico™ Loading System is an 
accessory used to compress and load the Portico™ valve onto the FlexNav™ Delivery System.   
The FlexNav™ Loading System is identical in design and operation to the current Portico™ Loading 
System with changes to the loading base (integrated guide tube), and modified loading base insert 
(modified for inner ring diameter to fit the integrated guide tube). The integrated guide tube of the 
FlexNav™ Loading System eliminates the potential for the tip of the delivery system to interact with the 
valve leaflets during loading of the valve onto the delivery system. All other FlexNav™ Loading System 
components (loading funnel, loading tube, leaflet tester) are the same as the current system.  The method 
of loading the Portico™ valve onto the FlexNav™ Delivery System is also unchanged.  Figure 5 shows the 
individual components of FlexNav™ Loading System. The materials of construction for the FlexNav™ 
Loading System are identical to the current loading system components.   
The 18F FlexNav™ Loading System is used for loading the 23 or 25mm Portico™ valves on the 18F 
FlexNav™ Delivery System; the 19F FlexNav™ loading system is used for loading the 27 or 29mm 
Portico™ valves on the 19F FlexNav™ Delivery System.   
 
 
 
 
 
 
 
 
Figure 5: FlexNav™ Loading System  
1. Loading Funnel 
2. Base Insert 
3. Loading Base 
4. Loading Tube 
5. Leaflet Tester 

ABT-CIP-10260 Ver. [A] 
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 Summary of Preclinical Studies  
Refer to the Preclinical Studies section of the Investigational Brochure (IB) for summary of results.   
 Device Handling  
The Sponsor requires all investigational products to be stored according to the labeling and Instructions 
for Use (IFU) in a secure area to prevent unauthorized access or use. 
 
3 
CLINICAL INVESTIGATION DESIGN 
3.1 Purpose 
The purpose of this clinical investigation is to characterize the safety of the FlexNav™ Delivery System for 
transfemoral implantation of the Portico™ Transcatheter Aortic Heart Valve. Safety data collected as part 
of the study will be used to support CE Mark of the FlexNav™ Delivery System and Loading System in 
Europe.  
 
3.2 
Design Overview 
This CE Mark study is a prospective, multi-center, single-arm investigational study to support 
commercialization of the FlexNav™ Delivery System and Loading System in Europe. 
The design of this clinical investigation is in compliance to ISO standards 14155:2011 and 5840-3:2013.  
A maximum of 200 patients with symptomatic, severe AS considered by both a local Heart Team and 
independent Subject Selection Committee to be high or extreme risk for surgical aortic valve implantation 
will be enrolled from up to eight (8) experienced, high-volume TAVI implant centers in Europe.  Experienced 
implant centers are defined as those sites that have completed the commercial Portico implant training 
program and have at least one primary implanting physician that has performed 50 or more Portico 
implants within the previous 12 months. No investigational site may enroll more than 20% of the maximum 
study sample (n=40). 
To support CE Mark of the FlexNav™ Delivery System and Loading System, data from a minimum of 73 
subjects who undergo a Portico™ valve implant attempt will be included in a pre-specified primary safety 
endpoint analysis at 30 days. To achieve the minimum required sample size, prospective data from 
subjects enrolled in the FlexNav study of the Portico US IDE pivotal trial (“US IDE FlexNav study”) may be 
combined with FlexNav EU study subjects.   
Subject selection and key data collection in the FlexNav EU study will follow the US IDE FlexNav study to 
facilitate pooling of safety outcomes data at 30 days.  An independent Subject Selection Committee will 
be responsible for final approval of the subject’s eligibility and risk classification. Upon provision of informed 
consent, subjects will undergo Portico™ valve implantation via a transfemoral access approach according 
to the site’s anesthesia protocol for TAVR procedures (conscious sedation or general anesthesia).  
Subject enrollment in the FlexNav EU study will continue up to a maximum of 200 subjects, in order to 
allow implanters continued access to the FlexNav™ Delivery System while the results for the primary 
endpoint are collected, assessed and CE Mark submission is under BSI review (expected review duration 
of 9 months).  

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The total enrollment duration of the study is expected to be 10 months. Subject case report forms (CRFs) 
will be collected for screening, baseline, procedure, at discharge, and at 30 days, 6 months and 12-months 
post-index procedure. Assessments required at each visit in the FlexNav EU study are outlined in section 
3.3.   
3.3 Clinical Investigation Procedures and Follow-up Schedule 
The Flow Chart and the Follow-up requirements of this clinical investigation are described below. 
Subjects will be screened for study eligibility by the Investigator as well as the local Heart Team per the 
inclusion and exclusion criteria.  Subjects will then be reviewed by an independent Subject Selection 
Committee to confirm anatomical suitability and appropriateness of surgical risk classification assigned by 
the local Heart Team. 
If the Subject Selection Committee determine the subject’s anatomy precludes transfemoral implantation 
of the Portico™ valve using the FlexNav™ Delivery System the subject will be exited from the study as a 
screen failure. Additionally, if the Subject Selection Committee assign a surgical risk classification that the 
local Heart Team does not agree with, the subject will be exited from the study as a screen failure.  
For subjects approved by the Subject Selection Committee, clinical investigation visits will occur at 
baseline, implant procedure, discharge, 30 days, 6 months and 12 months post-implantation (Figure 6).  
It is strongly recommended the baseline visit be scheduled within 14 days of receiving Subject Selection 
Committee approval. 
Follow-up visits will be conducted in-person at the investigational site and will include a combination of 
standard of care and study-specific testing. If an in-office visit is not possible for a patient, medical records 
from another care facility and a phone visit may be conducted.  All enrolled subjects will be followed to 
their 12-month visit.  
At the conclusion of the 12-month follow-up visit, participation in the clinical investigation will end and 
subjects will be followed as part of standard of care.  
 
 
 
 
 
 
 
 

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Figure 6: Clinical Investigation Flow Chart 
 
3.4 Measures Taken to Avoid and Minimize Bias 
The study will include the following measures to minimize bias in the conduct of the study and analysis of 
clinical data: 
• 
Screening by an inter-disciplinary local Heart Team 
• 
Assessment of Anatomical Suitability by a Computed Tomography (CT) sizing Core Laboratory  
• 
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  
• 
Monitoring Follow-Up Compliance 
• 
Standardized Administration of Patient-Reported Outcomes Assessments 
Informed Consent/ 
Screening Visit
Independent Subject Selection Committee  
Eligibility Review
Baseline Visit
Portico Implant 
Attempt
Clinical Follow-Up 
Discharge Visit
30 Day Visit                    
(Primary Safety 
Endpoint)
6 Month Visit
12 Month Visit

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 Screening by an inter-disciplinary local Heart Team 
At each investigational site, a local 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 investigation. The Primary Investigator may serve the role 
of the cardiac surgeon or interventional cardiologist on the local heart team. 
 Assessment of Anatomical Suitability by a Computed Tomography (CT) sizing Core 
Laboratory  
An independent Computed Tomography (CT) Core Laboratory will be used for anatomical assessments 
of each patient prior to enrollment in the study (Refer to section  5.4 for definition of Subject Enrollment). 
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 (left or right) and valve size selection. 
Each investigational site is responsible for performing the CT scan according to the core laboratory 
imaging protocol. If the CT Core Laboratory determines that the data is unreadable, the site will be 
responsible for having the subject return for another assessment. 
 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 technical suitability (i.e. anatomical criteria) for 
implant in conjunction to the protocol and sizing recommendations provided in the IFU. SSC review and 
approval is required prior to scheduling a subject for a baseline visit. 
The same independent SSC responsible for reviewing patients in the Portico US IDE trial will be utilized 
for the current clinical investigation.   
The composition, guiding policies and operating procedures governing the SSC in this clinical investigation 
is further defined in a separate 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 or identified by Safety personnel in the clinical investigation as defined in 
the CEC Manual of Operations Charter. Events related to primary and descriptive endpoint criteria will be 
adjudicated according to the Valve Academic Research Consortium (VARC-2) definitions. The CEC will 
have final adjudication responsibilities for subject outcomes related to primary and descriptive outcome 
measures.  
The same CEC used in the Portico US IDE pivotal trial will be utilized for this clinical investigation. 
 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 at discharge as well as 30 days, 6 months and 12-months 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 not be responsible for notifying the site of any 
abnormal findings that are identified in the study. The responsibility of the core laboratory is to complete 
the data collection forms and submit these to the Sponsor. 
 Monitoring 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 trial, 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 trial conduct. 
Withdrawals from the trial will require discussion between Investigator and the Sponsor. 
 
 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.  
3.5 Suspension or Early Termination of the Clinical Investigation 
No formal statistical rule for early termination of the clinical investigation for insufficient safety or 
performance of the device under investigation is defined.  

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The Sponsor reserves the right to discontinue the clinical investigation at any stage or reduce the follow-
up period with suitable written notice to the investigator. Possible reason(s) may include, but are not limited 
to: 
• 
Unanticipated adverse device effect (e.g., UADE) occurs and it presents an unreasonable risk to 
the participating subjects 
• 
Steering committee makes a recommendation to stop or terminate the clinical investigation (such 
as higher frequency of anticipated adverse device effects) 
• 
Further product development is cancelled 
Should the clinical investigation be discontinued by the Sponsor, subjects will be followed per routine 
hospital practice with device-related AEs reported to the Sponsor as per vigilance/commercial reporting 
requirements. 
Should this occur, the investigator shall return all clinical investigation materials (including devices) to the 
Sponsor, and provide a written statement as to why the premature termination has taken place to the EC 
(if applicable). All applicable clinical investigation documents shall be subject to the same retention policy 
as detailed in [Section 11.5] of the CIP.  
A Principal Investigator, EC or regulatory authority may suspend or prematurely terminate participation in 
a clinical investigation at the investigational sites 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 investigation at an individual site in the 
interest of safety, the Sponsor will inform all other Principal Investigators. 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing resources 
to fulfill the obligations from the CIP and existing agreements for following the subjects enrolled in the 
clinical investigation, and the Principal Investigator or authorized designee will promptly inform the enrolled 
subjects at his/her site, if appropriate. 
4 
ENDPOINTS 
4.1 Primary Endpoint and Rationale  
The primary safety endpoint of the FlexNav EU study is VARC-2 defined major vascular complications at 
30 days post index procedure.   
According to VARC-2 criteria, a major vascular complication is defined as:  
• Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical 
aneurysm/pseudo-aneurysm or 
• Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-
venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, compartment syndrome, 
percutaneous closure device failure) leading to death, life-threatening or major bleeding*, visceral 
ischemia or neurological impairment or 
• Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in 
amputation or irreversible end-organ damage or 
• The use of unplanned endovascular or surgical intervention associated with death, major bleeding, 
visceral ischemia or neurological impairment or 

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• Any new ipsilateral lower extremity ischemia documented by patient symptoms, physical exam, 
and/or decreased or absent blood flow on lower extremity angiogram or 
• Surgery for access site-related nerve injury or 
• Permanent access site-related nerve injury 
 
The endpoint has been selected as key system modifications to the FlexNav™ Delivery System are 
expected to have a direct impact on the rate of access-site and access-related major vascular 
complications during transfemoral implantation of the Portico™ valve.    
Acceptable safety of the FlexNav™ Delivery System will be determined by comparing the estimate for 
VARC-2 defined major vascular complications at 30 days with data published in the literature. 
4.2 Descriptive Endpoint(s)  
A selection of descriptive endpoints including valve performance parameters, clinical function assessments 
and adverse events defined according to VARC 2 criteria will be assessed at 30 days and at 12 months 
as defined below. All descriptive endpoints will be summarized separately using descriptive statistics. 
Descriptive endpoints to be assessed at 30 days and included in the CE Mark submission: 
• Non-hierarchical composite of all-cause mortality, disabling stroke, life threatening bleeding 
requiring blood transfusion, acute kidney injury requiring dialysis, or major vascular 
complications at 30 days from the index procedure. 
• All-cause mortality at 30 days from the index procedure. 
• Disabling stroke at 30 days from the index procedure. 
• Non-disabling stroke at 30 days from the index procedure. 
• Life threatening bleeding requiring blood transfusion at 30 days from the index procedure. 
• Major bleeding at 30 days from the index procedure. 
• Acute kidney injury at 30 days from the index procedure. 
• Minor vascular complication rates at 30 days from the index procedure. 
• Permanent pacemaker insertion at 30 days from the index procedure. 
• Paravalvular Leak (PVL) at 30 days from the index procedure. 
• NYHA functional classification at 30 days from the index procedure. 
• KCCQ Quality of Life (QOL) score from baseline to 30 days from the index procedure. 
• Technical device success defined as successful vascular access, delivery and deployment of 
the Portico Valve; retrieval with the delivery system and correct positioning of a single valve in 
the proper anatomical location. 
 
Additional descriptive endpoints to be assessed at one year but not included in the CE Mark submission: 
• Composite of all-cause mortality or disabling stroke at one year from the index procedure.  
• All-cause mortality at one year from the index procedure. 
• Disabling stroke at one year from the index procedure. 

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• Non-disabling stroke at one year from the index procedure. 
• Paravalvular Leak (PVL) at one year from the index procedure. 
• KCCQ Quality of Life (QOL) score from baseline and one year from the index procedure. 
• NYHA functional classification at one year from the index procedure. 
 
 
5 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 Subject Population 
This clinical investigation will enroll male and female subjects from a valvular disease population who have 
symptomatic, severe AS and are determined to be at high or extreme operative risk for SAVR. 
Subjects must sign and date the informed consent prior to conducting 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 the Society of Thoracic Surgeons 
(STS) Adult Cardiac Surgery Risk Calculator score and the EuroSCORE II score.   
Subject case review will be conducted by the SSC to determine the patient’s anatomical eligibility to receive 
a Portico 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 ≥8%. 
Patients with an STS risk score that is <8% 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, severe mitral regurgitation, moderate-severe 
tricuspid regurgitation, diabetes, chronic kidney disease, chronic and 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 >8%, aged >90 years and with a frailty index≥2 will automatically 
qualify for extreme risk classification. 

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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 investigation, 
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 investigation-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, height) 
2. Medical History (including previous cardiovascular operations and events, coexisting 
cardiovascular diseases, clinically significant peripheral vascular disease, previous peripheral 
vascular operations, other coexisting medical conditions e.g., diabetes, hypertension, kidney and 
lung disease, endocarditis) 
 
3. Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
4. Surgical Risk Assessment tools (STS Risk Score and EuroSCORE II) 
5. Forced Expiratory Volume (FEV1) Test, if clinically indicated 
6. Physical Exam (including weight, heart rate, blood pressure)  
7. 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) 
8. Lab Measurements (including CBC and Platelet count, BUN and creatinine, BNP or ProBNP, and 
Albumin) 
9. 12 Lead Electrocardiogram (ECG) 
10. Computed Tomography Scan with Angiography for chest, abdomen and pelvis: aortic root and 
valve annulus sizing, assessment of suitability of iliofemoral 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. 
11. 3D Transesophageal Echocardiogram (TEE) if CT is contraindicated 
12. New York Heart Association (NYHA) Functional Classification 
13. Frailty Index Assessment (Katz index of Activates of Daily Living, Grip Strength, 5 meter walk test) 
14. 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. 
15. Adverse Event Assessment 
 
Subjects must be screened for clinical investigation eligibility by a member of the study site’s clinical 
investigation team (Principal Investigator and/or Research Coordinator) previously trained to the CIP, and 
if applicable will be entered into a site-specific screening log. 

