International Long-term Follow-up Study of Patients Implanted With a Portico™ Valve
Conditions: Aortic Valve Stenosis
Sponsor: Abbott Medical Devices

          
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CPRB Code 
: CV-12-054-EU-PV 
Project Acronym 
: PORTICO I 
Project Version 
: 5.0 
Version Date 
: 14JUL2016 
 
PORTICO I STUDY 
International Long-term Follow-up Study of Patients 
Implanted with a PORTICO™ Valve 
Clinical Investigation Plan (CIP)  
 
Sponsor 
 
St. Jude Medical Coordination Center BVBA  
The Corporate Village 
Da Vincilaan 11- box F1 
B-1935 Zaventem  
Belgium 
Tel: +32 2 774 69 37 
Fax: +32 2 774 69 46 
 
 
Clinical 
Coordinating 
Investigators 
Prof L. Søndergaard 
Rigshospitalet Copenhagen UniversityHospital 
Kardiologisk Klinik B 
Blegdamsvej 9 
2100 Copenhagen 
Denmark 
Tel: +45 35452018 
 
Prof F.Maisano, MD 
FESC Head of Cardiovascular Surgery 
University Hospital Zurich   
Ramistrasse 100  
Zurich CH-8091  
Switzerland 
Tel: +41 (0)44 255 33 81 
 
Signature 
______________________________________ ____________________________________ 
Date 
______________________________________ ____________________________________ 
 
National 
Principal 
Investigators 
Prof S. Worthley, M.B., B.S., Ph.D, F.R.A.C.P, 
R.A.C.C., F.C.S.A.N.Z. 
Dept Cardiology 
St Andrews Hospital 
350 South Terrace Adelaide 
SA, 5000 
Australia 
Tel: +61 8 8223 4288 
 
Dr. J. Rodes 
Institut Universitaire De Cardiologie Et De 
Pneumologie de Québec (ICUPQ) 
2725 ch Sainte-Foy,  
Québec, QC  
G1V 4G5 
Canada 
Tel: +1 418 656 8711 
 
Signature 
______________________________________ 
____________________________________ 
Date 
______________________________________ 
____________________________________ 
 
 
 
 
 
 
 
 
All rights reserved. No portion of this work may be reproduced in whole or in part without the express written permission of SJM International, Inc. 
Portico™ Valve will be referred as Portico Valve in the rest of the document. 

          
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Coordinating Investigator 
SIGNATURE PAGE 
 
 
CIP PORTICO I 
International Long-term Follow-up Study of Patients 
Implanted with a PORTICO™ Valve 
 
Version 5.0 
14JUL2016 
Reference #:  
 
I have read and agree to adhere to the clinical investigational plan and all regulatory requirements 
applicable in conducting this clinical study.   
 
Coordinating Investigator  
 
Printed name:  
 ____________________________________ 
 
Signature: 
 
____________________________________ 
 
Date:   
 
 ____________________________________ 
 

          
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Revision History 
Amendment 
N° 
Project 
Version 
Date 
Rationale 
Details 
NAP 
V1.0 
28JAN2013 
First release of the CIP 
 
1 
V2.0 
29APR2013 
Global modification of the CIP : 
• 
To allow collection of any other 
data acquired as part of patient’s 
native aortic valve assessment not 
captured by default in the case 
report forms (CRF). 
• 
To address comments received from 
l’Agence nationale de sécurité du 
médicament et des produits de santé 
(ANSM)  in France regarding 
device deficiencies. 
See summary 
of changes (in 
CIP V2.0) 
2 
V3.0 
25JUN2013 
Global Modification of the CIP: 
• 
To include two additional countries 
(Canada and Australia) to 
participate into the clinical 
investigation and to adjust 
subsequently the approximate 
number of sites. 
To include an additional 
exclusion criterion. 
See summary 
of changes (in 
CIP V3.0) 
3 
V4.0 
17DEC2013 
Global modification of the CIP: 
• 
To include additional assessments 
and recommendations strongly 
advised by Steering Committee 
members.  
• 
To clarify 1 exclusion criterion and 
certain study activities required by 
the protocol in order to avoid 
misinterpretation and to ensure all 
required examinations are 
performed. 
 
See summary 
of changes (in 
CIP V4.0) 
4 
V5.0 
22JUN2016 
Global modification of the CIP:  
• 
To integrate all local revisions 
(Australia, Canada, France and 
Other EU version) into one Global 
version. 
• 
To update the protocol to match 
routine practice for TAVI patient 
follow-up. 
See summary 
of changes (in 
CIP V5.0) 
 
 
 
 

          
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Table of Contents 
1 
Summary of changes ................................................................................................................................... 7 
1.1 
Rationale for revision .......................................................................................................................... 7 
2 
Synopsis .................................................................................................................................................... 10 
2.1 
Clinical investigation flow charts ...................................................................................................... 12 
3 
Contacts .................................................................................................................................................... 14 
4 
Background ............................................................................................................................................... 15 
5 
Clinical study design ................................................................................................................................. 17 
5.1 
Purpose .............................................................................................................................................. 17 
5.2 
Objectives .......................................................................................................................................... 17 
5.2.1 
Primary Objective .......................................................................................................................... 17 
5.2.2 
Secondary Objective ...................................................................................................................... 17 
5.3 
Endpoints ........................................................................................................................................... 17 
5.3.1 
Primary Endpoint ........................................................................................................................... 17 
5.3.2 
Secondary Endpoints ..................................................................................................................... 17 
5.4 
Population .......................................................................................................................................... 18 
5.5 
Device description ............................................................................................................................. 18 
5.6 
Geographical device considerations .................................................................................................. 19 
5.6.1 
For EU sites: .................................................................................................................................. 19 
5.6.2 
For Australian and Canadian sites: ................................................................................................ 19 
5.6.3 
Investigational device accountability for Australian and Canadian sites: ..................................... 19 
5.7 
Hospital heart team ............................................................................................................................ 20 
5.8 
Patient screening ................................................................................................................................ 20 
5.9 
Point of enrollment ............................................................................................................................ 20 
5.10 
Inclusion and Exclusion Criteria ....................................................................................................... 21 
5.10.1 
Inclusion Criteria ........................................................................................................................... 21 
5.10.2 
Exclusion Criteria .......................................................................................................................... 21 
5.10.3 
Additional considerations .............................................................................................................. 23 
6 
Procedures ................................................................................................................................................. 24 
6.1 
Clinical investigation flow chart........................................................................................................ 24 
6.1.1 
Cohort A (Prospective) .................................................................................................................. 24 
6.1.2 
Cohort B ........................................................................................................................................ 24 
6.2 
Clinical investigation activities and visits ......................................................................................... 26 
6.2.1. 
Enrollment Visit ............................................................................................................................ 33 
6.2.2. 
Baseline Visit (Cohort A only) ...................................................................................................... 34 
6.2.3. 
Portico Valve Implant visit - Index procedure (Cohort A only) .................................................... 34 
6.2.4. 
Pre-Discharge visit (Cohort A only) .............................................................................................. 36 
6.2.5. 
30 Day follow-up visit (Cohort A only) ........................................................................................ 36 
6.2.6. 
1 Year follow-up visit (Cohort A only) ......................................................................................... 37 
6.2.7. 
2 Year follow-up visit .................................................................................................................... 37 
6.2.8. 
3 Year follow-up visit .................................................................................................................... 38 
6.2.9. 
4 Year follow-up visit .................................................................................................................... 38 
6.2.10. 
5 Year follow-up visit .................................................................................................................... 39 
6.2.11. 
Unscheduled Visit ......................................................................................................................... 39 
6.2.12. 
Description of activities performed by Sponsor Representatives .................................................. 39 
6.2.13. 
Description of post-investigational provision of medical care ...................................................... 40 
7 
Clinical Investigation Conduct ................................................................................................................. 41 
7.1 
Statements of Compliance ................................................................................................................. 41 
7.1.1. 
Adherence to the Clinical Investigation Plan ................................................................................ 41 
7.1.2. 
Repeated non-compliance.............................................................................................................. 42 
7.2 
Informed Consent Process ................................................................................................................. 42 
7.2.1. 
General Process ............................................................................................................................. 42 

          
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7.2.2. 
Patient unable to read or write ....................................................................................................... 43 
7.3 
Adverse Event, Adverse Device Effect, Device Deficiency ............................................................. 43 
7.3.1. 
Definitions (ISO 14155:2011) ....................................................................................................... 43 
7.3.2. 
Procedure for assessing, recording and reporting adverse events, adverse device effects, serious 
adverse events, serious adverse device effects and device deficiencies ........................................................ 45 
7.4 
Patient Death ..................................................................................................................................... 46 
7.4.1. 
Procedure for recording and reporting Patient Death .................................................................... 46 
7.5 
Criteria and procedures for patient withdrawal or discontinuation ................................................... 47 
7.6 
Document and data control ................................................................................................................ 48 
7.6.1. 
Traceability of documents and data ............................................................................................... 48 
7.6.2. 
Definition of source data ............................................................................................................... 48 
7.6.3. 
Recording of data .......................................................................................................................... 48 
7.6.4. 
Review of data (source data verification) ...................................................................................... 48 
7.7 
Monitoring ......................................................................................................................................... 48 
7.7.1. 
Designated Monitors...................................................................................................................... 49 
7.7.2. 
Monitoring Plan ............................................................................................................................. 49 
7.7.3. 
National Competent Authority (NCA)/ National Regulatory Authority (NRA) Inspections ........ 49 
7.8 
Investigation Termination ................................................................................................................. 49 
7.8.1. 
Investigation Conclusion ............................................................................................................... 50 
8 
Risks and Benefits of the clinical investigation ........................................................................................ 51 
8.1 
Anticipated clinical benefits .............................................................................................................. 51 
8.2 
Anticipated Adverse Events and Adverse Device Effects ................................................................. 51 
8.3 
Possible interactions with concomitant medical treatments .............................................................. 51 
8.4 
Steps that will be taken to control or mitigate the risks ..................................................................... 51 
8.5 
Risk-to-Benefit Rationale .................................................................................................................. 51 
9 
Statistical considerations........................................................................................................................... 52 
9.1 
Analysis population ........................................................................................................................... 52 
9.2 
Sample size estimation ...................................................................................................................... 52 
9.2.1 
Cohort A ........................................................................................................................................ 52 
9.2.2 
Cohort B ........................................................................................................................................ 52 
9.3 
Primary endpoint analysis ................................................................................................................. 52 
9.4 
Secondary endpoint analysis ............................................................................................................. 53 
9.5 
Interim reporting ................................................................................................................................ 53 
10 
Data Management ..................................................................................................................................... 54 
10.1 
Data Management Plan ...................................................................................................................... 54 
11 
Document Retention ................................................................................................................................. 55 
12 
Amendments to Clinical Investigation Plan ............................................................................................. 56 
13 
Publication Policy ..................................................................................................................................... 57 
14 
Investigation Organization ........................................................................................................................ 58 
14.1 
Investigation Management/Sponsor .................................................................................................. 58 
14.1.1 
Sponsor Responsibilities................................................................................................................ 58 
14.2 
Clinical Investigators ......................................................................................................................... 59 
14.2.1 
Investigator’s responsibilities ........................................................................................................ 59 
14.2.2 
Clinical Coordinating Investigators ............................................................................................... 60 
14.2.3 
Source Data and Patient Files ........................................................................................................ 60 
14.3 
Boards ................................................................................................................................................ 61 
14.3.1 
Steering Committee ....................................................................................................................... 61 
14.3.2 
Clinical Event Committee ............................................................................................................. 61 
14.4 
Outsourcing of duties and functions .................................................................................................. 61 
14.4.1 
Power of Attorney ......................................................................................................................... 61 
15 
Bibliography ............................................................................................................................................. 63 
 