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In case the subject does not meet all inclusion criteria or meets any of the exclusion criteria, the subject 
will be considered a screening failure. The Principal Investigator or the delegated clinical investigation 
personnel will record the screening failure in the hospital records and on a screening log as applicable. 
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 investigation. These patients will also be entered into 
the screening log.  
Providing Informed Consent is the first step in the enrollment process however the subject is not fully 
enrolled in the study until all enrollment steps are complete per protocol (see section 5.4). However, once 
the patient has provided Informed Consent, study-specific subject data will be collected in the clinical 
investigation. Screening tests that are specifically study-related and would generally not be considered 
standard of care in Europe include: 
• 
Frailty Index Assessment (Katz index of Activates of Daily Living, Grip Strength, 5 meter walk 
test) 
• 
Forced Expiratory Volume Test (if clinically required) 
• 
New York Heart Association (NYHA) Functional Classification 
• 
Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
 
Refer to APPENDIX VII for a description of the tests involved in the Frailty Index Assessment. 
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 60 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. 
Upon initial screening of eligibility of patients by the local Heart Team, subject case reviews will be 
conducted by an independent SSC to confirm a patient’s eligibility to transfemorally receive a Portico™ 
valve. 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 
enrollment in the study.   If the SSC does not approve the patient, they will be exited from the study as a 
screen failure.  
 Informed Consent 
The Investigator or his/her authorized designee will conduct the Informed Consent process, as required by 
applicable regulations and the center’s EC. This process will include a verbal discussion with the subject 
on all aspects of the clinical investigation that are relevant to the subject’s decision to participate, such as 
details of clinical investigation procedures, anticipated benefits, and potential risks of clinical investigation 
participation. Subjects must be informed about their right to withdraw from the clinical investigation at any 
time and for any reason without sanction, penalty or loss of benefits to which the subject is otherwise 
entitled. Withdrawal from the clinical investigation will not jeopardize their future medical care or 
relationship with the investigator.  
During the discussion, the Principal Investigator or his/her authorized designee will avoid any improper 
influence on the subject and will respect subject’s legal rights. 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 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 

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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 investigation-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. 
Failure to obtain informed consent from a subject prior to clinical investigation enrollment should be 
reported to Sponsor within 5 working days and to the reviewing center’s EC according to the EC’s reporting 
requirements. 
If, during the clinical investigation, new information becomes available that can significantly affect a 
subject's future health and medical care, the Principal Investigator or his/her authorized designee will 
provide this information to the subject. If relevant, the subject will be asked to confirm their continuing 
informed consent in writing. 
 
 Vulnerable Populations 
Vulnerable patients are defined as patients whose willingness to volunteer in a clinical investigation could 
be unduly influenced by the expectation, whether justified or not, of benefits associated with participation 
or of retaliatory response from senior members of a hierarchy in case of refusal to participate.  Examples 
of populations which may contain vulnerable patients include: Individuals with lack of or loss of autonomy 
due to immaturity or through mental disability, persons in nursing homes, children, impoverished persons, 
subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and those 
incapable of giving informed consent. Other vulnerable patients include, for example, members of a group 
with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, 
employees of the sponsor, members of the armed forces, and persons kept in detention.   
This clinical investigation will not permit enrollment of patients from vulnerable populations identified in ISO 
Standards 14155.  
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 investigation. If ANY of the exclusion criteria are met, the patient is 
excluded from the clinical investigation and cannot be enrolled. 
 Inclusion Criteria 
 Inclusion Criteria - High Risk Cohort 
 
Candidates for High Risk classification must meet all the following inclusion criteria: 
 
1. Subjects must have co‐morbidities such that the local heart team concur the predicted risk of 
operative mortality is ≥15% or a minimum STS score of 8%.  
 

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A candidate who does not meet the STS score criteria of ≥ 8% may be included in the study if at 
least one surgeon in the local heart team concludes and documents the patient’s predicted risk of 
operative mortality is ≥15%. The surgeon's assessment of operative comorbidities (including frailty 
indices) not captured by the STS score must be documented in the study case report form as well 
as in the patient medical record. 
 
2. Subject is of legal age or older for consent in the host country. 
 
3. Subject has senile degenerative aortic valve stenosis with echo-derived criteria: mean gradient >40 
mmHg or jet velocity greater than 4.0 m/s or doppler velocity index (DVI) <0.25 and an initial aortic 
valve area (AVA) of ≤ 1.0 cm2 (indexed EOA ≤ 0.6 cm2/m2). (Qualifying AVA baseline 
measurement must be within 60 days prior to informed consent). 
 
4. Subject has symptomatic aortic stenosis as demonstrated by NYHA Functional Classification of II, 
III, or IV. 
 
5. 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 Ethics Committee (EC) of the respective clinical site. 
 
6. The subject and the treating physician agree that the subject will return for all required post‐
procedure follow‐up visits. 
 
7. Subject’s aortic annulus is 19‐27mm diameter 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 echo and non‐contrast CT of chest and abdomen/pelvis may be accepted.  
 
 Inclusion Criteria - Extreme Risk Cohort: 
 
All candidates for Extreme Risk classification must meet # 2, 3, 4, 5, 6, 7 of the above criteria, and  
 
1. After formal consultation with the local heart team (including at least one surgeon) it is agreed that 
medical factors preclude the subject from undergoing operation, based on a conclusion that the 
probability of death or serious, irreversible morbidity exceeds the probability of meaningful 
improvement. Specifically, the probability of death or serious, irreversible morbidity should exceed 
50%. The local heart teams' consult notes shall specify the medical or anatomic factors leading to 
that conclusion and include a printout of the calculation of the STS score to additionally identify the 
risks in these patients. 
 
 Exclusion Criteria - High and Extreme Risk Cohort 
 
Candidates will be excluded if any of the following conditions are present: 
 
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. Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is non-calcified as verified by 
echocardiography. 
 
3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic 
regurgitation 3-4+). 
 

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4. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior 
to index procedure. 
 
5. 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 LVOT, 
severe (greater than 3+) mitral insufficiency, or severe mitral stenosis with pulmonary compromise.  
 
6. Blood dyscrasias as defined: leukopenia (WBC<3000 mm3), acute anemia (Hb < 9 g/dL), 
thrombocytopenia (platelet count <50,000 cells/mm³).  
 
7. History of bleeding diathesis or coagulopathy. 
 
8. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support. 
 
9. Untreated clinically significant coronary artery disease requiring revascularization. 
 
10. Hemodynamic instability requiring inotropic support or mechanical heart assistance. 
 
11. Need for emergency surgery for any reason. 
 
12. Hypertrophic cardiomyopathy with or without obstruction (HOCM). 
 
13. Severe ventricular dysfunction with LVEF <20% as measured by resting echocardiogram. 
 
14. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. 
 
15. Active peptic ulcer or upper GI bleeding within 3 months prior to index procedure. 
 
16. A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine (Ticlid), or clopidogrel 
(Plavix), or sensitivity to contrast media which cannot be adequately premedicated. 
 
17. Recent (within 6 months prior to index procedure date) cerebrovascular accident (CVA) or a 
transient ischemic attack (TIA). 
 
18. Renal insufficiency (creatinine > 3.0 mg/dL) and/or end stage renal disease requiring chronic 
dialysis. 
 
19. Life expectancy < 12 months from the time of informed consent due to non-cardiac co-morbid 
conditions. 
 
20. Significant aortic disease, including abdominal aortic or thoracic aneurysm defined as maximal 
luminal diameter 5cm or greater; marked tortuosity (hyper acute 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.  
 
21. Native aortic annulus size < 19 mm or > 27 mm per the baseline diagnostic imaging. 
 
22. Aortic root angulation > 70°. 
 
23. Currently participating in an investigational drug or device study. 
 
24. Active bacterial endocarditis within 6 months prior to the index procedure. 
 
25. Bulky calcified aortic valve leaflets in close proximity to coronary ostia. 
 
26. Non-calcified aortic annulus. 
 

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27. 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, or 
severe tortuosity. 
 
28. In the judgment of the investigator, a condition that could limit a patient’s 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  
5.4 Subject Enrollment 
A patient will be considered enrolled in the study after completion of all of the following steps:  
1. Signed informed consent is obtained. 
2. Based on the screening assessments, it is determined that the subject meets all of the inclusion 
and none of the exclusion criteria. 
3. Subject is approved by the Subject Selection Committee. 
4. Portico implant attempt defined as insertion of the FlexNav™ Delivery System into the subject’s 
vasculature. 
The following terms will be used to describe potential study subjects: 
• 
Screen Failure: Consented subjects who undergo study-specific testing and are found to have met 
exclusion criteria or not all inclusion criteria. Additionally, if a site disagrees with the Subject 
Selection Committee’s final decision regarding risk classification the subject will not be eligible for 
enrollment in the study and will be considered a screen failure.   
• 
Pre-procedural Exclusion: Consented subjects who undergo study-specific testing and meet 
study criteria but do not undergo a Portico implant attempt will not be considered enrolled and will 
be exited from the study without further follow up.   
• 
Enrolled: These subjects will be considered enrolled in the study and will fall into one of the 
following categories: 
o Attempted-to-Treat: Subjects who undergo a Portico implant attempt but do not have 
a Portico valve implanted will be followed for 30 days post procedure for adverse events 
and then formally withdrawn from the study 
o Implanted: Subjects who have a Portico valve implanted will be followed according to 
the clinical investigation and will be included in the analysis population.  
o CIP Deviations: Subjects who have a Portico valve implanted and are later found to 
have met exclusion criteria or not all inclusion criteria.  These subjects will be followed 
according to the clinical investigation and will be included in the analysis population. 
Notification of enrollment to the Sponsor is considered to have occurred when the Sponsor has received 
the applicable CRF (Procedure Form). 
To ensure enrollment balance across study sites, no investigational site will be permitted to enroll more 
than 20% of the analysis population. 
5.5 Subject Withdrawal 
Each enrolled study subject shall remain in the clinical investigation until completion of the required follow-
up period; however, a subject’s participation in any clinical investigation is voluntary and the subject has 

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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 3.5]. 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will provide this 
information to the Sponsor. Investigators must also report this to their respective 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 
investigation, except for the status (deceased/alive if subject agrees). 
However, if a subject withdraws from the investigation due to problems related to the safety or performance 
of the device under investigation, the investigator shall ask for the subject's permission to follow his/her 
status/condition outside of the clinical investigation. 
 Lost-to-Follow-up 
If the subject misses two consecutive scheduled follow-up time points and the attempts at contacting the 
subject detailed below are unsuccessful, then the subject is considered lost-to-follow-up. Site personnel 
shall make all reasonable efforts to locate and communicate with the subject (and document these efforts 
in the source documents), including the following, at each contact time point: 
• 
A minimum of two telephone calls on different days over the specified follow-up windows to contact 
the subject should be recorded in the source documentation, including date, time and initials of site 
personnel trying to make contact. 
• 
If these attempts are unsuccessful, 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 investigation cardiologist or relative without 
the presence of the subject or indirect documentation obtained via discharge letters will not be considered 
as subject contact. 
5.6 Total Expected Duration of the Clinical Investigation 
The total expected duration of the clinical investigation is approximately 2.5 years, consisting of 10 months 
of enrollment plus 12-months of follow-up and 6-8 months for results reporting and study closure activities. 
All enrolled subjects will be followed until their 12-month 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. 
5.7 Expected Duration of Each Subject’s Participation 
The expected duration of each subject’s participation in the clinical investigation is 12 months.  

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5.8 Number of Subjects  
Up to 200 subjects will be enrolled in the clinical investigation, with a predefined minimum of 73 subjects 
required to analyze the primary safety endpoint.  No site may enroll more than 20% of the maximum 
number of enrolled subjects (n=40). 
5.9 Estimated Time Needed to Select Required Number of Subjects 
The expected duration of enrollment for a maximum of 200 subjects is 10 months.  
6 
TREATMENT AND EVALUATION OF ENDPOINTS 
For patients that have successfully completed screening and been approved by the SSC, scheduled 
visits will be performed in the following order: Baseline, Index Procedure, Discharge, 30-day, 6 months 
and 12 months.  A description of study-specific assessments to be performed at the scheduled visits is 
provided in APPENDIX IV. 
6.1 Baseline Assessments 
 Baseline Laboratory and Clinical Tests 
Patients who are deemed eligible for transfemoral implantation of a Portico™ valve using the FlexNav™ 
Delivery System will undergo a baseline visit within 14 days of the scheduled implant procedure (may occur 
on the day of, but prior to the implant procedure). 
The following baseline data will be collected for all subjects prior to the index procedure. 
1. Chest X-ray  
 
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, EQ-5D and KCCQ) 
 
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/Anticoagulation Medications  
Antiplatelet/Anticoagulation and other medications should be administered pre-procedure per the standard 
of care at the investigational site. 
 Pre-Procedure Blood Test 
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 
 Procedure Involved in the Use of the Investigational Devices  
Please refer to IFU for instructions on handling and preparation of the FlexNav™ Delivery System, 
FlexNav™ Loading System and Portico™ valve. All Investigators must read and understand the IFU and 
Investigator Brochure. 
 Anticoagulation Therapy 
Anticoagulation use during the procedure is left to the physician’s discretion or should be established as 
with any other biological 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. 
 Treatment Procedures  
The local heart team's interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the 
intra-operative technical aspects of the TAVR procedure. 
It is strongly encouraged that the index procedure occur within 14 calendar days following SSC approval. 
At least one transcatheter aortic valve may be implanted in a subject who has signed the Informed Consent 
Form, and Data Protection Form (if applicable). 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 (Valve-in-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 wedge pressure (PCWP) immediately pre- and post implant 
4. Cardiac Rhythm Monitoring 
Rhythm changes will be monitored and recorded at the following time points: 

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a) Upon crossing native valve with the guidewire 
b) Upon positioning of the guidewire 
c) Prior to valvuloplasty (if performed) 
d) Immediately post valvuloplasty (if performed)  
e) Before valve crosses the AV valve 
f) After valve crosses the annulus 
g) After valve is deployed in final position  
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 XVIII for a description of standardized methods for measuring aortic 
regurgitation according to VARC II criteria and instructions for assessing implant depth in the LVOT.  
During the procedure, the implanting physician may determine implantation of the Portico™ 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 not be considered enrolled. Refer to Section 5.4 Subject 
Enrollment. 
If the implant procedure was attempted (i.e. the FlexNav™ Delivery System was introduced into subject’s 
vasculature) but the Portico™ valve could not be implanted (e.g. Portico 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. 
Sponsor Representatives will be involved in providing support during the implant procedure. 
Following the procedure, the FlexNav™ Delivery and Loading Systems should be securely disposed as 
per hospital requirements for hazardous materials. If there are any concerns noted with the FlexNav™ 
Delivery System, FlexNav™ Loading System, or Portico™ valve during the procedure, they should be 
returned to the Sponsor for evaluation per the instructions provided in  
 

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APPENDIX XIX and APPENDIX XX.  
 Final (Post-procedure) Imaging  
Subjects implanted with a transcatheter aortic valve (Portico™ valve or other commercially- available 
valve) will be required to undergo an echocardiogram within 48 hours of the procedure.  
6.3 Post–procedure (In-hospital) 
 Post-procedure Laboratory and Clinical Tests  
The following laboratory tests should be performed in-hospital post-implant procedure:  
1. Troponin, or CK / CK-MB should be collected within approximately 12-24 hours after procedure, 
approximately 24 hours thereafter, 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 Plan 
The discharge visit will take place at the time of hospital discharge or up to 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. Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
 
3. Modified Rankin Scale (mRS) 
 
4. NIH Stroke Scale (NIHSS) 
 
5. Barthel Index 
 
6. Echocardiogram (if not performed during the post procedure testing within 48 hours after 
procedure) 
 
7. 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) 
 
8. Cardiovascular medications documentation 
 
9. Adverse events assessment 
 
10. 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) 
 

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6.5 
Follow Up Visits 
 Follow-up Medications  
Medications administered to subjects during the follow-up period will at the physician’s discretion and 
should be prescribed according to current guidelines and standard of care.  
 Follow-up for All Enrolled Subjects  
Required clinical follow-up will be performed at the following intervals for all subjects who underwent a 
Portico implant attempt and were implanted with a Portico™ valve: 
 • 30 days (-7 days/ +21 days) follow-up site visit (visit must be conducted even if subject is in hospital) 
• 6 months (180 days ± 30 days) follow up site visit 
• 12 months (365 days -30 days, +45 days) follow up site visit 
 
Subjects with a Portico implant attempt that did not have a Portico™ valve implanted will only be required 
to complete the 30 day follow up visit.   
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, whenever 
possible, by the same individual who performed the baseline tests.   
 
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.  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.  Protocol deviations 
will be required for all missed testing.  
 
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. 
 
 30 Day Follow-Up 
The 30-day follow-up visit will take place 30 days (-7/+21 days) post-index procedure, and will include the 
following assessments: 
1. Physical exam (weight, heart rate, blood pressure) 
2. Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
3. Modified Rankin Scale (mRS) 

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4. NIH Stroke Scale (NIHSS) 
5. Barthel Index 
6. Echocardiography  
7. 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) 
8. 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) 
9. NYHA Functional Classification 
10. Frailty Index Assessment (Katz Index of Activities of Daily Living, Grip Strength, 5 meter walk 
test) 
11. Quality of Life Measures (SF-36, EQ-5D and KCCQ) 
12. MMSE-2:SV 
13. Six Minute Walk Test (6MWT)  
14. Cardiovascular medications documentation 
15. Adverse events assessment 
 
 6 Month Follow-Up 
The 6-month follow-up visit will take place at 6 months (±30 days) post-index procedure, and will include 
the following assessments: 
1. Physical exam 
2. Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
3. Modified Rankin Scale (mRS) 
5. NIH Stroke Scale (NIHSS) 
6. Barthel Index 
7. Echocardiography  
8. 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) 
9. 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) 
10. NYHA Functional Classification  
11. Frailty Index Assessment (Katz Index of Activities of Daily Living, Grip Strength, 5 meter walk 
test) 
12. Quality of Life Measures (SF-36, EQ-5D and KCCQ) 
13. MMSE-2:SV 

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14. Six Minute Walk Test (6MWT)  
15. Cardiovascular medications documentation 
16. Adverse events assessment 
 
 12-Month Follow-Up 
The 12-month follow-up visit will take place at 12 months (-30 days, +45 days) post-index procedure, and 
will include the following assessments: 
1. Physical exam (weight, heart rate, blood pressure) 
2. Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
3. Modified Rankin Scale (mRS) 
4. NIH Stroke Scale (NIHSS) 
5. Barthel Index 
6. Echocardiography  
7. 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) 
8. 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) 
9. NYHA Functional Classification  
10. Frailty Index Assessment (Katz Index of Activities of Daily Living, Grip Strength, 5 meter walk 
test) 
11. Quality of Life Measures (SF-36, EQ-5D and KCCQ)  
12. MMSE-2:SV 
13. Six Minute Walk Test (6MWT)  
14. Cardiovascular medications documentation 
15. Adverse events assessment 
 Unscheduled Follow-up  
 Unscheduled Follow-Up Visits for Evaluation of Suspected Neurological Event 
If the subject experiences a neurological event (trans-ischemic attack (TIA), stroke, or encephalopathy), 
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 

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Refer to APPENDIX XV for a copy of the Modified Rank Score and APPENDIX XVI for a copy of the NIH 
Stroke Scale.  
 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 investigation: 
• 
EuroQoL (EQ) 5D-3L Questionnaire 
• 
SF-36 
• 
KCCQ 
• 
Mini-Mental State Examination (MMSE-2) 
• 
Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
 
• 
New York Heart Association Functional Classification  
 
• 
Barthel Index 
Refer to APPENDIX VIII-XIV for copies of the exact format and version of PRO measures that will be 
administered as part of the clinical investigation 
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. 
 EQ-5D-3L questionnaire 
The EuroQol 5D 3 level version (EQ-5D-3L) questionnaire is a standardized instrument used as a measure 
of health outcome and quality of life. The self-administered questionnaire consists of two pages: the EQ-
5D descriptive system and the EQ visual analogue scale (EQ VAS). The questionnaire is cognitively simple 
and takes only a few minutes to complete. The EQ-5D-3L descriptive system comprises the following five 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension 
has three levels: no problems, some problems, extreme problems. The EQ VAS records the respondent’s 
self-rated health on a 20cm vertical, visual analogue scale where the endpoints are labelled ‘100 =Best 
imaginable health state’ and ‘0=Worst imaginable health state’. This information can be used as a 
quantitative measure of health outcome as judged by the individual respondents. An EQ-5D health state 
may be converted to a single summary index by applying a formula that attaches weights to each of the 
levels in each dimension.  Refer to APPENDIX X for the sample questionnaire. 
 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.  

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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 XI for the sample questionnaire. 
 Kanas City Cardiomyopathy Questionnaire (KCCQ) 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, validated, self-administered 
instrument that quantifies physical function, symptoms (frequency, severity and recent change), social 
function, self-efficacy and knowledge, and quality of life in patients with congestive heart failure or 
weakened heart muscle due to prior heart attacks, heart valve problems, viral infections, or other causes. 
The KCCQ evaluates eight (8) clinically relevant domains including: physical limitations, symptoms 
(frequency and severity), change over time, self-efficacy and knowledge, social function and quality of life. 
The questionnaire requires, on average, 4–6 minutes to complete. The KCCQ is scored by assigning each 
response an ordinal value, beginning with 1 for the response that implies the lowest level of functioning 
and summing items within each domain. Missing values within each domain are assigned the average of 
the answered items within that same domain. Scale scores are transformed to a 0 to 100 range by 
subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. To 
facilitate interpretability, two summary scores were developed; functional status score and a clinical 
summary score where higher scores reflect better health status. Refer to APPENDIX XII for the sample 
questionnaire. 
 Mini-Mental State Examination 
The Mini Mental State Examination (MMSE) is a validated, 11-question tool used to assess mental status. 
The MMSE 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 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 XIII for the sample questionnaire. 
 Canadian Cardiovascular Society (CCS) Angina Scale Assessment 
The Canadian Cardiovascular Society angina grading scale (CCS Angina Scale) is a widely used, self-
administered four-point ordinal scale that classifies angina pectoris from mild (class I: angina occurring 
only during strenuous or prolonged physical activity) to severe (class IV: inability to perform any activity 
without angina, or angina at rest) and includes the full spectrum of angina from chronic stable to unstable. 
The assessment takes approximately 1-2 minutes to complete. Refer to APPENDIX IX 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 

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limited during physical activity; the limitations/symptoms are in regard to normal breathing and varying 
degrees in shortness of breath and/or angina. The NHYA 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 VIII 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 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 
XIV for the sample questionnaire. 

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 Schedule of Events 
Table 3 provides a tabulated schedule of the study-required activities and standard of care data collection in the clinical investigation.  
 
Table 3: Study-related assessments and data collection schedule 
CIP Activity 
Screening 
 
Baseline 
Procedure 
 
Discharge 
 
30 days 
[-7/+21 
days] 
6 months 
[± 30 
days] 
12 
months1 
[-30, +45 
days] 
Subject Interview and Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
X 
X 
X 
X 
CCS Status of Angina Scale 
X 
 
 
 
X 
X 
X 
X 
NYHA Classification 
X 
 
 
 
 
X 
X 
X 
Cardiovascular Medications documentation 
 
 
X 
 
X 
X 
X 
X 
Coronary and Aortic Angiogram (with runoff if 
clinically indicated) 
X (within 12 months 
prior to consent) 
 
 
National Institute of Health Stroke Scale (NIHSS) 
 
 
X 
 
X 
X 
X 
X 
Modified Rankin Scale (mRS) 
 
 
X 
 
X 
X 
X 
X 
Barthel Index 
 
 
X 
 
X 
X 
X 
X 
Mini Mental State Exam (MMSE-2:SV) 
 
 
X 
 
 
X 
X 
X 
Neurological Assessment 
 
A neurological assessment must be performed at 90 days (±14 days) from the date of a 
suspected neurological event 
Surgical Risk Assessment (STS, EuroSCORE II) 
X 
 
 
Six Minute Walk Test (6MWT) 
 
 
X 
 
 
X 
X 
X 
Frailty Index (Katz Index of ADLs, Grip strength, 5 
meter walk test) 
X 
 
 
 
 
X 
X 
X 
FEV1 
X (if clinically 
indicated) 
 
 
Non-Invasive Tests 
 
 
12 lead Electrocardiogram (ECG)2 
X 
 
 
 
X 
X 
X 
X 
Cardiac rhythm monitoring 
 
 
 
X 
 
 
 
 
Echocardiogram  
X 
 
 
X (optional 
data 
collection) 
X3 
X 
X 
X 

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1 In the event a 12 month visit per the requirements in the clinical investigational plan is not completed, the site may call the subject to document survival. 
2For subjects receiving a new permanent pacemaker, ECG should be completed showing the underlying rhythm as well as the current pacing programming. 
3To be done within 24-48 hours after procedure, or as close to discharge as possible (but no more than 7 days after procedure). 
4If CT is contraindicated and/or not possible to be obtained for certain subjects, a 3D TEE and non-contrast CT of chest and abdomen/pelvis may be accepted if approved by the subject 
selection committee.  
5To be collected within 72 hours before index procedure and within 72 hours after index procedure 
6 To be collected within 72 hours before index procedure and within 12-24 hours after the procedure, approximately 24 hours thereafter, and at approximately 72 hours (or at discharge, if 
patient is discharged prior to 72 hours post procedure) to be consistent with VARC II guidelines. 
7 Subjects may take other anticoagulants/vitamin K antagonists in lieu of warfarin 
(X) indicates “if applicable” 
 
Angiogram 
 
                      X (optional  
                          data collection) 
3D Transesophageal Echocardiogram (TEE) 
X4 (if CT is 
contraindicated) TEE 
is also recommended 
after adverse events 
of ischemic stroke 
and myocardial 
infarction. 
 
 
CT Scan with Angiography for chest, abdomen 
and pelvis 
X (within 12 months 
of consent) 
 
 
Chest X-Ray 
 
 
X 
 
 
 
 
 
Quality of Life Measures 
SF-36 
 
 
X 
 
 
X 
X 
X 
EQ-5D 
 
 
X 
 
 
X 
X 
X 
KCCQ 
 
 
X 
 
 
X 
X 
X 
Lab Measurements 
CBC and Platelet count 
X 
 
 
 
X 
X 
X 
X 
BUN and Creatinine 
X 
 
 
X5 
X 
X 
X 
X 
BNP or ProBNP 
X 
 
 
 
 
X 
X 
X 
INR (if subject is on Coumadin or Warfarin7) 
 
 
X 
 
 
X 
X 
X 
Troponin or CK / CK-MB 
 
 
X 
X6 
(X) 
X 
X 
X 
Albumin (for Frailty Index) 
X 
 
 
 
 
X 
X 
X 
Other 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
X 
 
X 
X 
X 
X 
X 
X 
Deviation 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Device Deficiency 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Withdrawal 
 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Death 
(X) 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 

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6.6 Requirement for Core Laboratories 
Independent core laboratories used in the Portico US IDE pivotal trial will be utilized for evaluating CT 
images and echocardiograms in the clinical investigation. Contact details for the CT and echocardiographic 
core laboratories are included in APPENDIX XXII.  
CT scan and echo exams will be forwarded to the respective core laboratories for interpretation by each 
investigational site. The core laboratories will not be responsible for notifying the site of any abnormal 
findings that are identified in the study.  
The core laboratories will provide the study required interpretation and documentation of each data 
submission according to Standard Operating Procedures. 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 only 
the measurements provided by the core laboratories in data analyses. If the core laboratory determines 
that the data are 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 investigation adverse event reporting, the 
Sponsor has adopted uniform and worldwide applicable standard definitions and reporting timelines to be 
used and adhered to by the investigators.  
7.1 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, whether or not 
related to the medical device under investigation. 
 
Note 1: This definition includes events related to the medical device under investigation. 
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 medical devices under 
investigation. 
 Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
 
a) Led to a death 
b) Led to a serious deterioration in health of the subject, that either resulted in  
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalization or prolongation of existing hospitalization, or 

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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  
c) Led to fetal distress, fetal death or a congenital abnormality 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 to be an SAE. 
 
 Device Deficiency  
Device deficiency is defined as an inadequacy of a medical device related to its identity, quality, durability, 
reliability, safety or performance, such as malfunction, misuse or use error and inadequate labeling. This 
includes the failure of the device to meet its performance specifications or otherwise perform as intended.  
Note: Performance specifications include all claims made in the labeling of the device. 
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 (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. 
7.3 Adverse Event and Device Deficiency Reporting 
 Adverse Event Reporting 
Safety surveillance and reporting starts as soon as the patient is consented into the clinical investigation. 
Safety surveillance and reporting will continue until the last 12-month follow-up visit has been performed, 
the subject is deceased, the subject concludes participation in the clinical investigation or the subject 
withdraws from the clinical investigation. All 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.  
 
Adverse event reporting will include: 
 

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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. Device deficiencies, that could have led to a serious adverse device effect 
• 
if either suitable action had not been taken 
• 
if intervention had not been made or 
• 
if circumstances had been less fortunate 
 
 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. 
 
The date the study 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 EC according to the institution’s EC 
reporting requirements. 
 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC  
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 EC per EC 
requirements.  
 Device Deficiency  
All device deficiencies should be reported on the appropriate CRF form. 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 EC per the investigative site’s local requirements. 

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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 and/or randomization number 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. 
For investigational sites in Germany, clinical investigation SAEs and device deficiencies reportable per 
MedDEV 2.7/3 regulations will be submitted to European Competent Authorities by the Sponsor’s Clinical 
Safety Group. Contact details are provided in APPENDIX XVII].  
8 
STATISTICAL CONSIDERATIONS 
The following section describes the statistical methods for the clinical investigation. Additional details on 
statistical analyses, including justification of clinical investigation design, poolability analyses, handling of 
missing data and analysis of descriptive endpoints will be maintained in a separate Statistical Analysis 
Plan (SAP). 
8.1 Analysis Populations 
The analysis population will include all subjects in whom a Portico implant is attempted. A Portico implant 
attempt is defined as insertion of the FlexNav™ Delivery System into the subject’s vasculature. 
8.2 Statistical Analyses  
 Primary Safety Endpoint Analyses 
The primary safety endpoint of the FlexNav EU study is VARC II defined major vascular complications at 
30 days post index procedure. 
 