 
 

          
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List of Appendicies 
Appendix A: Abbreviations ............................................................................................................................... 65 
Appendix B: Declaration of Helsinki ................................................................................................................ 67 
Appendix C: Data Collection Method ............................................................................................................... 72 
Appendix D: VARC 2 Endpoints Definitions 19 ................................................................................................ 74 
Appendix E: Surgical Risk Assessment Tools .................................................................................................. 82 
Appendix F: Frailty Assessment ....................................................................................................................... 83 
Appendix G: ATS Guidelines (25) for the Six Minute Walk Test .................................................................... 84 
Appendix H: Structured Interview for the Modified Rankin Scale (mRS) ....................................................... 88 
Appendix I: Peri-procedural instructions .......................................................................................................... 89 
Appendix J: Instruction for paced rhythm assessment in patients with a TAVI related implantation of 
permanent pacemaker ........................................................................................................................................ 90 
Appendix K: Explant, Return, and Analysis of Valve....................................................................................... 91 
Appendix L: Instructions for device return - Large and Small Kits .................................................................. 92 
 
 
 

          
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1 Summary of changes 
1.1 
Rationale for revision 
The primary purpose of this revision is to create a single global Portico I Clinical Investigation Plan (CIP), 
compiling the EMEA, French, Australian and Canadian CIP versions into a single global version.  Minor 
geographical differences will be outlined as necessary in the appropriate sections.  A detailed Summary of 
Changes comparing each of the previous CIP versions is separately available. Additional modifications have 
been made to align the study assessments and data collection with current practice. 
 
Modification 1  
Local CIP versions (EMEA Revision 4.0 17DEC2013 France Revision 3.1 27JAN2014, Australian Revision 
4.1 28JAN2014, and Canadian Revision 4.1 22JAN2014) are consolidated into one global CIP version.  For 
this reason both Clinical Coordinating Investigators, Prof L.SØndergaard (EU), Prof F. Maisano (EU), and 
both National Principal Investigators, Prof S. Worthley (AU) and Dr. Rhodes (CA), are listed with their 
respective addresses including their signatures. Specific local requirements are provided in the global protocol 
in their respective sections. 
 
Modification 2 
The 6 Month visit was removed throughout the CIP because a visit at this interval is not done in routine 
practice. This includes the removal of all separate assessments at 6 months and their corresponding eCRFs. 
 
Modification 3 
The Secondary Endpoints have been modified to align with VARC 2 defined events. The rate of all-cause 
mortality, cardiovascular mortality, myocardial infarction, stroke (disabling and non-disabling), bleeding (life-
threatening, major and minor), acute kidney injury, vascular access complications (major and minor) through 
30 days following index procedure, new or worsened conduction disturbances and cardiac arrhythmias will be 
evaluated at 30 days and annually through 5 years post implant.  Prosthetic valve function and clinical benefit 
endpoints will be evaluated at 30 days and annually through 5 years post implant.  
 
Modification 4 
The Secondary Endpoint “Evaluation of the TAVI-related resource utilization up to 5-years post-implant” has 
been changed to “Evaluation of the TAVI-related resource utilization until discharge”. This includes a 
simplified hospital resources utilization section on the case report form. 
 
Modification 5 
The Secondary Endpoint “Evaluation of the device implantability characteristics” (deliverability, 
retrievability, and repositionability, placement accuracy and deployment) is removed. Separate characteristics 
on deliverability, retrievability, and repositionability, placement accuracy will still be collected. 
 
Modification 6 
The Secondary Endpoint “Reporting of the VARC 2 event rates for a sub-population comprising the non-
proctored cases only” has been removed. 
 
Modification 7 
The Secondary Endpoint “Impact of annulus sizing method (MSCT versus Echocardiography or other 
imaging modalities) on patient’s outcomes” has been removed. 
 
Modification 8 
The data collection for the Secondary Endpoint “Evaluation of impact of anesthesia on patient’s outcome” has 
been reduced. The type of anesthesia will still be collected. 
 
 
 

          
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Modification 9 
The time points for reporting on the Secondary Endpoint “Interim reporting of all-cause mortality on a subset 
of patients compared with an appropriate external comparator” has been changed from 6 months and 1year to 
30 days and 1 year.   
 
Modification 10 
The window for the echo Baseline measurement has been changed from within 45 days of index procedure to 
within 6 months of index procedure. 
 
Modification 11 
The Inclusion Criterion has underlined verbiage in addition: 
“Subject has senile degenerative aortic valve stenosis confirmed by echocardiographically derived criteria:  
• 
An initial aortic valve area (AVA) of less than or equal to (≤) 1.0 cm2 (or indexed EOA less than or 
equal to (≤) 0.6 cm2/m2) 
AND 
 
• 
A mean gradient greater than (>)40 mmHg or jet velocity greater than (>)4.0 m/s or Doppler Velocity 
Index less than (<)0.25.  
If the mean gradient is <40 mmHg and left ventricular ejection fraction (LVEF) <55%, then the site may as 
well perform a dobutamine stress echo to see if the mean gradient increases to >40 mmHg.” 
(Baseline measurement taken by echo within 6 months of index procedure.) 
 
Modification 12 
The Exclusion Criterion “Patient needs an embolic protection device” was removed.  
 
Modification 13 
The time point requirements for the frailty assessments (e.g. 5 meters walking time, grip strength with hand-
held dynamometer, wasting and malnutrition assessment (including blood sample to obtain serum albumin 
value)) and cognitive impairment or dementia assessment (via the mini-mental state examination (MMSE)) 
have been reduced.  These tests will be assessed at Enrollment/Baseline, 30d and 1Year only. 
 
Modification 14 
The time point requirements for the Modified Rankin Scale (mRS) have been reduced.  The mRS will be 
conducted Enrollment/Baseline, Pre-Discharge, 30 days, 1Year and (if possible) 90 days after any 
neurological event (stroke, TIA, encephalopathy). 
 
Modification 15 
The requirement to assess a 12 Lead ECG beyond the 1 year follow-up has been removed. In addition the 
uploading of the required 12 Lead ECG at Enrollment/Baseline, Pre-discharge, 30 days and 1 year has been 
removed. An ECG may still be requested in the case of potential cardiac related AE. 
 
Modification 16 
The requirement to provide Baseline CT Scan  (if routinely performed), angiography and echocardiography 
exams at the predefined visits to Sponsor has been removed. These recording will only be provided to Sponsor 
upon Sponsor request .  Echocardiography will be routinely provided to the Core Laboratory for analysis.  
 
Modification 17 
The requirement to complete and sign a record of the heart team’s recommendation for each patient enrolled 
in the study has been removed. The Heart team recommendation, including the presence of physicians, can be 
documented according to the sites standard procedure and available for periodic site monitoring. 
 
Modification 18 
The Steering Committee will consist of 4 members: Prof. L. SØndergaard (EU), Prof. F. Maisano (EU), Prof. 
S. Worthley (AU) and Dr. Rhodes (CA).   
 
Modification 19 

          
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The protocol section on the Internal Safety Committee is removed because an external committee will be 
used. 
 
Modification 20 
The 6 month Echo requirement has been removed.  
The requirement to use a separate echocardiographic guideline has been removed. Routine echocardiograms 
can be used to complete the reduced datafields on the echocardiogram study  Case Report Forms (CRFs). 
 
Modification 21 
Patients that undergo an implant attempt but did not receive a Portico Valve Implant will be followed for 
resolution of any procedure or Portico system related AEs. The patient should then be withdrawn from the 
clinical investigation. 
 
Modification 22 
Annual follow-up visits beginning at year 2 may be conducted at outside hospitals and reported to the study 
site provided the study site follows local laws and appropriately obtains the necessary source documents to 
complete the study Case Report Forms (CRFs). 
 
Modification 23 
Appendix J title has been changed from Instruction towards Recommendation for paced rhythm assessment in 
patients with a TAVI related implantation of permanent pacemaker. 
 
Other modifications 
Minor corrections of typos and grammatical errors having no impact on the content of the protocol have also 
been made. 
 