 Analysis Methodology 
The proportion of subjects experiencing a primary endpoint will be estimated from the binomial model. The 
95% upper confidence bound will be calculated using the exact binomial method.  The estimate will be 
descriptively compared with published data for the Portico valve using the first-generation Portico delivery 
system and commercially-available valves. 
 
 Analysis Population for Primary Safety Endpoint 
The analysis population will include subjects who undergo an implant attempt that is described in Section 
8.1 

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8.3 Sample Size Calculation and Assumptions 
The minimum sample size of 73 subjects is based on the desire to estimate the rate of major vascular 
complications at 30-days with a sufficient degree of precision so that the 95% upper confidence limit will 
be within the range of rates reported in other Portico studies and for commercially-available transcatheter 
valves.  
 
As reported in the Portico CE Mark study (NCT01493284) and the Portico I Post-Market Clinical Follow-
Up study (NCT01802788), the rate of major vascular complications at 30 days for subjects undergoing 
transfemoral Portico valve implantation using the first-generation Delivery System was 7.2%13 and 5.5%17 
respectively. In the CoreValve Evolut R US pivotal study (NCT02207569), access-site related major 
vascular complications at 30 days was reported to be 7.5% (includes transfemoral and alternative 
access).18 
 
Assuming an event rate of 7% at 30 days with the FlexNav™ Delivery System, a sample size of 69 subjects 
will produce a two-sided 95% confidence interval with a width equal to 13.5% (i.e. upper confidence limit 
of 15.8%). Accounting for an attrition rate of 5%, a minimum of 73 subjects will be required to undergo a 
Portico implant attempt with the FlexNav™ Delivery System. The expected upper confidence limit of 15.8% 
falls within the reported range for major vascular complications at 30 days (5% to 23.3%) in a weighted 
meta-analysis of 3519 patients from 16 TAVI studies.19     
8.4 Timing of Analysis 
The analysis to support CE Mark approval of the FlexNav™ Delivery System and Loading System in 
Europe will be conducted on a dataset locked after 73 attempted subjects have had 30-day study visit 
excepting deaths, withdrawals and loss-to-follow-up before 30 days or crossed the 30-day visit window 
without a visit (missed visit). 
8.5 Subgroup Analysis 
No subgroup analyses are planned for this clinical investigation.   
8.6 Multiplicity 
There is one primary endpoint with no hypothesis testing. Therefore, there are no multiplicity issues 
associated with multiple primary endpoints and multiple treatment comparisons. 
8.7 Pooling Strategy  
Additional information regarding the planned pooling strategy in this clinical investigation will be maintained 
in a separate Statistical Analysis Plan (SAP). 
                                               
17 Maisano F. Late-Breaking Session: Real-world Experience Using the Portico™ Transcatheter Aortic Valve: 30-day outcomes 
in 973 patients enrolled in the Portico I Study (Cohort A). May 22, 2018. EuroPCR Paris, France. 
18 Popma J, Reardon M, Khabbaz K et al.  Early clinical outcomes after transcatheter aortic valve replacement using a novel 
self-expanding bioprosthesis in patients with severe aortic stenosis who are suboptimal for surgery; Results of the Evolut R 
U.S. Study. J Am Coll Cardiol Intv 2017; 10:268-75 
19 Genereux P, Head S, Van Mieghem N, et al.  Clinical Outcomes After Transcatheter Aortic Valve Replacement Using Valve 
Academic Research Consortium Definitions: A Weighted Meta-Analysis of 3,519 Patients from 16 Studies. J Am Coll Cardiol 
2012;59:2317-2326 

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8.8 Procedures for Accounting for Missing Data 
There is no plan to impute missing data for this clinical investigation.  
8.9 Planned Interim Analysis 
No interim analyses are planned for this study. 
8.10 Statistical Criteria for Termination 
There are no statistical criteria for termination of this clinical investigation. 
8.11 Success Criteria 
The clinical investigation has a single primary safety endpoint without any formal hypothesis testing. The 
safety results will be compared with published data for the Portico valve using the first-generation Portico 
delivery system and commercially-available valves. 
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 investigation-related monitoring, audits, EC review and regulatory inspections. 
Subjects providing informed consent are agreeing to allow clinical investigation monitors or regulatory 
authorities to review, in confidence, any records identifying the subjects in this clinical investigation. 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 
investigation. Sites will be selected based upon review of a recent site assessment, if applicable, and the 
qualifications of the investigators who will participate in the clinical investigation. 
10.2 Clinical Investigation Finances and Agreements 
The clinical investigation will be financed by Abbott.  Investigational sites will be compensated by Abbott 
for participation in the clinical investigation per the conditions of agreement between the Sponsor and the 
Investigational site.  

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10.3 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 EC or equivalent committee of the 
CIP amendment (administrative changes) or obtaining EC’s approval of the CIP amendment (changes in 
subject care or safety), according to the instructions provided by the Sponsor with the CIP amendment.   
Acknowledgement/approval by the 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. 
10.4 Training 
 Site Training 
All Investigators and clinical investigation personnel are required to attend Sponsor training sessions, 
which may be conducted at an Investigator's meeting, a site initiation visit or other appropriate training 
sessions. Over-the-phone or self-training may take place as required. Training of Investigators and clinical 
investigation personnel will include, but is not limited to, the CIP requirements, investigational device 
usage, electronic case report form completion and clinical investigation personnel responsibilities. All 
Investigators and clinical investigation personnel that are trained must sign a training log (or an equivalent) 
upon completion of the training. Prior to signing the training log, Investigators and clinical investigation 
personnel must not perform any CIP-related activities that are not considered standard of care at the site.  
 Training Required for the Use of the FlexNav™ Delivery System 
 
Training on the FlexNav™ Delivery System will be conducted with all implanting physicians prior to their 
first case. Training will be performed in-person and will require physicians to complete both a didactic and 
simulated- training component. The didactic component will include a detailed overview of the new delivery 
system features, associated procedural steps for using the FlexNav™ Delivery System via a transfemoral 
access route and review of optimal Portico valve implant techniques. The simulated-training component 
will require physicians to deploy the Portico valve with the new delivery system via a transfemoral approach 
using a bench top model. A minimum of two successful deployments with the bench top model using either 
the 18F or 19F delivery system will be required. 
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.  
Training will be valid for 60 calendar days only. If a physician does not implant a Portico value using the 
FlexNav™ Delivery System within 60 calendar days of initial training they will be required to undergo a 
review of the FlexNav™ Delivery System and implant procedure with an Abbott Field Clinical Procedural 
Specialist or commercial training personnel prior to use (Benchtop deployments optional). 
10.5 Monitoring  
Sponsor and/or designee will monitor the clinical investigation over its duration according to the CIP-
specific monitoring plan which will include the planned extent of source data verification.  
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following criteria 
are met:  

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• 
The investigator understands and accepts the obligation to conduct the clinical investigation 
according to the CIP and applicable regulations, and has signed the Clinical Trial Agreement  
• 
The Investigator and his/her staff should have sufficient time and facilities to conduct the clinical 
investigation and should have access to an adequate number of appropriate subjects to conduct 
the clinical investigation.  
• 
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 investigation-related documents. 
10.6 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 inform their EC or equivalent committee of all CIP deviations in 
accordance with their specific EC or equivalent committee reporting policies and procedures.  
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or company 
representative will attempt to secure compliance by one or more of the following (and not limited to):  
• Visiting the investigator and/or delegate 
• Telephoning the investigator and/or delegate 
• Corresponding with the investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the CIP or any other conditions of the clinical 
investigation may result in further escalation in accordance with the Sponsor’s written procedures, 
including securing compliance or, at its sole discretion, Sponsor may terminate the investigator's 
participation in the clinical investigation. Table 4 describes potential study protocol deviations in the clinical 
investigation.   
 
 
 
 
 
 
 

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Table 4: Examples of Potential Study Protocol Deviations 
Type of Protocol Deviation 
Classification  
Informed Consent Not Obtained 
Major Deviation 
Other Informed Consent Deviation 
Minor Deviation 
Inclusion/Exclusion Criteria Not Met 
Major Deviation 
Visit Not Done  
Minor Deviation 
Required Testing/Assessment Not Done or Not Done Per Protocol 
Minor Deviation 
Missing Study Procedure  
Minor Deviation 
Visit Outside of Window  
Minor Deviation 
Required Reporting Timeline Not Followed Per Protocol 
Minor Deviation 
10.7 Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical investigation records, including 
source documentation, for inspection during a Quality Assurance audit.  
In the event that an investigator is contacted by a Regulatory Agency in relation to this clinical investigation, 
the Investigator will notify Sponsor immediately. The Investigator and Research Coordinator must be 
available to respond to reasonable requests and audit queries made during the audit process. The 
Investigator must provide Sponsor with copies of all correspondence that may affect the review of the 
current clinical investigation (e.g., Form FDA 483, Inspectional Observations, Warning Letters, Inspection 
Reports, etc.). Sponsor may provide any needed assistance in responding to regulatory audits. 
10.8 Sponsor Auditing 
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. 
10.9 Committees  
The clinical investigation will utilize three separate committees: 
• 
Subject Selection Committee (SSC) 
• 
Clinical Events Committee (CEC) 
• 
Steering and Publication Committee 
 Subject Selection Committee 
The Subject Selection Committee (SSC) will consist of cardiac surgeons, cardiac interventionalists, and a 
neurologist who will be responsible for ensuring subject eligibility in the clinical investigation according to 

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the study protocol. After Subject Informed Consent is obtained and study eligibility is confirmed by the local 
Heart Team, subject data will be reviewed by the SSC prior to scheduling a baseline visit to confirm 
anatomic suitability for the Portico 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 enrollment in the study. 
The same SSC membership and process used in the Portico US IDE pivotal trial will be utilized for this 
clinical investigation. Refer to APPENDIX XXII for a full list of SSC members. 
 Clinical Events Committee 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of qualified 
physicians (at a minimum, an interventional cardiologist, cardiothoracic surgeon, and a neurologist) who 
are not participants in the clinical investigation or the Portico US Pivotal IDE trial. The CEC will review and 
have final adjudication responsibilities for the studies primary safety endpoint and pre-specified descriptive 
adverse events reported by investigators or identified by Safety personnel for the clinical investigation as 
defined in the CEC Standards of Operation Charter and according to definitions provided in this CIP.   
The same CEC used in the Portico US IDE pivotal trial will be utilized for this clinical investigation. 
 Steering and Publications Committee 
 
A Steering and Publication Committee shall be established to oversee the clinical investigation and its 
publications, including publication planning and authorship determinations. 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 investigation generated data. The committee will also review all external requests for 
accessing clinical investigation-related data and strategies aligning with the Sponsor’s presentation and 
publication team expectations. The Committee will also follow the Sponsor’s applicable policies and 
Standard Operating Procedures. 
11 DATA HANDLING AND RECORD KEEPING 
 
Sponsor and/or its affiliates will maintain documentation of the systems and procedures used in data 
collection for the duration of the clinical investigation.  
CRF data collection will be performed through a secure web portal and only authorized personnel will 
access the 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 investigation, completed CRF images with the date-and-time stamped 
electronic audit trail indicating the user, the data entered, and any reason for change (if applicable) will be 
provided to the investigational sites, if requested.  

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For the duration of the clinical investigation, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical investigation progress records, 
laboratory reports, CRFs, signed ICFs, device accountability records (if applicable), correspondence with 
the EC and clinical investigation monitor/Sponsor, adverse event reports, and information regarding 
subject discontinuation or completion of the clinical investigation. 
11.1 Protection of Personally Identifiable Information 
The Sponsor respects and protects personally identifiable information collected or maintained for this 
clinical investigation. The privacy of each subject and confidentiality of his/her information will be preserved 
in reports and when publishing any data. Confidentiality of data will be observed by all parties involved at 
all times throughout the clinical investigation. All data will be secured against unauthorized access. 
11.2 Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, data cleaning, and issuing 
and resolving data discrepancies. If appropriate, the DMP may be updated throughout the duration of the 
clinical investigation. 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 investigation: 
• 
Medical history/physical condition of the subject before involvement in the clinical investigation 
sufficient to verify CIP entry criteria 
• 
Dated and signed notes on the day of entry into the clinical investigation referencing the Sponsor, 
CIP number, subject ID number and a statement that informed consent was obtained 
• 
Dated and signed notes from each subject visit (for specific results of procedures and 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 investigation 
(including start and stop dates) 
• 
Subject’s condition upon completion of or withdrawal from the clinical investigation 
• 
Any other data required to substantiate data entered into the CRF 
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. 

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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 
investigation as per the applicable regulatory record retention requirements. The Investigator must obtain 
permission from Sponsor in writing before destroying or transferring control of any clinical investigation 
records. 
11.6 Investigational Devices Accountability 
The Sponsor ships investigational products only to the Principal Investigator (the responsible leader of the 
investigational site) or his/her legal designee of each site, after 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 Medical Ethics Committee Review and Approval 
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 investigation. The approval letter must be received prior to the start of this clinical 
investigation 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 EC requirements.  
No changes will be made to the CIP or ICF or other written information provided to the patient without 
appropriate approvals, including EC, the Sponsor, and the regulatory agencies (if applicable).  
Until the clinical investigation is completed, the Investigator will advise his/her EC of the progress of this 
clinical investigation, per EC requirements. Written approval must be obtained from the EC yearly to 
continue the clinical investigation, or according to each institution’s EC requirements.  
No investigative procedures other than those defined in this CIP will be undertaken on the enrolled subjects 
without the written agreement of the EC and the Sponsor. 

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13 CLINICAL INVESTIGATION CONCLUSION 
The clinical investigation will be concluded when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators or the Sponsor has provided formal 
documentation of clinical investigation closure. 
14 PUBLICATION POLICY 
The data and results from the clinical investigation are the sole property of the Sponsor. The Sponsor shall 
have the right to access and use all data and results generated during the clinical investigation. The 
Investigators will not use this clinical investigation-related data without the written consent of the Sponsor 
for any purpose other than for clinical investigation completion or for generation of publication materials, 
as referenced in the Clinical Trial Agreement. Single-center results 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. 
The Sponsor will be responsible for determining whether to register the clinical investigation on 
www.clinicaltrials.gov or any other clinical trials, in accordance with the International Committee of Medical 
Journal Editors guidelines, or any other applicable guidelines. In the event Sponsor determines that the 
clinical investigation should be registered, Sponsor shall be responsible for any such registration and 
results posting as required by the ClinicalTrials.gov website. Institution and/or Principal Investigator(s) shall 
not take any action to register the clinical investigation. 
15 RISK ANALYSIS 
 
15.1 Anticipated Clinical Benefits 
There are no guaranteed clinical benefits associated with participation in this clinical investigation. It is 
expected that patients implanted with a Portico™ valve using the FlexNav™ delivery system will 
experience the same improvements in symptoms related to severe aortic stenosis as patients implanted 
with other commercially available transcatheter valves. This includes improvements in chest pain, 
fatigue, shortness of breath, dizziness and fainting. 
 
While the FlexNav Delivery System is not anticipated to add new clinical benefits, the new design 
modifications may result in a reduced risk of major vascular complications, specifically access-site 
complications (e.g. bleeding, unplanned surgical closure, infection, hematoma) and vascular injury such 
as vessel dissection during the implant procedure.   
 
 
 
Table 5 summarizes the anticipated clinical impact of design modifications to the FlexNav™ Delivery 
System.  
 
 
 

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Table 5: Anticipated Clinical Impact of Design Modifications to FlexNav™ Delivery System 
Design 
Feature 
Function of Design Feature 
Clinical Impact 
Integrated 
Sheath 
- Non-removable introducer to allow sheathless 
insertion into vasculature 
- Hydrophilic coating on exterior to ease 
insertion  
- Can also be used with standard introducers 
- Use of the integrated sheath 
decreases insertion profile which 
is important for vascular access 
and managing the puncture site 
post-procedure 
Stability Layer 
- Acts as stabilizing layer during deployment by 
isolating motion between 
introducer/vasculature and delivery system 
- Minimizes user adjustment of system at 
access site to maintain position during 
deployment 
- Significantly reduces amount of 
delivery system/sheath 
manipulation during deployment, 
may aid in more consistent valve 
deployment 
Proximal inner 
member shaft 
- 18F/19F: stainless steel multifilar shaft on 
both sizes 
- Reduced stiffness to aid valve alignment and 
improve re-sheath closure 
- Shaft welded to stainless steel components 
both ends 
- Design enhancements increase 
system tensile strength and 
flexibility to aid valve alignment 
Handle 
- Automatically engaged partial deployment 
release button 
- Labeling to identify deployment/re-sheath 
direction and partial deployment actuation 
- Rotating knob for closing gap between valve 
capsule and proximal end of DS tip  
- Ergonomic improvements to improve user 
comfort and make use more intuitive 
- Improved ergonomics and handle 
labels would not adversely affect 
clinical performance; same 
procedural steps for valve 
deployment 
 
Additionally, information gained from the conduct of this clinical investigation may be of benefit to other 
people with the same medical condition in the future.  
15.2 Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Risks associated with the use of the FlexNav™ delivery system and implant procedure, together with their 
likely incidence, are described in APPENDIX XXIII.   There may be risks related to the FlexNav™ delivery 
system under investigation that are unknown at present.  Likewise, the exact frequency of the risk may be 
unknown.  
 Potential Anticipated Adverse Events 
The FlexNav™ Delivery System and Loading System are not intended or anticipated to introduce any new 
risks beyond that observed for the current (first-generation) Portico™ Delivery System and Loading System 
when implanting the Portico™ valve. For that reason, the potential anticipated adverse events associated 

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with use of the FlexNav™ Delivery System will be similar to those associated with any routine TAVI 
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: 
1. access site complications (e.g., pain, bleeding, infection, hematoma, pseudoaneurysm, etc.)  
2. acute coronary obstruction  
3. acute myocardial infarction  
4. allergic reaction to antiplatelet agents, contrast medium, or valve components  
5. aortic rupture  
6. ascending aorta trauma  
7. atrio-ventricular node block  
8. cardiac arrhythmias  
9. embolism  
10. endocarditis  
11. heart failure  
12. hemodynamic compromise  
13. hemolysis  
14. hemolytic anemia  
15. hemorrhage  
16. hypotension or hypertension  
17. infection  
18. myocardial ischemia  
19. mitral valve insufficiency  
20. multi-organ failure  
21. non-structural dysfunction (i.e., entrapment by pannus, paravalvular leak, inappropriate sizing or 
positioning)  
22. pericardial effusion  
23. perforation of the myocardium or a blood vessel  
24. pannus  
25. renal insufficiency or renal failure  
26. sepsis  
27. stroke  
28. structural deterioration (i.e., calcification, leaflet tear)  
29. thrombosis  
30. tamponade  
31. valve migration  
32. vessel dissection or spasm.  
 
It is possible these complications could lead to:  
 
1. transfusion  
2. conversion to open surgical procedure  
3. reoperation  
4. emergent balloon valvuloplasty  
5. emergent percutaneous coronary intervention (PCI)  
6. emergent surgery (i.e., coronary artery bypass, heart valve replacement)  
7. explantation  
8. permanent disability  

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9. death  
10. permanent pacemaker  
 
Subjects experiencing an adverse event shall be treated per the standard of care at the investigation site. 
15.3 Residual Risks Associated with the Device Under Investigation, as Identified in the 
Risk Analysis Report 
Risk analysis for the FlexNav™ Delivery System and Loading System has been performed in accordance 
with the Risk Analysis Plan (on file; internal ref: 90163677 Ver. C). The risk analysis utilizes Hazard 
Analysis (on file; internal ref: 90163681) and Failure Mode Effect Analysis (FMEA) (on file; internal ref: 
90163679, and 90163680) tools to systematically identify potential hazards associated with the design, 
and use of the devices.   Based upon the preclinical, clinical and bench-testing data, all risks have been 
identified and determined to be within acceptable levels.  
No additional residual risk has been identified with the use of the FlexNav™ Delivery System and Loading 
System. 
15.4 Risks Associated with Participation in this Clinical Investigation 
Protocol-required assessments are summarized in Table 3 of Section 6.5.5. 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). 
 
Study-specific assessments that are not considered standard of care and are associated with additional 
risk include the six-minute walk test, blood collection for laboratory tests and echocardiogram exam during 
scheduled follow-up visits (excluding at discharge). Table 6 summarizes known risks associated with these 
study-specific assessments and measures taken in the clinical investigation to mitigate risk to subjects. 
 
 
Table 6: Known Risks Associated with Study-Specific Assessments and Mitigation Measures 
Study 
Assessment 
Known risks 
Mitigation measures 
Six-minute walk 
test  
Experience of fatigue, shortness of 
breath, chest pain and/or leg 
cramps. 
This test will be performed under the supervision of a 
trained professional in a testing area where medical 
care is immediately available. The test will be 
immediately stopped if subjects experience chest 
pain, intolerable shortness of breath, leg cramps or 
pale appearance. 
 
Blood sample 
 
The risk of inserting a needle into a 
vein in the arm may include 
temporary discomfort from the 
needle stick.  There is also a small 
risk of infection, bruising, swelling, 
bleeding or fainting.   
These risks are minimized by cleansing the site 
carefully prior to obtaining the blood sample and 
applying pressure to the site after the blood sample is 
obtained. 
Echocardiogram 
For a Transthoracic 
Echocardiogram (TTE), a lubricant 
(gel) is used on the skin to improve 
picture quality and this may feel 
The procedure will be explained to subjects by a 
trained professional prior to starting to the procedure.   
There are no known risks associated with receiving a 
TTE echocardiogram. 

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cold.  There may be discomfort 
from the pressure of the 
transducer as the images are 
taken. 
 
15.5 Steps Taken to Control or Mitigate Risks 
In-depth recommendations, special precautions and instructions regarding patient selection, vessel sizing, 
device handling, device placement and system removal are included in the IFU that will be provided with 
all devices to be used in the clinical investigation.  
It is also stated in the IFU 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. 
Risks associated with the use of the device under investigation are minimized through device design, 
investigator selection and training, pre-specified patient eligibility requirements, and study monitoring to 
ensure adherence to the protocol. These risk management aspects are detailed below: 
 
Device Design: The design of the for FlexNav™ Delivery System(s) and FlexNav™ Loading System(s) 
include multiple features to minimize potential risk to subjects which are described below:  
 
Delivery System:  
• 
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.  
• 
Delivery system construction utilizes common catheter materials and manufacturing technologies. 
• 
Handle features an automatically engaged partial deployment release button to retract the outer 
sheath and prevent full deployment when releasing the valve. To fully deploy the valve, the 
deployment lock button is depressed and the deployment/resheath wheel is turned in a 
downwards direction.   
 
Loading System:  
• 
The FlexNav Loading System facilitates valve preparation/loading onto the FlexNav Delivery 
System.  
 

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• 
The Loading System includes a loading base, loading funnel, loading tube, base insert, and 
leaflet tester. 
 
• 
The loading base has been modified to include an integrated guide tube to eliminate the potential 
for the tip of the delivery system to interact with valve leaflets during loading of the valve onto the 
delivery system.  
 
 
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 
investigation:  
• 
Investigators will be carefully selected based on their knowledge of, and experience implanting and 
managing, TAVR devices, including Portico TAVI system. The protocol requires investigational 
sites to have completed the commercial Portico implant training program and have at least one 
primary implanting physician that has performed 50 or more Portico implants within the previous 
12 months. 
 
• 
Investigators will be trained with regards to implantation technique of the Portico valve using the 
FlexNav™ Delivery System.  
 
• 
Investigators in the clinical investigation will be provided with a Clinical Instructions for Use (IFU) 
as a reference. 
 
• 
The local Heart Team's interventional cardiologist(s) and cardiac surgeon(s) must jointly participate 
in the intra-operative technical aspects of TAVR.  
 
• 
Interventional cardiologists must be experienced and skilled in percutaneous, structural heart 
interventions (such as BAV). 
 
• 
Cardiovascular surgeons performing procedures must be board certified (or equivalent).  
 
• 
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. 
 
Ensuring Strict Adherence to the Clinical Investigational Protocol: The clinical investigation will be 
monitored by the Sponsor to ensure adherence to the CIP. Subjects will be carefully selected through 
rigorous screening by both a local Heart Team and independent SSC using pre-specified inclusion and 
exclusion criteria as stated in section 5.3. 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 replacement4.  
As subjects participating in this study are indicated for a TAVI procedure as part of their standard medical 
management and no additional risks have been identified with the use of the FlexNav™ Delivery System 
compared to the first-generation Portico™ Delivery System, we do not anticipate the risks to a subject 
undergoing transfemoral implantation of a Portico™ valve using the FlexNav™ Delivery System to be any 

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different to that reported for a standard TAVI procedure using a commercially-available transcatheter 
delivery system.  
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 CIP 
with appropriate mitigation for each risk to the lowest level possible. 
Clinical evaluation of the Portico™ TAVI System in the PORTICO TAVI System CE Mark study13 and the 
post-market PORTICO I PMCF study20 have established the early safety of the first-generation Portico™ 
Delivery System to transfemorally implant the Portico™ valve in a high or extreme surgical risk patient 
cohort. While the FlexNav™ Delivery System is not expected to add any new clinical benefits, recent 
design modifications to the delivery system may potentially improve patient safety compared to the first-
generation Portico Delivery System, despite the procedure to load or deploy the Portico™ valve 
remaining unchanged. Specifically, the FlexNav™ Delivery System has been modified to improve device 
performance related to valve placement accuracy, trackability, reduced profile, and user experience with 
the device handle and general ergonomics. The delivery system will also feature an integrated sheath to 
enable a sheathless delivery option. 
Given the FlexNav™ Delivery System is not intended to introduce any new risks or new benefits beyond 
that observed for the current (first-generation) Portico™ delivery system the risk-to-benefit analysis for 
the current (first-generation) Portico™ delivery system is also applicable for the second-generation 
FlexNav™ Delivery System.   
All aspects utilized in the design and development of the FlexNav™ Delivery System support that the 
benefits outweigh the risks associated with the evaluation of this device in a clinical investigation. 
 
 
 
                                               
20 Maisano F, Worthley S, Rodés-Cabau J, et al. Early commercial experience from transcatheter aortic valve implantation using the Portico™ 
bioprosthetic valve: 30-day outcomes in the multicenter PORTICO I study. EuroIntervention. 2018. 14- online publish ahead of print August 2018 

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16 APPENDICES 
APPENDIX I: ABBREVIATIONS AND ACRONYMS 
Abbreviation 
Term 
6MWT 
Six Minute Walk Test 
ACT 
Activated Clotting Time 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AHA 
American Heart Association 
AS 
Aortic Stenosis 
AVA 
Aortic Valve Area 
AVR 
Aortic Valve Replacement 
BARC 
Bleeding Academic Research Consortium 
BNP 
B-type Natriuretic Peptide 
CAD 
Coronary Artery Disease 
CBC 
Complete Blood Count 
CE 
Conformité Européene (European Conformity) 
CEC 
Clinical Events Committee 
CIP 
Clinical Investigation Plan 
CPB 
Cardiopulmonary Bypass 
eCRF 
Electronic Case Report Form 
CT 
Computed Tomography 
CVA 
Cerebral Vascular Accident 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
Echo 
Echocardiography 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EF 
Ejection Fraction 
EOA 
Effective Orifice Area 
EU 
European Union 
GI 
Gastro Intestinal 
HOCM 
Hypertrophic cardiomyopathy with or without obstruction 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
INR 
International Normalized Ratio 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
Kg 
Kilogram 
LBBB 
Left Bundle Branch Block 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MAC 
Mitral Annular Calcification 
MI 
Myocardial Infarction 
MMSE 
Mini-mental state examination 

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MR 
Mitral Regurgitation 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NIHSS 
NIH Stroke Scale 
NYHA 
New York Heart Association 
PA 
Pulmonary Artery 
PCI 
Percutaneous Coronary Intervention 
PCWP 
Pulmonary Capillary Wedge Pressure 
PI 
Principal Investigator 
QoL 
Quality of Life 
PVD 
Peripheral Vascular Disease 
PVL 
Paravalvular Leak 
RA 
Right Atrium 
RV 
Right Ventricular 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAVR 
Surgical Aortic Valve Replacement 
SJM 
St. Jude Medical, Cardiovascular Division 
SSC 
Subject Selection Committee 
STS 
Society of Thoracic Surgeons 
TAVI 
Transcatheter Aortic Valve Implantation 
TAVR 
Transcatheter Aortic Valve Replacement 
TEE 
Transesophageal Echocardiogram (same as TOE) 
TIA 
Transient Ischemia Attack 
TTE 
Transthoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Effect 
USA 
United States of America (same as US) 
VARC 2 
Valve Academic Research Consortium 2 
WBC 
White Blood Cell 
 
 

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APPENDIX II: VARC II ENDPOINTS 
Source 
Definition 
Cardiovascular 
Mortality 
(VARC 2) 
Any one of the following criteria: 
• 
Death due to proximate cardiac cause (e.g. myocardial infarction, cardiac tamponade, 
worsening heart failure) 
• 
Death caused by non-coronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular 
disease 
• 
All procedure-related deaths, including those related to a complication of the procedure or 
treatment for a complication of the procedure 
• 
All valve-related deaths including structural or nonstructural valve dysfunction or other 
valve-related adverse events 
• 
Sudden or unwitnessed death 
• 
Death of unknown cause 
Myocardial  
Infarction 
(VARC 2) 
Peri-procedural MI (less than or equal to (≤) 72 h after the index procedure) 
New ischemic symptoms (e.g., chest pain or shortness of breath), or new ischemic signs (e.g. 
ventricular arrhythmias, new or worsening heart failure, new ST-segment changes, 
hemodynamic instability, or imaging evidence of new loss of viable myocardium or new wall 
motion abnormality),  
AND  
Elevated cardiac biomarkers within 72 h after the index procedure consisting of at least one 
sample post-procedure with a peak value exceeding 15x upper reference limit (troponin) or 5x 
for CK-MB. If cardiac biomarkers are increased at baseline (>99th percentile), a further 
increase of at least 50% post-procedure is required AND the peak value must exceed the 
previously stated limit. 
Spontaneous MI (greater than (>) 72 h after the index procedure) 
Any one of the following criteria: 
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least one 
value above the 99th percentile URL, together with evidence of myocardial ischemia with at 
least one of the following: 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia [new ST-T changes or new Left Bundle Branch 
Block (LBBB)] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion abnormality 
• Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST-segment 
elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/ 
or at autopsy, but death occurring before blood samples could be obtained, or at a time 
before the appearance of cardiac biomarkers in the blood. 
• Pathological findings of an acute myocardial infarction. 
Stroke 
(FDA/VARC 2) 
This study is following the FDA’s definition of Stroke per FDA’s Current Thinking Regarding 
Neurological Assessments for Transcatheter Valve Trials (Revised: 25 Aug 2011) and VARC 
2 (2012) 
  
1. Definitions:  
a. Stroke: Stroke is an acute episode of focal or global neurological dysfunction caused by 
the brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction.  
Sub classifications of stroke:  
i. Ischemic Stroke is defined as an acute symptomatic episode of focal cerebral, 
spinal, or retinal dysfunction caused by an infarction of central nervous system tissue.  