 
 
 
 

          
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2 Synopsis 
Title: 
International long-term follow-up study of patients implanted with a PORTICO 
valve. 
Acronym: 
PORTICO I 
Purpose: 
The purpose of this clinical investigation is to further assess the performance and 
safety profile of the Portico™ TAVI System in patients with severe symptomatic 
aortic stenosis. 
Objectives: 
The primary objective of this clinical investigation is to assess the 1 year all-cause 
mortality of patients with severe symptomatic aortic stenosis, implanted with a 
Portico Valve as per current guidelines.1 The secondary objective of this clinical 
investigation is to assess the 30 day and long-term performance and safety profile 
of the Portico valve in patients with severe symptomatic aortic stenosis. 
Endpoints: 
The primary endpoint is all-cause mortality at 1 year post implant 
 
The secondary Endpoints are: 
• 
Evaluation of the VARC-219 defined event* rates at 30 days, 1 year, 2 years, 3 
years, 4 years and 5 years post implant.  
o All-Cause Mortality 
o Cardiovascular Mortality 
o Myocardial Infarction 
o Stroke (disabling and non-disabling) 
• 
Evaluation of the VARC-219 defined event* rates at 30 days from the index 
procedure 
o Vascular access site complication (major and minor) 
o Bleeding (life-threatening, major and minor) 
o Acute kidney injury 
• 
New or worsened conduction disturbances and cardiac arrhythmias (including 
pacemaker implantation rate at 30 days and new-onset atrial fibrillation (AF)) 
• 
Prosthetic valve function at 30 days, 1 year, 2 years, 3 years, 4 years and 5 
years post implant. (Prosthetic valve stenosis and prosthetic valve 
regurgitation). 
• 
Clinical benefit endpoints as measured with NYHA classification and 6MWT, 
at 30 days, 1 year, 2 years, 3 years, 4 years and 5 years post implant, and 
QOL (EQ-5D questionnaire) until 1 year post implant. 
 
• 
Evaluation of the TAVI-related resource utilization through hospital 
discharge (e.g. index procedural hospital/physician resources). 
 
• 
Interim reporting at 30 days and 1-year all-cause mortality data may be 
performed on a subset of patients and compared with an appropriate external 
comparator. The results will be presented to appropriate agencies in France 
and in other countries where it will be deemed necessary for reimbursement 
purposes. 
 
*Events will be adjudicated as specified in the CEC charter. 
Design: 
This is an international multicenter, prospective, non-randomized clinical 
investigation without concurrent or matched control, designed to assess the 1 year 
all-cause mortality rate of patients implanted with a Portico Valve. In addition, 
performance and safety profile data of the Portico Valve will be evaluated at 30 
days, 1 year, 2 years, 3 years, 4 years and 5 years.  

          
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Devices used: 
For EU sites:  
Any commercially available Portico Valve, delivery system, loading system or 
other accessory may be used according to its labeling. 
 
For Australian and Canadian sites:  
Any investigational Portico devices approved for inclusion in the trial by the 
respective governing regulatory authorities may be utilized in Canada and 
Australia.  As these products are approved commercially in these countries, they 
may continue to be utilized in the trial.    
 
Future iterations of Portico devices and expanded indications may be included in 
this clinical study as they become either commercially available or approved for 
inclusion as an investigational device by the respective governing regulatory body 
for each geography.    
 
Patient 
Population:  
The population to be enrolled in this clinical investigation comprises both male 
and female patients with severe symptomatic aortic stenosis (AS) who meet 
specific eligibility criteria defined within this document. The total population to 
be enrolled in the clinical investigation is at least 866 for COHORT A, added up 
with any additional patient enrolled in COHORT B, to a maximum of 1046 
patients in total. 
 
Cohort A: Patients enrolled directly into the Portico I study.  
 
Cohort B: Patients implanted in previous SJM sponsored regulated (pre-market) 
investigations and first-in-human trials whom consent for ongoing follow-up in 
the Portico I study after the completion of their participation in the initial study. 
This population has the same underlying disease as the target population of this 
clinical investigation; that is severe symptomatic aortic stenosis. 
 
The expected duration of participation in this clinical investigation of patients in 
Cohort A will be 5 years from the date of implant. For Cohort B, the expected 
duration of participation in this clinical investigation will be a maximum of 4 
years, depending on their inclusion time post-implant.  
 
Inclusion 
Criteria: 
 
1. Patient has signed the Patient Informed Consent prior to participating in the 
clinical investigation. 
2. Patient has been referred for a Portico Valve implant as per heart team 
decision. Or, patient has received a Portico Valve as participant in an SJM 
sponsored regulated (pre-market or first-in-human) trial. 
3. Patient has senile degenerative aortic valve stenosis confirmed by 
echocardiographically derived criteria*:  
• 
An initial aortic valve area (AVA) of less than or equal to (≤) 1.0 cm2 (or 
indexed EOA less than or equal to (≤) 0.6 cm2/m2) 
AND 
• 
A mean gradient greater than (>)40 mmHg or jet velocity greater than 
(>)4.0 m/s or Doppler Velocity Index less than (<)0.25.  
If the mean gradient is <40 mmHg and left ventricular ejection fraction (LVEF) 
<55%, then the site may as well perform a dobutamine stress echo to see if the 
mean gradient increases to >40 mmHg.” 
(Baseline measurement taken by echo within 6 months of index procedure.) 
4. Patient has a life expectancy of more than (>) 12 months.*  
Note*: This criteria is not applicable for a patient who has received a Portico 
Valve as a  participant in a SJM sponsored regulated (pre-market or first-in-

          
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human) trial. 
 
Additional criteria for  patients enrolled at a French site: 
5. Patient is at high risk for surgery as demonstrated by a Logistic EuroSCORE 
equal or more than (≥) 20 and/or a Society of Thoracic Surgeon (STS) mortality 
risk score of more than (>) 10% and/or by clinical judgment of the Heart Team 
based on the individual risk profile (comorbidities). 
 
Exclusion 
criteria: 
 
1. Any case in which the Portico Valve would not be indicated for the patient as 
per current IFU (i.e. any “off-label” use). 
2. Patient has a non-tricuspid aortic valve. 
3. Patient has a prosthetic valve or ring in the aortic position. 
4. Patient needs a concomitant structural heart procedure. 
5. Patient is unwilling or unable to comply with all clinical investigation-required 
follow-up evaluations. 
6. Patient is pregnant. 
 
 
2.1 
Clinical investigation flow charts 
 
All the patients enrolled prospectively will follow the below clinical investigation flow. This group of 
patients is in Cohort A. 
 
Figure 1: Clinical investigation flow chart (Cohort A) 
 
 
 
 
All the patients, who participated in a SJM sponsored regulated (pre-market or first-in-human) trial and 
who consented to participate in this extended follow-up clinical investigation will follow the below 
clinical investigation flow. This group of patients will constitute Cohort B. 
 
 
 
 

          
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Figure 2: Clinical investigation flow chart (Cohort B) 
 
 
 
 
 

          
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3 Contacts 
Sponsor 
St. Jude Medical Coordination Center BVBA 
The Corporate Village 
Da Vincilaan 11- box F1 
B-1935 Zaventem 
Belgium 
Tel: +32 2 774 69 37 
Fax: +32 2 774 69 46 
 
 
 
Coordinating Clinical Investigators                         
 
Prof L. Søndergaard 
 
 
 
 
Prof F. Maisano, MD 
Rigshospitalet Copenhagen University Hospital  
FESC Head of Cardiovascular Surgery 
Kardiologisk Klinik B  
 
 
 
University Hospital Zurich  
Blegdamsvej 9  
 
 
 
 
Ramistrasse 100 
2100 Copenhagen 
 
 
 
 
Zurich CH-8091 
Denmark 
 
 
 
 
 
Switzerland 
Tel: +45 35452018 
 
 
 
 
Tel: +41 (0)44 255 33 81 
 
 
National Principal Investigators 
 
Prof S. Worthley, M.B., B.S., Ph.D 
 
 
Dr. J. Rodes 
F.R.A.C.P, R.A.C.C., F.C.S.A.N.Z. 
 
 
Institut Universitaire De Cardiologie 
St Andrews Hospital 
 
 
 
 
Et De Pneumologie de Québec (ICUPQ) 
Dept Cardiology 
 
 
 
 
2725 ch Sainte-Foy, 
350 South Terrace Adelaide 
 
 
 
Québec, QC 
SA, 5000 
 
 
 
 
 
G1V 4G 
Australia 
 
 
 
 
 
Canada 
Tel: +61 8 8223 4288 
 
 
 
 
Tel: +1 418 656 8711 
 
 
 
 
 
 
 
 

          
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4 Background 
Calcific aortic valve stenosis is a common cardiovascular disease with an increasing incidence in 
an aging population.2  In cases of severe aortic stenosis, patients develop symptoms and functional 
limitation unavoidably followed by physical deterioration, heart failure and poor prognosis. 
For many decades, surgical aortic valve replacement has been an effective treatment improving 
symptoms and survival3 but more than one-third of patients with symptomatic severe aortic 
stenosis do not undergo surgery because of a high surgical risk; these patients are not referred, are 
refused or are declined surgery.4  
Transcatheter aortic valve implantation (TAVI), first performed in 2002, has permitted the 
treatment of patients with excessive surgical risk.5 Since the first TAVI case in 2002, 50.000 
transcatheter aortic valve procedures have been performed worldwide comparing favorably with 
surgery in selected cohorts of patients; TAVI being the only intervention for inoperable aortic 
stenosis that demonstrated to prolong life in a randomized study.6 Several studies have also 
reported symptomatic improvement in the short term7,8,9,10 and midterm11,12,14 after TAVI. 
However, nearly 20% of patients experienced no symptomatic improvement10,13 highlighting 
Aortic Regurgitation (AR) as the most frequent complication and one of the main factors affecting 
symptoms and survival. Although significant transvalvular AR is rare after TAVI, paravalvular 
regurgitation or leak (PVL) is more common, mainly due to incomplete annular sealing. 
Paravalvular leaks may occur due to device undersizing, a mismatch between the prosthesis size 
and the annulus or incomplete expansion also depending on the anatomical characteristics of the 
patient’s annulus and ascending aorta. PVL can be caused also by a non-optimal implantation site 
where the device is positioned too high or too low within the valve annulus. While severe PVL 
may result in severe hemodynamic consequences, some studies have shown moderate and even 
mild leaks are associated with less favorable late survival rates than no regurgitation 14,15 however 
the data is inconclusive on less severe PVL.  Although moderate and severe AR after surgical 
aortic valve replacement or balloon valvuloplasty has only been reported anecdotally, the 
prevalence of moderate and severe PVL after TAVI has ranged from 6% to 21%. Recently, the 
impact of moderate and severe PVL on survival and symptoms after TAVI has been highlighted. 
Significant PVL is a main contributor to in-hospital death and an independent predictor of 1-year 
mortality and poor treatment response. In the absence of approved therapies, strategies for the 
prevention of significant PVL seem to be warranted. Prevention and treatment of AR are of 
particular importance because there is an increase in the use of TAVI.15   
Regarding valve durability, mid-term reports of commercially available devices up to 5 years are 
showing a rare occurrence of leaflet failure and in vitro accelerated wear testing is comparable 
with surgical prostheses13,14,16 However, more studies and more time will be needed to 
demonstrate whether transcatheter bioprosthesis durability will equal that of surgical 
bioprosthesis. 
Another risk of TAVI is related to rhythm disturbances such as partial or complete heart block due 
to the position of the atrioventricular conduction system that passes superficially through the 
interventricular septum immediately below the aortic valve. Risk factors are demonstrated to be 
advanced age, right bundle branch block, atrioventricular delay, prosthesis oversizing and 
ventricular positioning. Published studies report a different number of new pacemaker implants 
according to the device used ranging from 4.5% at 1 year6 to 3-fold increase with other devices.17, 
18  
 