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ii. Hemorrhagic Stroke is defined as an acute symptomatic episode of focal or global 
cerebral or spinal dysfunction caused by a nontraumatic intraparenchymal, 
intraventricular, or subarachnoid hemorrhage.  
Stroke Disability (consistent with VARC 2 Definitions):  
i. Disabling:  an mRS score of 2 or more at 90 days and an increase of at least one mRS 
category from an individual’s pre-stroke baseline 
ii. Non-disabling:  an mRS score of < 2 at 90 days or one that does not result in an 
increase of at least one mRS category from an individual’s pre-stroke baseline 
b. Cerebral Infarction: Evidence of brain cell death from imaging studies or pathological 
examination. If there are clinical symptoms, then it is a stroke; otherwise, it is an 
asymptomatic cerebral infarction.  
c. Transient Ischemic Attack (TIA): A transient (less than (<) 24 hrs) episode of neurological 
dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute 
infarction. No evidence of infarction if imaging performed.  
d. Encephalopathy: Altered mental state (e.g., seizures, delirium, confusion, hallucinations, 
dementia, coma, psychiatric episode, etc.).  
e. Intracranial Hemorrhage: Collection of blood between the brain and skull. Subcategorized 
as epidural, subdural, and subarachnoid bleeds.  
 
Bleeding 
(VARC 2) 
 
Life-threatening or disabling bleeding 
• Fatal bleeding (BARC type 5) OR 
• Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial 
necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 
3b and 3c) OR 
• Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or 
surgery (BARC type 3b) OR 
• Overt source of bleeding with drop in hemoglobin of greater than or equal to (≥) 5 g/dl or 
whole blood or packed red blood cells (RBCs) transfusion greater than or equal to (≥) 4 U 
(BARC type 3b). Given 1 U of packed RBC typically will raise blood hemoglobin 
concentration by 1 g/dl, an estimated decrease in hemoglobin will be calculated. 
 
Major bleeding (BARC type 3a) 
• Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dl or 
requiring transfusion of two or three units of whole blood/ RBC, or causing hospitalization or 
permanent injury, or requiring surgery AND 
• Does not meet criteria of life-threatening or disabling bleeding  
 
Minor bleeding (BARC type 2 or 3a, depending on the severity) 
• Any bleeding worthy of clinical mention (e.g., access site hematoma) that does not qualify 
as life-threatening, disabling or major 
 
Acute Kidney 
Injury (AKIN 
Classification) 
(VARC 2) 
Change in serum creatinine (up to 48 h) compared with baseline 
 
Stage 1  
Increase in serum creatinine to 150% to 199% (1.5 to 1.99 X increase compared with 
baseline) or increase of greater than or equal to (≥) 0.3 mg/dl (≥26.4 mmol/l) or 
Urine output <0.5 ml/kg per hour for > 6 but < 12 hours 
 
Stage 2  
Increase in serum creatinine to 200% to 299% (2.0 to 2.99 X increase compared with 
baseline) or  
Urine output <0.5 ml/kg per hour for > 12 but < 24 hours 

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Stage 3  
Increase in serum creatinine to greater than or equal to (≥) 300% (>)3 X increase compared 
with baseline) or serum creatinine of ≥ 4.0 mg/dl (≥354 mmol/l) with an acute increase of at 
least 0.5 mg/dl (44 mmol/l) or Urine output < 0.3 ml/kg per hour for > 24 hours or anuria for > 
12 hours. Patients receiving renal replacement therapy are considered to meet Stage 3 
criteria irrespective of other criteria. 
Vascular Access 
Site and Access-
Related 
Complications 
(VARC 2) 
Major vascular complications 
• 
Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new 
apical aneurysm/pseudo-aneurysm or 
• 
Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, 
arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, 
compartment syndrome, percutaneous closure device failure) leading to death, life-
threatening or major bleeding*, visceral ischaemia or neurological impairment or 
• 
Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in 
amputation or irreversible end-organ damage or 
• 
The use of unplanned endovascular or surgical intervention associated with death, major 
bleeding, visceral ischaemia or neurological impairment or 
• 
Any new ipsilateral lower extremity ischemia documented by patient symptoms, physical 
exam, and/or decreased or absent blood flow on lower extremity angiogram or 
• 
Surgery for access site-related nerve injury or 
• 
Permanent access site-related nerve injury  
Minor vascular complications 
• 
Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, 
arterio-venous fistula, pseudoaneurysms, hematomas, percutaneous closure device 
failure) not leading to death, life-threatening or major bleeding*, visceral ischemia or 
neurological impairment or 
• 
Distal embolization treated with embolectomy and/or thrombectomy and not resulting in 
amputation or irreversible end-organ damage or 
• 
Any unplanned endovascular stenting or unplanned surgical intervention not meeting the 
criteria for a major vascular complication or 
• 
Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) or 
 
 
Percutaneous closure device failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to alternative 
treatment (other than manual compression or adjunctive endovascular ballooning) 
 
Acute Device 
Success 
(VARC 2 with 
modifications) 
1. Acute device success defined as: 
o 
Absence of procedural mortality 
o 
Correct positioning of a single prosthetic heart valve into the proper anatomical 
location 
o 
Intended performance of the prosthetic heart valve (mean aortic valve gradient <20 
mmHg or peak velocity <3 m/s, no moderate or severe prosthetic valve regurgitation) 
o 
Successful access was obtained as intended by group assignment 
Device success is a ‘technical’ composite endpoint meant to characterize the acute device 
and procedural factors which underlie vascular access, delivery, and performance of the TAVI 
system. Echocardiography should be routinely utilized as the standard for measuring 
prosthetic valve stenosis and regurgitation immediately after TAVI, and should always be 
performed in a resting state, either within 24–48 h after the index procedure or before hospital 
discharge. 

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FDA 
Individual Patient Success 
1. Acute device success 
2. Discharged alive from the hospital without device-related major AEs (Includes AI ≤ 1+) 
3. Survival to one year with:  
o 
No disabling stroke  
o 
No device-or procedure-related mortality  
o 
NYHA class ≤ 2, or improvement in NYHA class by at least 1 level from 
baseline 
o 
No re-hospitalizations for valve related complications/dysfunction or CHF due 
to aortic valve related causes 
4. No pacemaker dependency at 1 year (Excluding subjects with pre-procedural conduction 
abnormalities) 
Prosthetic Valve 
Stenosis Criteria 
In conditions of 
normal or near 
normal stroke 
volume (50–70 
ml). 
(VARC 2) 
 
Parameter  
Normal 
Mild Stenosis 
Moderate/ severe 
Stenosis 
Peak velocity (m/s) 
less than (<) 3 
3–4 
greater than (>) 4 
Mean gradient (mm 
Hg) 
less than (<) 20 
20–40 
greater than (>) 40 
Doppler velocity index 
greater than or equal 
to (≥) 0.35 
0.35–0.25 
less than (<) 0.25 
Effective orifice area 
(cm2) 
greater than (>) 1.1∗ 
1.1–0.8 
less than (<) 0.80 
Prosthetic Valve 
Regurgitation 
Criteria  
(VARC 2) 
Diastolic flow reversal in the descending aorta (semi-quantitative parameters) 
Diastolic flow 
reversal in the 
descending aorta  
PW Doppler 
Absent or brief early 
diastolic 
Intermediate 
Prominent, 
holodiastolic 
Circumferential 
extent of 
paraprosthetic AR 
less than (<) 10% 
10–29% 
greater than or equal 
(>) 30% 
Doppler parameters (quantitative) 
Regurgitant 
volume (ml/beat) 
less than (<) 30% 
30–59% 
greater than or equal 
(>) 60% 
Regurgitant 
fraction 
less than (<) 30% 
30–49% 
greater than or equal 
(>) 50% 
EROA (cm2) 
0.10 cm2 
0.10-0.29 cm2 
≥0.30 cm2 
 
 
 
                                               
∗ Effective orifice area (EOA) used in this protocol is 1.0 cm2 for Portico valve of 23mm diameter. 

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APPENDIX III: NON-STUDY SPECIFIC DEFINITIONS 
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device under clinical investigation. 
 
This definition includes adverse events related to the investigational medical device. 
This definition includes events related to the procedures involved. 
 
Serious Adverse Event (SAE) 
An adverse event that led to: 
• 
Death 
• 
A serious deterioration in the health of the subject, that either resulted in: 
o 
A life-threatening illness or injury OR 
o 
A permanent impairment to a body structure or a body function OR 
o 
An in-patient or prolonged hospitalization OR 
o 
A medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function OR 
o 
Chronic disease 
• 
Fetal distress, fetal death or a congenital abnormality or birth defect 
 
A planned hospitalization for a pre-existing condition, or a procedure required by the CIP is not 
considered a serious adverse event. 
 
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) 
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) 
A serious adverse device effect which by its nature, incidence, severity or outcome has been previously 
identified in the risk analysis report. 

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Unanticipated Serious Adverse Device Effect (USADE) 
A serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
 
Device Deficiency (DD) 
A device deficiency is defined as an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device deficiencies include malfunctions, use errors and 
inadequate labeling. 
 
 

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APPENDIX IV: STUDY-SPECIFIC ASSESSMENTS 
Study -Specific Assessments 
Study Activity 
Definition 
Adverse Event 
Assessment 
Adverse events will be documented according to definitions in APPENDIX II. 
Barthel Index 
A scale used to measure performance in activities of daily living (ADL). Each 
performance item is rated on this scale with a given number of points 
assigned to each level or ranking. It uses ten variables describing ADL and 
mobility where a higher number is associated with a greater likelihood of 
being able to live at home with a degree of independence following discharge 
from the hospital. 
Lab Work 
 
Blood lab tests will be collected at each required interval.  The specific lab 
tests are indicted in Table 3: Study-related assessments and data collection 
schedule.Error! Reference source not found. 
Cardiac Rhythm 
Monitoring 
Assessment of heart rate, QRS and dominant rhythm pre-procedure and 
during the procedure. 
CCS Status of 
Angina Scale 
A 4-point scale used to classify angina pectoris from mild (class I: angina 
occurring only during strenuous or prolonged physical activity) to severe 
(class IV: inability to perform any activity without angina, or angina at rest) 
Echocardiography 
 
Each site is responsible for performing the echocardiogram (echo) according 
to the Echocardiographic protocol. Echocardiogram will be copied to CD/DVD 
(or other large media storage device) and provided to an Echocardiographic 
Core Lab for evaluation.  
Electrocardiogram 
(ECG) 
Assessment of dominant rhythm, heart rate, and QRS interval via 12-lead.  
Frailty Index 
 
Used to assess if frailty is a high-risk factor for subjects. Frailty index 
assessments will include the following tests: 
• 
Katz index of Activates of Daily Living 
• 
Grip Strength 
• 
5 meter walk test 
The process to complete these tests are defined in APPENDIX VII  
Medication 
Assessment 
Only the following medication will be collected at each specified interval: 
• 
Beta Blockers 
• 
Calcium Channel Blockers 
• 
Anticoagulants  
• 
Antiplatelet agents including Aspirin  
• 
Diuretics 
• 
ACE-Inhibitors 
• 
Angiotensin Receptor Blocker (ARBs) 
Mini Mental Sate 
Exam (MSSE-2:SV) 
An 11-question tool used to assess mental status. The self-administered 
MMSE tests five areas of cognitive function: orientation, registration, attention 
and calculation, recall, and language.  
Modified Rankin 
Stroke Scale(mRS) 
This assessment must be completed by a rater who has a current certificate 
that demonstrates completion of an accredited training program for this stroke 
scale, using the structured interview found in APPENDIX XV. 
 
The modified Rankin Scale (mRS) is functional measurement to assess the 
degree of disability or dependence in the daily activities of people who have 
suffered a stroke. 

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NIH Stroke Scale 
This assessment must be completed by a rater who has a current certificate 
that demonstrates completion of an accredited training program for this stroke 
scale. 
The NIHSS is an 11-item neurologic examination stroke scale used to 
evaluate the effect of acute cerebral infarction on the levels of consciousness, 
language, neglect, visual-field loss, extraocular movement, motor strength, 
ataxia, dysarthria, and sensory loss. Certified personnel rate the patient’s 
ability to answer questions and perform activities. Ratings for each item are 
scored with 3 to 5 grades with 0 as normal, and there is an allowance for 
untestable items.  
NYHA Classification 
The New York Heart Association (NYHA) Functional Classification provides a 
simple way of classifying the extent of heart failure and defined in APPENDIX 
VIII. 
Physical Assessment 
The following measurements must be assessed at all scheduled visits: 
• 
Weight 
• 
Heart rate  
• 
Heart rhythm  
• 
Physical Assessment   
Procedure 
Information 
Procedure information must be collected including: 
• 
Pre-procedure Information 
• 
Procedure Information 
• 
Procedure Evaluation 
• 
Post-procedure Information 
Procedural imaging  
All imaging collected during the procedure (intra-procedure) such as the 
cineangiogram and/or echocardiography should be collected and provided to 
the Sponsor. 
QoL Questionnaires 
The following self-administered, standardized instruments will be used to 
assess/measure health outcomes: 
• 
SF-36 
• 
EQ-5D 3L  
• 
KCCQ 
The process to complete these questionnaires are described in APPENDIX X, 
APPENDIX XI, and APPENDIX XII.  
Surgical Risk 
Assessment 
Consists of two assessments as defined in APPENDIX VI: 
• 
EuroSCORE II 
• 
STS Risk Score 
Six Minute Walk Test 
(6MWT) 
Used to quantitatively assess submaximal exercise tolerance as defined in 
APPENDIX XVII. 
 