 

          
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The Portico transcatheter aortic valve is indicated for transcatheter delivery in patients with 
symptomatic severe native aortic stenosis who are considered high surgical risk.  It has been 
designed to minimize the incidence of paravalvular leakage and damage to the conduction system. 
Durability is aimed to be comparable to that of currently available TAVI bioprostheses. The self-
expanding stent is designed to be fully resheathable and repositionable at the implant site and 
retrievable if needed. Additionally the low leaflet/cuff within the stent design allows for sealing 
without the valve extending deep into the LVOT, potentially reducing the risk of damage to the 
AV node or His bundle and subsequent need for permanent pacemaker implantation. Large stent 
cells in the annulus section of the stent allows for tissue to conform around calcific nodules 
potentially minimizing paravalvular leaks. Bovine leaflets and porcine cuff are treated with 
Linx™ Anti-calcification Technology. 
The aim of this study is to evaluate the Portico transcatheter aortic Valve up to five years, 
according to the VARC 2 criteria.19 
 
 
 

          
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5 Clinical study design 
This is an international multicenter, prospective, non-randomized clinical investigation without 
concurrent or matched control, designed to assess the mid-term safety and performance of the 
Portico valve in patients with severe symptomatic aortic stenosis whom are high risk for surgical 
valve replacement.  The primary endpoint is 1 year all-cause mortality. In addition, the 
performance and safety profile of the Portico valve will be further evaluated at 30 days, 1 year, 
and annually through 5 years post-implant.  
The investigation will be conducted at approximately 65 centers in approximately 15 countries in 
Europe, Middle-East, Africa, Canada, Australia and New Zealand.  
The clinical investigation is expected to last approximately 9 years; it includes the enrollment 
period (3 years), the follow up period (5 years) and the close-out and termination period (1 year). 
5.1 
Purpose 
The purpose of this clinical investigation is to further assess the performance and safety profile of 
the Portico Valve implanted using the Portico Delivery System and the Portico Loading System in 
patients with severe symptomatic aortic stenosis. 
5.2 
Objectives 
5.2.1 Primary Objective 
The primary objective of this clinical investigation is to assess the 1 year all-cause mortality of 
patients, with severe symptomatic aortic stenosis, implanted with a Portico Valve as per current 
guidelines1. 
5.2.2 Secondary Objective 
The secondary objectives of this clinical investigation are to assess the peri-procedural and long-
term performance and safety profile of the Portico Valve implanted, using the Delivery System 
and the Loading System, in patients with severe symptomatic aortic stenosis. 
5.3 
Endpoints 
5.3.1 Primary Endpoint 
• 
The primary endpoint is all-cause mortality at 1 year post implant (according to VARC-219). 
 
5.3.2 Secondary Endpoints 
• 
Evaluation of the VARC-219 defined event rates at 30 days, 1 year and annually through 5 
years post implant.  Definitions are detailed in Appendix D: VARC 2 Endpoints Definitions. 
o All-Cause Mortality 
o Cardiovascular Mortality 
o Myocardial Infarction 
o Stroke (disabling and non-disabling) 
o New or worsened conduction disturbances and cardiac arrhythmias (including pacemaker 
implantation rate at 30 days and new-onset atrial fibrillation (AF) 
 
• 
Evaluation of the VARC-219 defined event rates at 30 days from the index procedure.  
o Vascular access site complication (major and minor)  
o Bleeding (life-threatening, major and minor) 
o Acute kidney injury 

          
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• 
Prosthetic valve function at 30 days, 1 year and annually through 5 years post implant. 
(Includes prosthetic valve stenosis and prosthetic valve regurgitation). 
 
• 
Clinical benefit endpoints at 30 days, 1 year and annually through 5 years post implant (if 
available)  
o NYHA functional classification 
o 6 Minute Walk Test (6MWT) 
o Quality of life measured with EQ-5D questionnaire through 1 year post-implant 
 
• 
Evaluation of the TAVI-related resource utilization through hospital discharge (e.g. index 
procedural hospital/physician resources) 
 
• 
Interim reporting at 30 days and 1-year all-cause mortality data may be performed on a subset 
of patients and compared with an appropriate external comparator. The results will be 
presented to appropriate agencies in France and in other countries where it will be deemed 
necessary for reimbursement purposes. 
 
NOTE: Should new VARC or ESC Guidelines be published, endpoint analysis would be adjusted 
accordingly and analyzed to the extent that the previously gathered data supports the analyses based on 
the most current guidelines. 
 
5.4 
Population 
The population to be enrolled in this clinical investigation comprises both male and female patients 
with severe symptomatic aortic stenosis (AS) who meet specific eligibility criteria defined within this 
document. The total population to be enrolled in the clinical investigation is at least 866 for COHORT 
A, added up with any additional patient enrolled in COHORT B, to a maximum of 1046 patients in 
total. 
 
Cohort A: Patients enrolled directly into the Portico I study.  
 
Cohort B: Patients implanted in previous SJM-sponsored regulatory (pre-market) investigations and 
first-in-human trials whom consent for ongoing follow-up in the Portico I study after the completion 
of their participation in the initial study. This population has the same underlying disease as the target 
population of this clinical investigation; that is severe symptomatic aortic stenosis. 
 
The expected duration of participation in this clinical investigation of patients in Cohort A will be 5 
years from the date of implant. For Cohort B, the expected duration of participation in this clinical 
investigation will be a maximum of 4 years, depending on their inclusion time post-implant.  
 
5.5 
Device description 
The Portico Valve is a catheter-delivered aortic prosthetic valve that combines a bioprosthetic valve 
mounted on a self-expandable stent. The Portico Valve, the Delivery System and the Loading System 
are indicated for use in high risk patients with severe aortic stenosis who require aortic valve 
replacement (AVR). The Portico Valve, the Delivery System and the Loading System are to be used in 
accordance with the Instructions for Use (IFU). Please refer to the Instructions for Use and the 
Investigator Brochure for further details. The Instruction for Use of the devices used in this 
investigation can be obtained upon request. 
 
The legal manufacturer of the Portico Valve, the Delivery System and the Loading System is St. Jude 
Medical, Cardiovascular Division, located at 177 E. County Road B, St. Paul, MN  55117, USA which 
has various sites for its manufacturing activities. 

          
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Future iterations of Portico devices and expanded indications may be included in this clinical study as 
they become either commercially available or approved for inclusion as an investigational device by 
the respective governing regulatory body for each geography.    
 
Table 11 contains terminology that will be employed throughout this document. The terminology 
defined in Table 1 will accommodate any new device size and access type.  The only device that is 
implanted in the study patient is the Portico valve. 
Table 1: Devices glossary 
Item 
Prosthetic valve 
Delivery system 
Loading system 
Definition 
Aortic prosthetic valve 
(device under evaluation). 
Manual system that 
allows the aortic 
prosthetic valve to be 
implanted in the patient. 
Manual system that 
allows the operator to 
load the prosthetic valve 
into the delivery system. 
Commercial 
name 
Portico™ Transcatheter 
Aortic Valve 
 
Portico™ Delivery 
System 
Portico™ Loading 
System 
Terminology 
used in this CIP 
 
Portico Valve 
Delivery System 
Loading System 
 
5.6 
Geographical device considerations 
5.6.1 For EU sites:  
In Europe, any commercially available (CE Marked) Portico valve, delivery system, loading system or 
other accessory may be used in this trial according to its labeling (IFU).  It is the responsibility of the 
investigator to ensure that the devices: 
• 
Will be used according to the IFUs 
• 
Will be accounted for together with the patient’s contact details in the Patient 
Identification Log (PIL) 
 
 
5.6.2 For Australian and Canadian sites:  
Portico devices utilized in this trial in Canada and Australia may be investigational and used according 
to their respective regulatory submission documents.  These products may continue to be used in the 
trial upon commercial release in each country. It is the responsibility of the investigator to ensure that 
the devices: 
• 
Will be used according to the IFUs/IB 
• 
Will be accounted for together with the patient’s contact details in the Patient 
Identification Log (PIL)  
• 
Will be traced using the appropriate traceability documentation (Note: this requirement 
applies to investigational devices only)  
 
5.6.3 Investigational device accountability for Australian and Canadian sites: 
Access to devices which haven’t received regulatory approval shall be controlled and these devices 
shall be used only in the clinical investigation and according to the CIP and IFU/IB.  
 

          
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The sponsor shall keep records to document the physical location from shipment of these devices to 
the investigation sites until use, return or disposal.  The Principal Investigator or authorized designee 
shall keep records documenting the date of receipt, the unique identification or lot number of each 
investigational device, the patient identification, the date of use, the expiry date, the date on which the 
investigational device was returned/explanted from the patient (if applicable) and the date of return of 
unused, expired or malfunctioning investigational devices (if applicable). 
 
5.7 
Hospital heart team 
The “Heart Team” is a multi-disciplinary team involving at least (but not limited to): 
• 
Two physicians of which one should be a cardiologist or an interventional cardiologist and a 
cardiac surgeon 
• 
Any other relevant function such as an imaging specialist or a TAVI nurse. 
 
The objective of the Heart Team is to review and interpret patient’s clinical data in order to obtain a 
consensus on the optimal treatment strategy for each patient. The heart team will be responsible for 
ensuring and documenting patient’s eligibility to receive a Portico Valve. 
Investigational sites will use their standard documentation to report the heart team’s recommendations, 
including the members of the heart team, for each patient prospectively or retrospectively enrolled in 
the study.  This instruction only applies to Cohort A. 
In certain circumstances, it might be decided to send relevant clinical data (such as echocardiogram, 
CT/MRI or Angiogram) out of the hospital for further analysis to determine if patient’s valve anatomy 
is suitable for participation in the clinical investigation. If required, an authorization form to release 
medical information outside the hospital is available for sign-off by the patient. 
5.8 
Patient screening 
Patient candidates for a TAVI procedure or who already received a Portico Valve as part of a SJM-
sponsored regulatory or first-in-human trial can be screened by any member of the investigational 
team trained on the CIP and delegated to do so. Patients who do not meet the inclusion/exclusion 
criteria will not be eligible to participate in this clinical investigation. Patients meeting the 
inclusion/exclusion criteria will be fully informed about the clinical investigation and asked to 
participate. In case a patient agrees to participate, a duly signed and dated Patient Informed Consent 
(PIC) will be obtained. 
All patient candidates for a TAVI procedure should be accounted for and documented on the screening 
and enrollment log in an anonymous fashion. This log should be kept up to date throughout the clinical 
investigation by the principal investigator or his/her authorized designee.  
The investigational sites involved in previous SJM-sponsored regulatory or first-in-human trials 
involving the Portico Valve will also be asked to contact the patients who participated and invite them 
to participate in this extended follow-up clinical investigation. These patients shall be accounted for in 
a separate screening and enrollment log. 
5.9 
Point of enrollment 
Patients will be considered enrolled in the clinical investigation once they have provided signed and 
dated written Informed Consent (refer to section 7.2 for the Informed Consent Process). 
Once enrolled, a patient is expected to comply with the required clinical investigation visits and 
assessments. All patients enrolled in the clinical investigation (including those withdrawn or lost to 
follow-up) shall be accounted for and documented on the Patient Identification Log, assigning an 
identification code linked to their names, alternative identification or contact information. This log 
shall be kept up to date throughout the clinical investigation by the principal investigator or his/her 
authorized designee. Since patient privacy and confidentiality of data must be maintained throughout 
the clinical investigation, this log will remain on site. 

          
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5.10 Inclusion and Exclusion Criteria  
The following inclusion and exclusion criteria will be used to determine a patient’s enrollment 
eligibility in the clinical investigation. Candidates for this clinical investigation must meet all the 
inclusion criteria and none of the exclusion criteria. 
5.10.1 Inclusion Criteria 
All candidates will meet the following inclusion criteria: 
 
1. Patient has signed the Patient Informed Consent prior to participating in the clinical 
investigation. 
2. Patient has been referred for a Portico Valve implant as per Heart Team decision or 
patient has received a Portico Valve as per participation in an SJM sponsored regulatory 
or first-in-human trial. 
3. Patient has senile degenerative aortic valve stenosis confirmed by echocardiographically 
derived criteria*:  
▪ 
An initial aortic valve area (AVA) of less than or equal to (≤) 1.0 cm2 (or 
indexed EOA less than or equal to (≤) 0.6 cm2/m2) 
 
 
AND 
 
▪ 
A mean gradient greater than (>)40 mmHg or jet velocity greater than (>)4.0 
m/s or Doppler Velocity Index less than (<)0.25.  
If the mean gradient is <40 mmHg and left ventricular ejection fraction (LVEF) <55%, 
then the site may as well perform a dobutamine stress echo to see if the mean gradient 
increases to >40 mmHg.” 
(Baseline measurement taken by echo within 6 months of index procedure.) 
4. Patient has a life expectancy more than (>) 12 months.* 
 
For patients enrolled in a French site: 
5. Patient is at high risk for surgery as demonstrated by a Logistic EuroSCORE equal or 
more than (≥) 20 and/or a Society of Thoracic Surgeon (STS) mortality risk score of more 
than (>) 10% and/or by clinical judgment of the Heart Team based on the individual risk 
profile (comorbidities). 
 
 
*Not applicable for a patient who has received a Portico Valve as per participation in an SJM 
sponsored Regulatory or First-In-Human trial. 
 
 
5.10.2 Exclusion Criteria 
Candidates will be excluded from the clinical investigation if any of the following criteria is present:  
1. Any case in which the Portico Valve would not be indicated for the patient as per current 
IFUs (i.e. any “off-label” use). 
2. Patient has any other aortic valve than tricuspid one. 
3. Patient has a prosthetic valve or ring in the aortic position. 
4. Patient needs a concomitant structural heart procedure. 
5. Patient is unwilling or unable to comply with all clinical investigation-required follow-up 
evaluations. 
6. Patient is pregnant. 
 
 
 

          
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The figure below summarizes the screening, enrollment and eligibility assessment scheme for 
Cohort A. 
Figure 3: Patient’s eligibility assessment scheme (Cohort A) 
 
*If required, an Authorization form to release medical information to be signed 
*

          
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5.10.3 Additional considerations 
In case of patient’s death and/or occurrence of adverse events (serious or not) prior to the Portico 
valve implant, these events will be reported separately and will not be taken into account in the 
study endpoints reporting. 
In case a patient signed the PIC but would not receive a Portico Valve, reasons for patient not 
receiving a Portico Valve will be reported separately and will not be taken into account in the 
study endpoints reporting. Patient will then be withdrawn from the study.  However, if the Portico 
valve or delivery system entered the patient’s body but was not successfully implanted, the patient 
should continue in follow-up until 30 days or until all adverse events associated with the Portico 
device or procedure are resolved (whichever occurs first).  Possible reasons for patient not 
receiving a Portico Valve are listed below but are not limited to: 
• 
Screening failure (patient did not meet all inclusion criteria or/and meet one exclusion 
criteria) before the index procedure 
• 
Investigator’s decision to withdraw the patient before the procedure 
• 
Adverse event affecting patient’s eligibility to TAVI 
• 
Procedural exclusion 
• 
Unsuccessful implant attempt 
• 
Consent withdrawn, lost to follow-up or death before the procedure 
 

          
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6 Procedures 
6.1 
Clinical investigation flow chart 
 
6.1.1 Cohort A (Prospective) 
All the patients enrolled prospectively will follow the below clinical investigation flow. This group of patients is in Cohort A. 
 
Figure 4: Clinical investigation flow chart (Cohort A-prospective) 
 
 
 
 
 
 
 
 
  
 
 
 
6.1.2 Cohort B  
All the patients, who participated in a SJM sponsored regulatory or first-in-human trial and who consented to participate in this extended follow-up 
clinical investigation will follow the below clinical investigation flow. This group of patients will constitute Cohort B. 
• 
For these patients, the data collection will start after consent is obtained and will include any study related event (AE, unscheduled visit, etc.) 
documented after the patient has exited the SJM sponsored regulatory or first-in-human trial. 
• 
For these patients, the data collected up to the 1 year follow-up visit will not need to be re-collected. 
 
 
 
 
 

          
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Figure 5: Clinical investigation flow chart (Cohort B) 
 

          
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6.2 Clinical investigation activities and visits 
Table 2 : List of clinical investigation activities and visits 
Study activities and visits 
En/Bas* 
Imp* 
P-Dis* 
30 d* 
1 Y* 
2 Y 
3 Y 
4 Y 
5 Y 
Visit window 
-6m-0** 
0 
0-7d 
-7d+14d 
±90d 
±90d 
±90d 
±90d 
±90d 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Patient’s eligibility assessment 
X 
 
 
Angiography 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical and Cardiovascular History 
X 
 
 
Native aortic valve assessment 
X 
 
 
 
 
 
 
 
 
Access site assessment 
X 
 
 
 
 
 
 
 
 
Surgical risk assessment 
X 
 
 
Frailty assessment: 
 
 
 
 
 
 
 
 
 
- 5 meters walking time 
X 
 
 
X 
X 
 
 
 
 
- Grip strength 
X 
 
 
X 
X 
 
 
 
 
- Wasting and malnutrition parameters 
X 
 
 
X 
X 
 
 
 
 
- Cognitive impairment or dementia  
   (MMSE) 
X 
 
 
X 
X 
 
 
 
 
Blood sample: 
 
 
 
 
 
 
 
 
 
- Serum Albumin (Frailty assessment) 
X 
 
 
X 
X 
 
 
 
 
- Hemoglobin, Creatinine (if available) 
X 
 
X 
X 
X 
 
 
 
 
- Troponin 
X 
 
Xa 
X 
X 
 
 
 
 
Physical assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
12 lead ECG 
X 
 
Xb 
X 
X 
 
 
 
 
Paced rhythm assessmentf 
 
 
 
(X) 
 
 
 
 
 
Medication assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 

          
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Echocardiography 
X 
Xc 
X 
X 
X 
X 
X 
X 
X 
NYHA Classification 
X 
 
X 
X 
X 
X 
X 
X 
X 
QoL questionnaire (EQ-5D) 
Xd 
 
X 
X 
X 
 
 
 
 
The six-minute walking test 
X 
 
 
X 
X 
X 
X 
X 
X 
Modified Rankin Scalee 
X 
X 
X 
X 
 
 
 
 
Adverse Events Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Device Deficiency Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resources utilization 
X 
X 
 
 
 
 
 
 
 (X) as applicable 
* For Cohort B, the informed consent and eligibility assessment will be conducted but all the other above mentioned data up to 1 year will not be re-collected 
(equivalent to grey background). Depending on time point of informed consent signed, the patient will enter the Portico I study at 1Y or later. 
** For Cohort A, tests to confirm baseline measurements (e.g. Angio, CT, echocardiogram) should be within 6 months of index procedure. 
a Blood Sample for Troponin to be obtained between day 2 and 4 post-implant or at discharge whatever occurs first. 
b ECG within 24 hrs Post-implant AND at discharge but no later than 7 days Post-implant-whatever occurs first.   
c Assess aortic regurgitation with TEE if available or via fluoroscopy/angiography 
d The QoL questionnaire should be completed by the patient the closest possible to the implant date 
e The Modified Rankin scale should be completed additionally (if possible) 90 days after any neurological event (stroke, TIA, encephalopathy). 
f The permanent paced rhythm assessment is performed only if applicable 
 

          
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Table 3: Clinical investigation activity definition 
Study activities 
Definitions 
Informed Consent 
An Ethics Committee (EC) and Sponsor approved Informed Consent must be obtained in accordance 
to section 7.2 (Informed Consent Process) of this Clinical Investigation Plan. 
Patient’s eligibility assessment 
Refer to the patient’s eligibility assessment process as illustrated in Figure 3. 
Demographics 
(NAP for Cohort B) 
Patient’s Age and Gender 
Medical and Cardiovascular History 
(NAP for Cohort B) 
Medical and Cardiovascular history of the patient: 
• 
Cardiovascular and neurovascular history 
• 
Previous cardiovascular procedures 
• 
Other medical conditions (e.g., diabetes, kidney disease, lung disease, etc.) 
• 
Baseline status and risk factors 
Native aortic valve assessment 
(NAP for Cohort B) 
Native aortic valve information such as annulus size or valve morphology will be collected based on 
examinations conducted at the investigational site as standard of care. We recommend the use of Multi 
Slice Computed Tomography (MSCT) in particular for annulus sizing; however other imaging 
modalities, such as Trans Esophageal Echocardiography (TEE) are also acceptable.  
It is recommended to perform both non-contrast and contrast MSCT, if routinely performed. 
It is also recommended to perform both thoracic and abdominal CT, if routinely performed.  
 