 

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APPENDIX V: SITE CONTACT INFORMATION 
Contact information for each participating clinical site is available under a separate cover by contacting the 
Sponsor at: 
 
Contact Name: Paolo Amato, Clinical Project Manager: FlexNav EU CE Mark Study 
Contact Address:  Abbott 
                             The Corporate Village 
                             Da Vincilaan 11 Box F1 
                             1935 Zaventem, Belgium 
Contact Email: paolo.amato@abbott.com 
Contact Phone: +39 335 6140573  
 
 

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APPENDIX VI: 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, Version 2.73 
(http://riskcalc.sts.org/STSWebRiskCalc273/de.aspx) 
2. Euro SCORE II (http://euroscore.org/calc.html) 

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 APPENDIX VII: FRAILY ASSESSMENT 
The Frailty Index Data Collection Form will be used as an assessment tool to determine if frailty is a risk 
factor for subjects prior to enrollment. This assessment will be performed after the informed consent has 
been obtained and prior to procedure. The assessment can be administered by either an investigator or 
research coordinator. 
The frailty assessment consists of three evaluations: 
1. Katz Index of Independence in Activities of Daily Living  
2. Grip Strength 
3. 5 Meter walk test 
 
 
1. Katz Index of Independence in Activities of Daily Living Activities  
 
Points (1 or 0)  
Independence 
(1 Point) 
NO supervision, direction or personal 
assistance 
Dependence 
(0 Points) 
WITH supervision, direction, personal 
assistance or total care 
BATHING  
Points: ________  
(1 POINT) Bathes self completely or 
needs help in bathing only a single part 
of the body such as the back, genital 
area or disabled extremity  
(0 POINTS) Need help with bathing more than 
one part of the body, getting in or out of the tub 
or shower. Requires total bathing  
DRESSING  
Points: ________  
(1 POINT) Get clothes from closets and 
drawers and puts on clothes and outer 
garments complete with fasteners. May 
have help tying shoes.  
(0 POINTS) Needs help with dressing self or 
needs to be completely dressed.  
TOILETING  
Points: ________  
(1 POINT) Goes to toilet, gets on and off, 
arranges clothes, cleans genital area 
without help. 
(0 POINTS) Needs help transferring to the toilet, 
cleaning self or uses bedpan or commode. 
TRANSFERRING  
Points: ________  
(1 POINT) Moves in and out of bed or 
chair unassisted. Mechanical transfer 
aids are acceptable. 
(0 POINTS)Needs help in moving from bed to 
chair or requires a complete transfer. 
CONTINENCE  
Points: ________  
(1 POINT) Exercises complete self 
control over urination and defecation.  
(0 POINTS) Is partially or totally incontinent of 
bowel or bladder.  
FEEDING  
Points: ________  
(1 POINT) Gets food from plate into 
mouth without help. Preparation of food 
may be done by another person.  
(0 POINTS) Needs partial or total help with 
feeding or requires parenteral feeding.  
 
TOTAL Points:______________ 
 
 
 
 
2. Grip strength    
Subjects elbow should be at a 90 degree angle without arm supported or resting on table or against 
chest wall. Each grasp should be completed with the dynamometer in the dominant hand. 
 
Grasp 1____________ 
Grasp 2___________ Grasp3____________   Average_____________ 

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Grip Strength, stratified by gender and body mass index (BMI) quartiles  
 
Gender 
BMI 
Cutoff for grip strength (Kg) criterion for 
frailty 
Male 
 
 
≤24 
≤29 
 24.1–26 
≤30 
26.1–28 
≤31 
>28 
≤32 
Female 
 
 
≤ 23 
≤17 
23.1–26 
≤17.3 
26.1–29 
≤18 
>29 
≤21 
 
 
3.    5 Meter Walk Time    
This examination should be performed indoors, along a long, flat, straight, enclosed corridor with a hard 
surface that is seldom traveled.  The walking course must be 5 meters in length (15 feet).  The time to 
walk this distance is to be recorded.  
 
 _______________seconds 
 
Walk Time, stratified by gender and height  
Gender 
Height 
Cutoff values for Time to Walk 5 meters criterion for 
frailty 
Male 
 
 
 ≤ 173 cm 
≥ 7sec 
 > 173 cm 
≥ 6sec 
Female 
 
 
≤159 cm 
≥ 7sec 
> 159 cm 
≥ 6sec 
 
 
 

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APPENDIX VIII: 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 IX: CANADIAN CARDIOVASCULAR SOCIETY GRADING OF ANGINA PECTORIS  
Grade 
Description 
 
Grade I  
 
Ordinary physical activity does not cause 
angina, such as walking and climbing stairs. 
Angina with strenuous or rapid or prolonged 
exertion at work or recreation  
 
 
Grade II 
Slight limitation of ordinary activity. Walking or 
climbing stairs rapidly, walking uphill, walking or 
stair climbing after meals, or in cold, or in wind, 
or under emotional stress, or only during the 
few hours after awakening. Walking more than 
two blocks on the level and climbing more than 
one flight of ordinary stairs at a normal pace 
and in normal conditions  
 
 
Grade III 
 
Marked limitation of ordinary physical activity. 
Walking one or two blocks on the level and 
climbing one flight of stairs in normal conditions 
and at normal pace 
 
 
Grade IV 
 
Inability to carry on any physical activity 
without discomfort, anginal syndrome may be 
present at rest 
 
 
  
 
 

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APPENDIX X: QUALITY OF LIFE- EQ-5D 3L 
 
By placing a checkmark in one box in each group below, please indicate which statements best describe 
your own health state today. 
Mobility 
I have no problems in walking about 
 
 
I have some problems in walking about 
 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 
 
I have some problems washing or dressing myself 
 
 
I am unable to wash or dress myself 
 
 
Usual Activities (e.g. work, study, housework, family or leisure activities) 
I have no problems with performing my usual activities 
 
 
I have some problems with performing my usual activities 
 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
 
I have moderate pain or discomfort 
 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 
I am moderately anxious or depressed 
 
 
I am extremely anxious or depressed 
 
 
 
 

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To help people say how good or bad a health state is,  we have drawn a 
scale (rather like a thermometer) on which the best state you can 
imagine is marked 100 and the worst state you can imagine is marked 0. 
  
 
 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100 
Worst 
imaginable 
health state 
0 
Best  
imaginable 
health state 

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APPENDIX XI: QUALITY OF LIFE – SF-36v2 
 

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APPENDIX XII: QUALITY OF LIFE-KANAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ)  
 

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

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APPENDIX XIV: BARTHEL INDEX 
 
 
 
 

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APPENDIX XV: 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 XVI: NIH STROKE SCALE (NIHSS) 
 

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APPENDIX XVII: 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.  

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Patients with any of these findings should be referred to the physician ordering or supervising the test 
for individual clinical assessment and a decision about the conduct of the test. The results from a resting 
electrocardiogram done during the previous 6 months should also be reviewed before testing. Stable 
exertional angina is not an absolute contraindication for a 6MWT, but patients with these symptoms 
should perform the test after using their antiangina medication, and rescue nitrate medication should be 
readily available. A deviation from the Clinical Investigation Plan will need to be collected if the subject is 
unable to complete this test. 
LOCATION 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a hard 
surface that is seldom traveled. If the weather is comfortable, the test may be performed outdoors. The 
walking course must be 30 m in length. A 100-ft hallway is, therefore, required. The length of the 
corridor should be marked every 3 m. The turnaround points should be marked with 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. 

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Baseline Measurements 
1. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary equipment (lap 
counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point.  
Instruct the patient as follows:  
“The object of this test is to walk as far as possible for 6 minutes. You will walk back 
and forth in this hallway. Six minutes is a long time to walk, so you will be exerting 
yourself. You will probably get out of breath or become exhausted. You are 
permitted to slow down, to stop, and to rest as necessary. You may lean against the 
wall while resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly 
around the cones and continue back the other way without hesitation. Now I'm 
going to show you. Please watch the way I turn without hesitation." 
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.  
"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."  
 

ABT-CIP-10260 Ver. [A] 
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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. 
 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
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APPENDIX XVIII: 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 XIX: EXPLANT, RETURN, AND ANALYSIS OF VALVE 
 
The disposition of explanted valves warrants special consideration, as their proper return will allow for 
analyses providing valuable information. 
 
Clinical Study Sites’ Responsibilities for Explant and Return of Device: the Sponsor requests that all 
Portico™ transcatheter aortic valves that are explanted or recovered be returned as follows: 
 
o Contact the Abbott Clinical Manager(s) for this study as soon as it is learned that a Portico™ 
valve will be explanted, or recovered during an autopsy. The Clinical Representative(s) will obtain 
a RA# (used for returning products to the Sponsor), and then send a Product Return Kit to the 
site for return of the explanted valve 
o When possible, take in situ photographs of the valve. 
o Remove the valve from the patient and immediately place it in the inner jar of the product return 
kit. (If the explant kit is not available, place the valve in any specimen jar until the product return 
kit arrives.) 
o Cover the valve with a formalin solution (usual lab concentration 3-8%). If an alternate 
solution is used [i.e., alkaline glutaraldehyde (Cidex) at 0.5-1% concentration], please 
indicate the solution type and concentration on the specimen container. 
o Secure the cap. 
o Complete the round white label with device, patient, and surgeon information. 
o Place the completed label on the cap of the inner jar and fold tape edges down over jar. 
o Place the small labeled jar in the absorbent wrapping provided, and place inside the larger jar. 
o Secure the cap. 
o Place the outer jar into the shipping box. Tape the box closed. 
o Write the RA#, and the name and phone number of the person responsible for shipping the 
valve on the return shipping label. 
o For infectious specimens, complete the highlighted portions of the Shipper’s Declaration for 
Dangerous Goods form, and keep this form with the product return kit. 
o Send the packaged valve: 
Attention: Product Performance Engineering Team  
Roseville Distribution Center 
2305 Walnut Street 
Roseville, MN 55113 USA  
Tel.: (651) 756-2000 
 
o In situ photographs, and operative/autopsy notes will enter the EPIQ complaint system if the explant is 
associated with a complaint.  
 
ABBOTT Responsibilities for the Analysis of an Explanted and Returned Device: 
 
Any Portico™ transcatheter aortic valve that is explanted or recovered at autopsy and returned will, upon 
receipt at ABBOTT be evaluated according to documented ABBOTT procedures. Abbott does not 
investigate returned valves unless there is a complaint associated with the valve. 
 
 
 

ABT-CIP-10260 Ver. [A] 
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APPENDIX XX: INSTRUCTIONS FOR DEVICE RETURN- LARGE AND SMALL KITS 
 
Instructions for Packaging and Returning Products to the Sponsor, Abbott (formerly St. Jude Medical) 
from US and Outside of US Locations 
 
The Sponsor provides instructions and a Device Return Kit (DRK) for components being returned for 
analysis. Please follow these instructions when returning products. 
 
1- Email the completed product Complaint and Event Form or Field Experience Report. Please 
submit event within 2 calendar days of becoming aware of the event. 
 
(NOTE: ONLY ONE DEVICE PER RGA NUMBER AND DEVICE RETURN KIT) 
2- Clearly print the RGA number in the designated space on the event report form. 
3- Package device to be returned in DRK as follows: 
a. Insert hands into rubber gloves as provided in the DRK 
b. With gloved hands, place device to be retuned into zip lock bag and seal shut. 
c. Carefully position the sealed zip lock bag and device into the bio-hazard bag without 
damaging returned components. 
d. Place absorbent strip into bio-hazard bag. 
e. Follow instructions on the front facing bag to seal biohazard bag. 
f. Place plastic biohazard bag inside the tyvek envelope (follow instructions on the 
outside of the tyvek envelope). 
g. Assemble the box provided in the DRK following the directions on the box. 
h. Place the tyvek envelope with the sealed biohazard pouch into box, again being careful not to 
damage 
i. Close box using the instructions provided on the panel of the box and seal with Chem-Tran Box 
Sealing. 
j. Affix UN3373 Label to the area as shown on the outer shipping box. 
4- Clearly print the RGA number on the outer portion of the DRK box. 
5- Affix the address label provided to the outside of the box and return DRK to: 
 
Attention: Product Performance Engineering Team  
Roseville Distribution Center 
2305 Walnut Street 
Roseville, MN 55113 USA  
Tel.: (651) 756-2000 
 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
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APPENDIX XXI: GERMAN HANDLING OF SERIOUS ADVERSE EVENTS 
The scope of this section is to implement the reporting obligation in accordance with §3, section 5 of the 
German MPSV (Medical Products Safety Ordinance), taking into consideration that notification must be 
done immediately in accordance § 5, section 2 of the MPSV.  
 
1.  Definition of SAE according to §2, Section 5 MPSV:  
Serious Adverse Event: any untoward event occurring within a clinical investigation requiring 
authorization, which directly or indirectly led to, or which might have led or could lead to 
death or a serious deterioration in the health of the patient, a user or other person, without 
taking into account whether the event was caused by the medical device.  
2.  Notification of SAEs:  
• 
As soon as the investigator becomes aware of an SAE during the course of a study, the 
sponsor (Abbott) must be informed immediately, and in no case later than 72 hours after 
becoming aware.  
• 
The sponsor (Abbott) also has the obligation to inform the BfArM of all SAEs according to 
following table.  
 
Condition for reporting to 
BfArM 
Country of 
occurrence 
Timeline for 
reporting to 
BfArM 
Form 
a causal relationship 
between the SAE and the 
investigational medical 
device, a comparator 
device, diagnostic or 
therapeutic procedures 
performed as part of the 
clinical trial or other 
conditions of the trial 
conduct cannot be 
excluded 
Germany 
immediately 
Single report 
German SAE Report Form 
Please send to MPSAE@bfarm.de 
all other 
countries 
where the 
clinical trial 
is 
performed 
immediately 
Summary table 
MEDDEV 2.7/3 SAE report table 
 
All SAEs shall be documented using 
the same Excel file, in a cumulative 
manner, using the same Excel sheet. 
 
Please send to MPSAE@bfarm.de 
a causal relationship 
between the SAE and the 
investigational medical 
device, a comparator 
device, diagnostic or 
therapeutic procedures 
performed as part of the 
clinical trial or other 
conditions of the trial 
conduct can be excluded 
All 
quarterly 
Summary table 
MEDDEV 2.7/3 SAE report table 
Please complete the MEDDEV Excel 
sheet as outlined above. 
Please send to MPSAE@bfarm.de 
quarterly 
All SAEs 
All 
Quarterly 
SAE summary evaluation 
Evaluation 
Annex 3.1 complication rate 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
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Please send to MPSAE@bfarm.de 
Please observe our notes on 
completing the SAE summary 
evaluation 
 
o The German SAE Report Form is available on the BfArM homepage: 
http://www.bfarm.de/SharedDocs/Formulare/EN/MedicalDevices/report_form_clinical_trials_
SAE.html 
http://www.bfarm.de/DE/Medizinprodukte/form/functions/formmp-node.html 
• 
Please note that the SAE gets a unique ID which consists of 4 Parts: 
- 
The Study Code (CRD_XXX for the ABBOTT Study Code of this study) 
- 
The Center ID (ORACLEID = CenterName) 
- 
The Patient No 
- 
The Date of SAE in the format (Year(2-digits)MonthDay) 
Example: CRD_910_EU0284_01_160203 for an event which occurred on 3 February for 
Patient 1 in center EU0284 within the Study CRD_878. 
• 
The German Quarterly Report Template is available on the BfArM Homepage: 
http://www.bfarm.de/SharedDocs/Formulare/EN/MedicalDevices/sae_template.html 
Table Complication Rates 
http://www.bfarm.de/SharedDocs/Formulare/EN/MedicalDevices/sae_complication_rates.html 
Instructions for completing the quarterly assessment form for serious adverse events 
http://www.bfarm.de/SharedDocs/Formulare/EN/MedicalDevices/sae_template_notes.html 
 
• 
The investigator will be instructed on this obligation during the initiation visit. 
• 
Information about the obligation must be documented in the "training log".  
• 
Written confirmation that this working procedure has been passed on to the trial center is sent 
to the investigator and then attached to the study file.  
 
 
1. Responsibility of the investigators: 
 
1. The investigator has to notify the SAE to the sponsor without undue delay. 
2. SAEs should be reported either by  
1. eDC (primary reporting tool) 
2. E-Mail: AdverseEvent@sjm.com; study name and patient identification must 
always be reported in the subject of email. 
• 
The investigator or main investigator is obliged to respect the deadline for notification of 
SAEs. 
• 
A person within the study center will be designated to collect the necessary information. 
• 
A person within the study center will be designated to pass on this information to the 
sponsor. A list of people (including a representative) will be prepared for this purpose. 
 