MSCT exams (if routinely performed) and any other data acquired as part of patient’s native aortic 
valve assessment (such as additional (pre-) sizing information), should be sent to Sponsor on request 
only. If requested, MSCT should be recorded in Dicom format and all material should be de-identified 
and sent to the sponsor. 
Access site assessment 
(NAP for Cohort B) 
Patient’s recommended TAVI access site characteristics (Transfemoral, transapical, etc.) 
Surgical Risk Assessment 
(NAP for Cohort B) 
Three Surgical Risk Assessment tools will be used: Logistic EuroSCORE I, Logistic EuroSCORE II 
and the STS Risk Score. Refer to Appendix E: Surgical Risk Assessment Tools, for links to the on-
line score calculators. 
Frailty assessment 
(NAP for Cohort B) 
 
Patient Frailty index will be assessed at baseline, at 30 days and at 1 Year. Frailty is a risk factor not 
included in the current surgical risk assessment tools. Frailty Index assessment will include: 
- 5 meters walking time 
- Grip strength 
- Wasting and malnutrition parameters (including weight loss, BMI and Serum albumin value to be 
obtained via blood sample) 

          
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Study activities 
Definitions 
- Cognitive impairment or dementia as measured with the mini–mental state examination (MMSE). 
 
For further details/instructions, please refer to Appendix F: Frailty Assessment. 
Blood sample 
(NAP for Cohort B) 
• 
Albumin: see frailty assessment 
• 
Hemoglobin, Creatinine (if available) 
• 
Troponin: at Enrollment/Baseline and between day 2 and 4 Post-implant or at discharge whatever 
occurs first. 
Physical assessment 
(From 2Y visit onward for Cohort B) 
At the baseline visit the following measurement must be assessed: 
• 
Height 
• 
Weight 
• 
Systolic/Diastolic blood pressure 
The following measurements must be assessed at all visits: 
• 
Weight 
• 
Systolic/Diastolic blood pressure 
12 Leads ECG 
(NAP for Cohort B) 
Assessment of dominant rhythm, heart rate, PR interval, QRS duration, bundle branch block, 
fascicular block etc. 
The ECG is to be performed at baseline, within 24 hours Post-implant, at hospital discharge but no 
later than 7 days Post-implant, whatever occurs first and at 30days and 1 Year.  
Medication assessment 
(From 2Y visit onward for Cohort B) 
The following information on medication will be collected at each visit: 
• 
Beta Blockers 
• 
Calcium Channel Blockers 
• 
Anticoagulants  
• 
Antiplatelet agents including Aspirin  
• 
Diuretics 
• 
Ace-Inhibitors 
• 
Angiotensin Receptor Blocker (ARBs) 
• 
Statins 
 
At the implant visit the prophylactic antibiotics regimen will also be collected 
Echocardiogram 
(From 2Y visit onward for Cohort B) 
Each site will be responsible for performing and interpreting the baseline & post-implant and follow-up 
echocardiograms using the VARC 2 definitions.  
For further details on echocardiographic variables, please refer to Appendix D: VARC 2 Endpoints 
Definitions. 

          
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Study activities 
Definitions 
Echocardiograms can be requested to be sent to an echo Core Laboratory. 
If requested, exams should be recorded in Dicom format and should be de-identified prior to sending. 
Routine echocardiograms can be used to complete the echocardiogram study  Case Report Forms 
(CRFs). 
NYHA Classification 
(From 2Y visit onward for Cohort B) 
The New York Heart Association (NYHA) Functional Classification provides a simple way of 
classifying the extent of heart failure. 
QoL questionnaire (EQ-5D) 
(NAP for Cohort B) 
The EQ-5D questionnaire will be used. It is a standardized instrument for use as a measure of health 
outcomes. 
The six-minute walking test 
(From 2Y visit onward for Cohort B) 
The six-minute walking test (6MWT) is a commonly used objective measure of functional exercise 
capacity in individuals with moderately severe impairment.  
For further details/instructions, please refer to Appendix G: ATS Guidelines25 for the Six Minute 
Walk Test instructions. 
Modified Rankin scale (mRS) 
  
The modified Rankin Scale (mRS) is a functional measurement to assess the degree of disability or 
dependence in the daily activities of people who have suffered a stroke. 
mRS at Enrollment/Baseline, 30days, 1year and is to be completed additionally (if possible) 90days 
after any neurological event  (stroke, TIA, encephalopathy) 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 H: Structured Interview for 
the Modified Rankin Scale (mRS). 
Portico Valve Implant 
(NAP for Cohort B) 
Procedural information must be collected including: 
• 
Pre-implant information (such as access type, use of balloon valvuloplasty, etc.) 
• 
Implant information (such as prosthetic valve information, use of rapid pacing, etc.) 
• 
Aortic regurgitation  
• 
Implant depth and prosthesis-patient mismatch 
• 
Post-implant information including hemodynamics 
 
The assessment of aortic regurgitation must be performed with a combination of echocardiography, 
angiography and hemodynamic approach, preferably according to the instructions provided in 
Appendix I: Peri-procedural instructions.  
Implant depth measurement should be assessed via aortic root angiography and further instructions 
are also provided in Appendix I: Peri-procedural instructions. 
Prosthesis-patient mismatch will be measured by means of echocardiography according to the VARC 
2 guidelines. 
 

          
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Study activities 
Definitions 
Any other data acquired as part of the patient’s implant procedure (such as routinely performed 
aortography) can be collected by the Sponsor as well to obtain additional procedural information 
regarding the implant. 
Adverse Events Assessment 
(From 1Y visit onward for Cohort B) 
All adverse events will be documented according to Section 7.3 (Adverse Events, Adverse Device 
Effect, and Device Deficiency). 
Device Deficiency Assessment 
All device deficiencies will be documented according to Section 7.3 (Adverse Events, Adverse Device 
Effect, and Device Deficiency). 
Paced Rhythm Assessment 
(NAP for Cohort B) 
If the patient received a new permanent pacemaker, due to an AV-block, within 30 days after their 
TAVI procedure, then the patient’s dependence to pacemaker will be checked according to the 
recommendations provided in Appendix J: Recommendation for paced rhythm assessment in patients 
with a TAVI related implantation of permanent pacemaker. 
Resource utilization Assessment 
(until discharge for COHORT A) 
(NAP for Cohort B) 
Procedural resources: Material resources such as devices used during the procedure (valve, guiding 
catheters, valvuloplasty balloons, etc.), operators’ resources and procedure duration will be collected at 
procedure time. 
Hospital resources: length of stay in different wards (ICU, non ICU, etc.); will be collected at 
discharge. 
 

          
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Table 4: Data Collection Forms for COHORT A and  COHORT B (identical to Cohort A with exception of grey background boxes) 
 
Study activities 
En/Bas 
Imp 
P-Dis 
30 d 
1 Y 
2 Y 
3 Y 
4 Y 
5 Y 
Enrollment Form 
X 
 
 
 
 
 
 
 
 
Baseline Form 
X 
 
 
Portico Valve Implant Form 
 
X 
 
 
 
 
 
 
 
Echocardiogram Form 
X 
 
X 
X 
X 
X 
X 
X 
X 
EQ-5D Form 
X 
 
X 
X 
X  
 
 
 
 
Follow-Up Visit Form 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Device Deficiency Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Deviation Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Termination Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
X 
Death Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
 Exams 
All exams (ECG, Echo, angio, MSCT and any other exam) should be provided to Sponsor on request. In addition, 
Echocardiograms can be requested to be sent to an echo core laboratory. 
If requested, exams should be recorded in Dicom format and should be de-identified prior to sending. 
 
 

          
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6.2.1. Enrollment Visit 
For the patients who participated in a SJM-sponsored regulatory or first-in-human trial, the enrollment will occur retrospectively (after the date they 
received their Portico Valve). The historical data collected through 1 year in those trials will not need to be re-collected for this clinical investigation.   
 
For patients indicated for implantation of a new Portico Valve, the enrollment will occur prospectively (before the date they will receive their Portico 
Valve) at a maximum of 45 days prior to the date of the Portico Valve implant and no later than the date of the Portico Valve implant but before the 
implant takes place. 
 
The following enrollment activities are performed after the patient has been screened and must occur before any investigational procedure/visit. 
 
• 
The principal or delegated site personnel is responsible for screening all potential patients to determine patient eligibility for the investigation 
• 
If a patient meets all pre-procedural inclusion criteria and does not meet any of the pre-procedural exclusion criteria, he/she is eligible for the 
investigation. 
o Inform the eligible patient verbally about the investigation and provide the information sheet and consent to the patient. 
o Provide ample time for the patient to read and understand the information sheet and consent and to consider participation in the clinical 
investigation. Invite the patient to ask questions if needed. 
o Obtain the signature and date hand-written from the eligible patient on the EC approved informed consent (If an eligible patient does not sign 
and date the informed consent, he cannot participate in the investigation. No further protocol required activities are performed) 
o Obtain the signature and date from the principal or delegated investigator who obtained consent on the EC approved consent 
o Provide one copy  of the  signed and dated version of the informed consent to the patient (signed by both patient and investigator) 
o File the original signed and dated version of the informed consent in the Investigator Site Binder (ISB). 
• 
Record enrollment information (name of the investigation, date of consent and Inclusion/exclusion information) in the hospital records and 
complete the Enrollment form preferably within 5 days after enrollment (failure to meet this timeline will not be considered a protocol deviation) 
• 
Notify the sponsor by submitting the enrollment form. 
 
NOTE: As soon as the patient signs the PIC, adverse events and device deficiencies need to be reported according to the guidelines mentioned in section 
7.3. For Cohort B, patients, adverse event and device deficiency reporting includes events having occurred after their last documented follow-up visit. 
 
In case the patient was consented to participate in the investigation, but does not meet inclusion/exclusion criteria (i.e. screen failure before the index 
procedure), the following actions shall be taken: 
• 
Document enrollment information (consent and inclusion/exclusion) in the hospital records; complete the Enrollment, deviation and Termination 
forms. The form must be authorized / approved by the principal or delegated investigator. 
o Refer to Appendix C: Data Collection Method. 
o Inform the patient about his/her withdrawal. 

          
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o The EC/IRB and NCA/NRA should be notified appropriately about any deviations with regards to obtaining the informed consent. 
 
6.2.2. Baseline Visit (Cohort A only) 
This visit can take place the same day as the enrollment visit. The data from previously conducted diagnostic tests/procedures, as indicated with an “ (X) as 
applicable 
, performed as standard of care will be collected during this visit. It is not necessary to repeat these tests if they were collected within the clinical investigation 
visit window. All other data must be collected after obtaining clinical investigation specific consent and within 45 days prior to the TAVI procedure. The 
baseline visit consists of the following activities:  
• 
Demographics  
• 
Medical and Cardiovascular History 
• 
Native aortic valve assessment 
• 
Access site assessment (Trans-femoral, trans-apical, etc.) 
• 
Surgical Risk Assessment 
• 
Frailty Assessment (including assessment of 5 meters walking time, grip strength, wasting and malnutrition and cognitive impairment or dementia 
via MMSE) 
• 
Blood sample (Serum Albumin value as part of frailty assessment.  Creatinine, Hemoglobin if available (SOC) and Troponin values) 
• 
Physical Assessment 
• 
12 lead ECG 
• 
Medication assessment 
• 
Echocardiogram 
• 
NYHA Classification 
• 
QoL questionnaire (EQ-5D) 
• 
6MWT 
• 
Modified Rankin Scale 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
 
6.2.3. Portico Valve Implant visit - Index procedure (Cohort A only) 
The medical team performing the TAVI procedure will typically consist of: 
• 
An interventional cardiologist or a cardiac surgeon at the site will perform the procedure according to local guidelines. 
• 
A second operator (a cardiac surgeon or a cardiologist) may be present during the procedure as needed. 
• 
An anesthesiologist and/or a perfusionist as needed. 

          
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The implanting physician should be trained according to SJM Portico training program prior to implant of the Portico Valve. 
 
NOTE: The above medical team members do not need to be trained on the protocol if they only perform the Portico Valve implant and no other study 
related tasks. 
 
NOTE: Anticoagulation 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. 
 
At least one device may be deployed in every patient who has signed the PIC and is not procedurally excluded. Although not recommended, if a physician 
determines it is in the best interest of the patient to have a second device placed, a patient may receive an additional device. 
 
The procedure visit will consist of the following steps:  
• 
Pre-implant (access preparation) 
• 
Implant (valve deployment) 
• 
Aortic regurgitation assessment combining  angiography, echocardiography and hemodynamic approach 
• 
Implant depth and prosthesis-patient mismatch assessment 
• 
Post-implant (access closure) 
• 
Medication assessment 
• 
Device implantability assessment 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
• 
Resource utilization assessment 
 
It is strongly recommended to follow the peri-procedural instructions for the assessment of aortic regurgitation and implant depth as mentioned in 
Appendix I. However, failure to follow these instructions will not be considered a protocol deviation. 
 
Procedural Exclusion 
 
During the procedure, the implanting physician may determine the implantation of the Portico Valve is either not feasible or not in the best interest of the 
patient. Reasons for procedural exclusion may include, but are not limited to, anatomy that is not suitable for implantation, inability to gain access, 
ventricular arrhythmia, or any other contraindication. Any patient that does not have a delivery system enter his or her body will be considered 
“procedurally excluded.”  
Data will be collected on these subjects from the Baseline through the 30-day follow-up, including reason for exclusion and collection of possible adverse 
events. 

          
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The patient should then be withdrawn from the clinical investigation. 
 
Following the procedure, the delivery and loading systems should be securely disposed as per hospital requirements for hazardous materials. If there are 
any concerns noted with the delivery system, loading system, or valve during the procedure, they should be returned to SJM per instructions provided in 
Appendix K: Explant, Return, and Analysis of Valve and Appendix L: Instructions for device return - Large and Small Kits. 
 
6.2.4. Pre-Discharge visit (Cohort A only) 
The pre-discharge visit will take place at the time of hospital discharge or within seven days after the index procedure, whichever occurs first. If the 
patient is expected to be discharged over the weekend, the discharge tests may be completed on the last week day prior to discharge. The assessment will 
include: 
• 
Physical assessment 
• 
Blood sample (between day 2 to 4 Post-implant or at discharge whatever occurs first) to obtain Hemoglobin, Creatinine and Troponin values 
• 
12 lead ECG (within 24hrs Post-implant and at hospital discharge but no later than 7 days Post-implant, whatever occurs first). 
• 
Medication assessment 
• 
Echocardiography (if a post-procedure echo has been done within 24 hours prior to discharge, an additional discharge echo is not required) 
• 
NYHA functional classification 
• 
QoL questionnaire (EQ-5D) 
• 
Modified Rankin Scale 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
• 
Resource utilization assessment 
 
6.2.5. 30 Day follow-up visit (Cohort A only) 
The 30 Day visit will take place at 30days (-7 days, +14days) after the index procedure, and will include: 
• 
Frailty Assessment by means of the following components: 5 meters walking time, grip strength, wasting and malnutrition (including blood sample 
to obtain Serum Albumin value) and cognitive impairment or dementia (via MMSE) 
• 
Physical assessment 
• 
12 lead ECG 
• 
Medication assessment 
• 
Echocardiography 
• 
NYHA functional classification 
• 
QoL questionnaire (EQ-5D) 

          
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• 
6MWT 
• 
Modified Rankin Scale 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
• 
Permanent Pacemaker Control (if applicable) 
• 
Resource utilization assessment 
 
6.2.6. 1 Year follow-up visit (Cohort A only) 
The 1 Year visit will take place at 365 days (± 90days) after the index procedure, and will include: 
• 
Frailty Assessment by means of the following components: 5 meters walking time, grip strength, wasting and malnutrition (including blood sample 
to obtain Serum Albumin value) and cognitive impairment or dementia (via MMSE) 
• 
Physical assessment 
• 
12 lead ECG 
• 
Medication assessment 
• 
Echocardiography 
• 
NYHA functional classification 
• 
QoL questionnaire (EQ-5D) 
• 
6MWT 
• 
Modified Rankin Scale 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
• 
Resource utilization assessment 
 
6.2.7. 2 Year follow-up visit  
To accommodate subject referrals from distant hospitals, the referring physician may conduct the 2 Y follow-up visit. In such cases, the investigator may 
contact the referring physician’s office and/or obtain the appropriate source documents to complete Case Report Forms (CRFs). 
 
The 2 Year visit will take place at 730 days (± 90 days) after the index procedure, and will include:  
• 
Physical assessment 
• 
Medication assessment 
• 
Echocardiography 

          
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• 
NYHA functional classification 
• 
6MWT 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
 
6.2.8. 3 Year follow-up visit 
To accommodate subject referrals from distant hospitals, the referring physician may conduct the 3 Y follow-up visit. In such cases, the investigator may 
contact the referring physician’s office and/or obtain the appropriate source documents to complete Case Report Forms (CRFs). 
 
The 3 Year visit will take place at 1095days (± 90days) after the index procedure, and will include: 
• 
Physical assessment 
• 
Medication assessment 
• 
Echocardiography 
• 
NYHA functional classification 
• 
6MWT 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
 
6.2.9. 4 Year follow-up visit  
To accommodate subject referrals from distant hospitals, the referring physician may conduct the 4 Y follow-up visit. In such cases, the investigator may 
contact the referring physician’s office and/or obtain the appropriate source documents to complete Case Report Forms (CRFs). 
 
The 4 Year visit will take place at 1460days (± 90days) after the index procedure, and will include: 
• 
Physical assessment 
• 
Medication assessment 
• 
Echocardiography 
• 
NYHA functional classification 
• 
6MWT 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
 

          
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6.2.10. 5 Year follow-up visit 
To accommodate subject referrals from distant hospitals, the referring physician may conduct the 5 Y follow-up visit. In such cases, the investigator may 
contact the referring physician’s office and/or obtain the appropriate source documents to complete Case Report Forms (CRFs). 
 
The 5 Year visit will take place at 1825days (± 90days) after the index procedure, and will include: 
• 
Physical assessment 
• 
Medication assessment 
• 
Echocardiography 
• 
NYHA functional classification 
• 
6MWT 
• 
Adverse events assessment 
• 
Device Deficiency assessment 
6.2.11. Unscheduled Visit 
An unscheduled visit is defined as a visit that occurs between two scheduled investigational visits where the patient is examined for either a physician 
requested follow-up or for an adverse event. Any data collected related to the clinical investigation endpoints needs to be documented such as 
Echocardiography, ECG or modified Rankin Stroke Scale by completing the appropriate section of the Follow-up or Echocardiogram electronic Case 
Report Form (eCRF). 
 
NOTE:  The Modified Rankin scale should be completed at every visit and additionally (if possible) 90 days after any neurological event (stroke, TIA, 
encephalopathy). Use the unscheduled visit to record the Modified Rankin scale score. This score can be obtained over a telephonic interview. Failure to 
obtain the Modified Rankin scale score 90 days after the onset of a neurological event will not be considered a protocol deviation. 
 