 
2. Responsibilities of the monitor (Abbott): 
 
• 
The monitor will be instructed of his/her responsibilities with regard to SAEs. 

ABT-CIP-10260 Ver. [A] 
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• 
If the monitor discovers an SAE during the course of the study that was not notified or not 
notified within the notification deadline, the sponsor's action plan will take effect. The BfArM is 
then notified of the SAE without undue delay and the investigator is informed of it straight 
away.  
 
3. Responsibilities of the sponsor 
 
• 
The sponsor (Abbott) shall notify any SAEs without undue delay (at the latest however within 
72 hours) after awareness. 
• 
A person will be designated to verify SAEs that occur during the clinical study. 
• 
A list of Abbott people who shall be informed about SAEs is to be drawn up. 
• 
A person will be designated who is responsible for the assessment of any SAEs. 
• 
A person or team will be designated who is responsible for initiating corrective actions if 
necessary. 
 
4. Responsibilities of the sponsor in Germany 
 
• 
All people within Abbott who are involved in this clinical study be will instructed of the 
notification deadlines and are obliged to respect them. 
• 
SAEs/PERs (Product Event Reports) are coordinated by the German project manager (CPL) 
or by Jörg Scheiner (Manager Clinical Safety/Compliance, Germany). 
• 
SAE notifications to the BfArM and the Ethics Committee are to be made by the CPL or by 
Clinical Safety. 
• 
The Field Clinical Manager or the study office will take care of SAE/PER notifications should 
both of the above people be unable to do so. 
• 
Vigilanz-Responsible for this study: Jörg Scheiner (Manager Clinical Study Logistics, Abbott, 
Germany) 
Phone: +49-6196-7711-241, E-Mail: AdverseEvents-Germany@sjm.com 
 
5. Notification of SAEs in other countries 
 
SAEs are also reported to following countries when participation in the study: 
• 
Denmark 
• 
Italy 
• 
Netherlands 
• 
Sweden 
• 
Ukraine 
• 
United Kingdom 
 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
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APPENDIX XXII: INDEPENDENT COMMITTEE AND CORE LABORATORY CONTACT DETAILS 
Subject Selection Committee 
 
Interventional 
Cardiologists 
Raj Makkar, M.D. 
Cedars-Sinai Medical Center 
Los Angeles, CA 
David Brown, M.D. 
Heart Hospital Baylor 
Plano, TX 
Samir Kapadia, M.D. 
Cleveland Clinic 
Cleveland, OH 
Carlos Ruiz, M.D. 
Hackensack University Medical Center 
Hackensack, NJ 
Stephen Worthley, 
M.D. 
Genesis Care 
Adelaide, Australia 
Cardiovascular 
Surgeons Greg Fontana, M.D. 
Los Robles Hospital and Medical Center 
Thousand Oaks, CA 
Nimesh Desai, M.D.  
Hospitals of the University of Pennsylvania 
Philadelphia, PA 
William Brinkman, 
M.D. 
 
Heart Hospital Baylor 
Plano, TX 
Vinod Thourani, M.D. 
Washington Hospital Center, Washington, 
D.C 
Alfredo Trento, M.D.  
Cedars-Sinai Medical Center 
Los Angeles, CA 
Neurologist Jeffrey Saver, M.D. 
 
University of California 
Los Angeles, CA 
Sponsor St. Jude Medical (now 
Abbott) 
Plymouth, MN 
 
Echocardiography Core Laboratory 
Director 
Neil J. Weissman, 
M.D.  
Medstar Health Research Institute 
6525 Belcrest Road, Suite 700 
Hyattsville, MD 20782 
 
 
 
CT Sizing Core Laboratory 
Director 
Rahul Sharma, M.D.  
Cedars-Sinai Heart Institute 
8700 Beverly Blvd 
West Hollywood, CA 90048-1804 

ABT-CIP-10260 Ver. [A] 
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APPENDIX XXIII: RATES OF FORSEEABLE ADVERSE EVENTS 
The rates of foreseeable adverse events indicated in the table below are based on literature data and two Abbott- 
sponsored clinical studies that used the first-generation Portico™ Delivery System to transfemorally implant the 
Portico™ valve in a high or extreme surgical risk cohort (Portico TAVI System CE Mark Study, 222 subjects 
underwent an attempted Portico implant; and Portico I PMCF study, 941 subjects underwent an attempted Portico 
implant). Currently no clinical data is available for the second-generation FlexNav™ Delivery System. The rationale 
for basing rates from clinical studies that used the first-generation Portico™ Delivery System is the procedure to 
load and deploy the valve is the same for the FlexNav™ Delivery System and no additional risks have been 
identified for the FlexNav™ Delivery System compared to the first-generation Portico™ Delivery System.    
 
Potential Adverse Events 
Very 
common 
(≥10%) 
Common or 
frequent 
(≥1.0% to <10%) 
Uncommon or 
infrequent 
(≥0.1% to <1.0%) 
Rare 
(≥0.01% 
to<0.1%) 
Very rare 
(< 0.01%) 
access site complications (e.g., pain, bleeding, 
infection, hematoma, pseudoaneurysm, etc.) 
X 
 
 
 
 
 
 acute coronary obstruction 
 
 
X 
 
 
  acute myocardial infarction 
 
X 
 
 
 
allergic reaction to antiplatelet agents, contrast 
medium, or valve components 
 
 
 
X 
 
aortic rupture 
 
 
X 
 
 
ascending aorta trauma 
 
 
X 
 
 
 atrio-ventricular node block 
X 
 
 
 
 
 cardiac arrhythmias 
X 
 
 
 
 
embolism 
 
X 
 
 
 
endocarditis 
 
X 
 
 
 
heart failure 
 
X 
 
 
 
hemodynamic compromise 
X 
 
 
 
 
hemolysis 
 
 
 
X 
 
hemolytic anemia 
 
 
 
X 
 
hemorrhage (Bleeding) 
X 
 
 
 
 
hypotension or hypertension 
 
 
X 
 
 
infection 
 
X 
 
 
 
myocardial ischemia  
 
X 
 
 
 
mitral valve insufficiency 
 
 
 
X 
 
multi-organ failure 
 
 
 
 
X 
non-structural dysfunction (i.e., entrapment by pannus, 
paravalvular leak, inappropriate sizing or positioning) 
 
 
X 
 
 
pericardial effusion 
 
X 
 
 
 
perforation of the myocardium or a blood vessel 
 
X 
 
 
 
pannus 
 
 
X 
 
 
renal insufficiency or renal failure (Acute kidney injury) 
X 
 
 
 
 
sepsis 
 
X 
 
 
 
stroke 
 
X 
 
 
 
structural deterioration (i.e., calcification, leaflet tear) 
 
 
 
X 
 
thrombosis 
X 
 
 
 
 
tamponade 
 
X 
 
 
 
valve migration 
 
 
X 
 
 
vessel dissection or spasm. 
 
X 
 
 
 
transfusion 
X 
 
 
 
 
conversion to open surgical procedure 
 
X 
 
 
 
reoperation 
 
X 
 
 
 
emergent balloon valvuloplasty 
 
 
 
X 
 
emergent percutaneous coronary intervention (PCI) 
 
X 
 
 
 
emergent surgery (i.e., coronary artery bypass, heart 
valve replacement) 
 
 
 
X 
 
explantation 
 
X 
 
 
 
permanent disability 
 
 
 
X 
 
death 
 
X 
 
 
 
permanent pacemaker 
X 
 
 
 
 
Leakage, regurgitation 
X 
 
 
 
 

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APPENDIX XXIV: LABELS 
  
 
 

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

ABT-CIP-10260 Ver. [A] 
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APPENDIX XXVI: INFORMED CONSENT FORM 
The informed consent template will be kept under a separate cover and is available upon request from the 
Sponsor Clinical Project Manager for the clinical investigation. 
  
 

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APPENDIX XXVII: 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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Clinical Investigation Plan 
 
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APPENDIX XXVIII: CONTACT INFORMATION 
A list of site contacts can be obtained upon request from the Clinical Project Manager for the clinical 
investigation. 
 

ABT-CIP-10260 Ver. [A] 
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APPENDIX XXIX: 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. 
 
IRB/EC and relevant Regulatory Authorities, if applicable, will be notified of amendments to the CIP. 
 
Amendment 
Number 
Version 
Date 
Details 
Rationale 
Not Applicable 
A 
13SEP2018 
First release of CIP 
NA 
 
 
 

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APPENDIX XXX: CIP SUMMARY 
Clinical 
Investigation 
Name and Number 
ABT-CIP-10260 
FlexNav EU CE Mark Study 
Title 
Assessment of the Abbott FlexNav™ Delivery System for Portico™ 
Transcatheter Aortic Valve Implantation in High and Extreme Risk Patients with 
Symptomatic Severe Aortic Stenosis 
Objective(s) 
The primary objective of the FlexNav EU CE Mark study is to characterize the 
safety of the second-generation Portico™ FlexNav™ Delivery System (referred 
herein as the FlexNav™ Delivery System). 
Device 
Under 
Investigation 
Devices under investigation in this clinical investigation include the FlexNav™ 
Delivery System(s) (18 F and 19 F) and FlexNav™ Loading System(s) (Small 
and Large), which are both approved for investigational use only. Other devices 
to be used in the clinical investigation include all four (4) market released St. Jude 
Medical (SJM) Portico™ valve sizes (23mm, 25mm, 27mm and 29mm).  
Number 
of 
Subjects Required 
for 
Inclusion 
in 
Clinical 
Investigation 
Up to 200 subjects will be enrolled in the clinical investigation, with a predefined 
minimum of 73 subjects required to analyze the primary safety endpoint.  No site 
may enroll more than 20% of the maximum number of enrolled subjects (n=40). 
Clinical 
Investigation 
Design 
Prospective, single-arm, non-randomized, multi-center, CE Mark investigational 
study 
Primary 
Endpoint(s) 
The primary safety endpoint of the FlexNav EU CE Mark study is VARC II defined 
major vascular complications at 30 days post index procedure. 
Major 
(Powered) 
Secondary 
Endpoints  
Not applicable 
Subject Follow-up 
Subject data will be collected in-person at the investigational site at baseline, pre-
procedure, peri-procedure, post-procedure, discharge, 30 days, 6 months and 
one-year from the index procedure.  
 
Echocardiographic data will be collected at screening, peri-procedure (optional), 
and discharge as well as 30 days, 6 months and 12-months post implantation 
Inclusion Criteria 
Candidates for High Risk classification must meet all the following inclusion 
criteria: 
 
1. Subjects must have co‐morbidities such that the local heart team concur the 
predicted risk of operative mortality is ≥15% or a minimum STS score of 8%.  
 
a) A candidate who does not meet the STS score criteria of ≥ 8% may be 
included in the study if at least one surgeon in the local heart team 
concludes and documents the patient’s predicted risk of operative 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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express written consent of Abbott 
Template: 86357 Rev. E 
 
Page 130 of 132 
mortality is ≥15%. The surgeon's assessment of operative comorbidities 
(including frailty indices) not captured by the STS score must be 
documented in the study case report form as well as in the patient medical 
record. 
 
2. Subject is of legal age or older for consent in the host country. 
 
3. Subject has senile degenerative aortic valve stenosis with echo-derived 
criteria: mean gradient >40 mmHg or jet velocity greater than 4.0 m/s or 
doppler velocity index (DVI) <0.25 and an initial aortic valve area (AVA) of ≤ 
1.0 cm2 (indexed EOA ≤ 0.6 cm2/m2). (Qualifying AVA baseline 
measurement must be within 60 days prior to informed consent). 
 
4. Subject has symptomatic aortic stenosis as demonstrated by NYHA 
Functional Classification of II, III, or IV. 
 
5. 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) of the respective clinical site. 
 
6. The subject and the treating physician agree that the subject will return for all 
required post‐procedure follow‐up visits. 
 
7. Subject’s aortic annulus is 19‐27mm diameter 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 echo and non‐contrast 
CT of chest and abdomen/pelvis may be accepted.  
 
All candidates for Extreme Risk classification must meet # 2, 3, 4, 5, 6, 7 of the 
above criteria, and  
 
8. After formal consultation with the local heart team (including at least one 
surgeon) it is agreed that medical factors preclude the subject from 
undergoing operation, based on a conclusion that the probability of death or 
serious, irreversible morbidity exceeds the probability of meaningful 
improvement. Specifically, the probability of death or serious, irreversible 
morbidity should exceed 50%. The local heart teams' consult notes shall 
specify the medical or anatomic factors leading to that conclusion and include 
a printout of the calculation of the STS score to additionally identify the risks 
in these patients. 
Exclusion Criteria 
Candidates will be excluded if any of the following conditions are present: 
 
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. Aortic valve is a congenital unicuspid or congenital bicuspid valve, or is non-
calcified as verified by echocardiography. 
 
3. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with 
predominant aortic regurgitation 3-4+). 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
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express written consent of Abbott 
Template: 86357 Rev. E 
 
Page 131 of 132 
4. Any percutaneous coronary or peripheral interventional procedure performed 
within 30 days prior to index procedure. 
 
5. 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 LVOT, severe (greater than 3+) mitral 
insufficiency, or severe mitral stenosis with pulmonary compromise.  
 
6. Blood dyscrasias as defined: leukopenia (WBC<3000 mm3), acute anemia 
(Hb < 9 g/dL), thrombocytopenia (platelet count <50,000 cells/mm³).  
 
7. History of bleeding diathesis or coagulopathy. 
 
8. Cardiogenic shock manifested by low cardiac output, vasopressor 
dependence, or mechanical hemodynamic support. 
 
9. Untreated 
clinically 
significant 
coronary 
artery 
disease 
requiring 
revascularization. 
 
10. Hemodynamic instability requiring inotropic support or mechanical heart 
assistance. 
 
11. Need for emergency surgery for any reason. 
 
12. Hypertrophic cardiomyopathy with or without obstruction (HOCM). 
 
13. Severe ventricular dysfunction with LVEF <20% as measured by resting 
echocardiogram. 
 
14. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. 
 
15. Active peptic ulcer or upper GI bleeding within 3 months prior to index 
procedure. 
 
16. A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine 
(Ticlid), or clopidogrel (Plavix), or sensitivity to contrast media which cannot 
be adequately premedicated. 
 
17. Recent (within 6 months prior to index procedure date) cerebrovascular 
accident (CVA) or a transient ischemic attack (TIA). 
 
18. Renal insufficiency (creatinine > 3.0 mg/dL) and/or end stage renal disease 
requiring chronic dialysis. 
 
19. Life expectancy < 12 months from the time of informed consent due to non-
cardiac co-morbid conditions. 
 
20. 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.  
 
21. Native aortic annulus size < 19 mm or > 27 mm per the baseline diagnostic 
imaging. 
 

ABT-CIP-10260 Ver. [A] 
Study Name: FlexNav EU CE Mark Study 
Clinical Investigation Plan 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the 
express written consent of Abbott 
Template: 86357 Rev. E 
 
Page 132 of 132 
22. Aortic root angulation > 70°. 
 
23. Currently participating in an investigational drug or device study. 
 
24. Active bacterial endocarditis within 6 months prior to the index procedure. 
 
25. Bulky calcified aortic valve leaflets in close proximity to coronary ostia. 
 
26. Non-calcified aortic annulus. 
 
27. 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, or severe tortuosity. 
 
28. In the judgment of the investigator, a condition that could limit a patient’s 
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