NOTE: For cohort B patients, in the event of an unscheduled visit occurring after the patient 1 year follow-up, this visit is to be documented as part of this 
clinical investigation. 
6.2.12. Description of activities performed by Sponsor Representatives 
A physician proctor and SJM Field clinical Specialist (FCS) will attend all proctored procedures to answer device and procedural questions, until the 
implanting investigator is deemed trained and he and his team are ready for independence. Physician training and proctoring will be documented 
appropriately. 
 
It is permissible that a FCS will periodically attend procedures throughout the investigational study to observe the implanting investigator and his team.  
This will afford the opportunity for continued training if required and allow the investigator continued product support from the sponsor. 
 

          
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Sponsor personnel will not: 
• 
Perform the informed consent process 
• 
Practice medicine or participate directly in the procedure 
• 
Provide medical diagnosis or treatment to patients 
• 
Discuss a patient’s condition  or treatment with a patient  
• 
Independently collect clinical investigational data or complete study documentation 
6.2.13. Description of post-investigational provision of medical care 
When the patient’s participation in the clinical investigation has been completed the patient will return to medical care as per physician’s recommendation. 
 
 

          
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7 
Clinical Investigation Conduct 
7.1 
Statements of Compliance 
The investigation will be performed in accordance with the most current versions of the World Medical Association (WMA) Declaration of Helsinki and 
any regional and/or national regulations as appropriate. 
ISO14155 2011 shall be used as a guideline with following exceptions: limited adverse event  reporting and device accountability.  
 
The investigator shall not start enrolling patients or requesting informed consent prior to obtaining EC approval and national competent authority/national 
regulatory authority approval, if applicable, and authorization from the sponsor in writing for the investigation. In case additional requirements will be 
imposed by the EC or national competent authority/national regulatory authority they shall be followed, if appropriate. 
 
As sponsor, SJM has taken up general liability insurance in accordance with the requirements of the applicable local laws. If required, additional patient 
coverage or an investigation specific insurance shall be provided by the Sponsor as well. 
7.1.1. Adherence to the Clinical Investigation Plan 
The principal investigator and delegates are required to adhere to the CIP in order to prevent patients from being exposed to unreasonable risks. In 
addition, the principal investigator and delegates are required to be compliant with the signed clinical investigation agreement, applicable national or local 
laws and regulations, and any conditions required by the appropriate EC or applicable regulatory authorities are expected as well. Instances of failure, 
intentionally or unintentionally, to adhere to the requirements of the CIP are considered a deviation. 
 
In some cases failure to comply with the protocol may be considered failure to protect the rights, safety and well-being of patients, since the non-
compliance exposes patients to unreasonable risks. For example, failure to adhere to the inclusion/exclusion criteria: these criteria are specifically defined 
by the sponsor to exclude patients for whom the investigational device is not beneficial and the use involves unreasonable risks. This may be considered 
failure to protect the rights, safety and well-being of the enrolled patient. Similarly, failure to perform safety assessments intended to detect adverse events 
may be considered failure to protect the rights, safety and well-being of the enrolled patient. Investigators should seek minimization of such risks by 
adhering to the protocol. 
 
Simultaneously, in the event that adhering to the protocol might expose the patient to unreasonable risks, the investigator is also required to protect the 
rights, safety and well-being of the patient by intentionally deviating from the requirements of the CIP, so that patients are not exposed to unreasonable 
risks.  
It is the responsibility of the investigator to provide adequate medical care to a patient enrolled in an investigation. 
 
The PI shall promptly report to the sponsor any deviations from the CIP that affect the rights, safety or well-being of the patient or the scientific integrity 
of the clinical investigation, including those which occur under emergency circumstances. The reporting of these deviations should be done as soon as 

          
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possible but no later than 72 hours after the investigator becomes aware. The investigator shall also notify promptly the EC, as per their requirements.  
Any corrective and preventive actions required by the EC must be complied with by the site. 
 
The sponsor will notify the national competent authorities/national regulatory authorities and EC as per their requirements. 
7.1.2. Repeated non-compliance 
In the event of repeated non-compliance or a serious non-compliance, as determined by the sponsor, a clinical research associate or a clinical 
representative will attempt to secure compliance by one or more of the following actions: 
• 
Contacting the investigator by telephone 
• 
Contacting the investigator in writing 
• 
Visiting the investigator 
• 
Retraining of the investigator 
• 
Site “for-cause” audit 
• 
Implementation of corrective action preventive action (CAPA) plan 
 
If an investigator is found to be repeatedly non-compliant with the signed clinical investigation agreement, the CIP or any other conditions of the clinical 
investigation, the sponsor will either secure compliance or, at its sole discretion, terminate the investigator’s participation in the clinical investigation. 
7.2 
Informed Consent Process 
7.2.1. General Process 
Provision of the informed consent is mandatory. Informed consent is required from all patients (or their legal representatives) prior to participation in the 
clinical investigation. The process of obtaining informed consent shall comply with the most recent version of the declaration of Helsinki, ISO 14155 
2011 and all applicable regulations.  
 
The principal investigator or his/her authorized designee will conduct the informed consent process. This process will include a verbal discussion with the 
patient on all aspects of the clinical investigation that are relevant to the patient’s decision to participate in the clinical investigation. It is crucial that this 
discussion is documented in the source documents (records of the patient). 
The patient will be provided with the informed consent form that is written in native non-technical language, understandable for the patient, and has been 
approved by EC. The patient is given ample time to consider participation and ask questions if necessary.  
In order to avoid any possible coercion or undue improper influence on, or inducement of the patient to participate, the sponsor requests the investigator to 
only sign the informed consent form once the patient has signed and dated the document and therefore decided to participate in the investigation. 
Informed consent of a patient shall always be indicated by personally dated signature of the patient and by the investigator responsible for conducting the 
informed consent process. It is crucial that the signature of the informed consent is documented in the source documents (records of the patient). 

          
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One original signed consent document must be retained on file by the investigator and a copy of the signed and dated consent is provided to the patient 
(investigator’s responsibility). 
The patient’s legal rights will not be waived nor the appearance that these will be waived. Important new information that becomes available throughout 
the clinical investigation will have to be provided in writing to new and existing patients. If relevant, all affected patients shall be asked to confirm their 
continuing informed consent in writing. 
 
NOTE: In certain circumstances, it might be decided during screening to send relevant clinical data (such as echocardiogram, CT/MRI or Angiogram) out 
of the hospital for further analysis to determine if patient’s valve anatomy is suitable for participation in the clinical investigation. If required, an 
authorization form to release medical information outside the hospital is available for sign-off by the patient. In case this authorization form is signed by 
the patient, the patient is not yet considered enrolled. 
7.2.2. Patient unable to read or write 
Informed consent shall be obtained through a supervised oral process if a patient or legally authorized representative is unable to read or write. An 
independent witness shall be present throughout the process. The written informed consent form and any other information shall be read aloud and 
explained to the prospective patient or his/her legally authorized representative and, whenever possible, either shall sign and personally date the informed 
consent form. The witness also signs and personally dates the informed consent form attesting that the information was accurately explained and that 
informed consent was freely given. 
 
7.3 
Adverse Event, Adverse Device Effect, Device Deficiency  
7.3.1. Definitions (ISO 14155:2011) 
Medical device 
Any instrument, apparatus, implement, machine, appliance, implant, software, material or other similar or related article 
• 
Intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the specific purpose(s) of 
o Diagnosis, prevention, monitoring, treatments or alleviation of disease, 
o Diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury, 
o Investigation, replacement, modification, or support of the anatomy or of a physiological process, 
o Supporting or sustaining life, 
o Control of conception, 
o Disinfection of medical devices and 
• 
Which does not achieve its primary intended action in or on the human body by pharmacological, immunological or metabolic means, but which may 
be assisted in its intended function by such means 

          
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Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including abnormal laboratory findings) in patients, users or 
other persons, whether or not related to the medical device. 
This definition includes events related to the medical device or the comparator. 
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 patient, 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 OR 
o A malignant tumor 
• 
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 a 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 medical device. 
This definition includes any event resulting from the use error or from intentional misuse of the 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 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. 
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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Device Deficiency (DD) 
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. 
7.3.2. Procedure for assessing, recording and reporting adverse events, adverse device effects, serious adverse events, serious 
adverse device effects and device deficiencies 
Safety surveillance and reporting will be done for all patients enrolled in this investigation. 
 
Safety surveillance within this clinical investigation and safety reporting, both performed by the investigator, starts as soon as the patient is enrolled in this 
clinical investigation (date of signature of the informed consent). The safety surveillance and the safety reporting will continue until the last 
investigational visit has been performed or the patient is deceased or the patient/investigator concludes his participation into the clinical investigation.  
NOTE: If an adverse event is documented at the patient’s last follow up visit, both the notification and follow-up information on the AE eCRF are to be 
provided to the sponsor. 
 
• 
All Serious Adverse Events (regardless of their relationship with the device or the procedure) and all Adverse Device Effects (serious or non-
serious) are to be documented and reported to the sponsor maximum 3 calendar days after becoming aware of the event. 
• 
All Device Deficiencies, that could have led to a Serious Adverse Device Effect, 
o if either suitable action had not been taken;  
o if intervention had not been made or 
o if circumstances had been less fortunate, 
are to be documented and reported to the sponsor maximum 3 calendar days after becoming aware of the event. 
• 
Non-serious adverse events documentation and reporting are limited to cardiovascular and neurovascular events; they all have to be reported 
regardless of their relationship with the device or the procedure. 
 
7.3.3. Should an AE or DD occur, record AE or DD information in the hospital records, document the information into the 
adverse event form or device deficiency form as soon as possible. By completing the form, the sponsor will be notified. Refer 
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and Appendix C: Data Collection Method. In case of EDC failure, notify Sponsor via Fax or via AdverseEvent@sjm.com. 
 
The Sponsor safety department will be responsible for ensuring the assessment of immediate AE and DD ‘reportability’ or ‘non-reportability’ to the national 
competent authorities/national regulatory authorities. All the AEs and DDs will be documented and reported in periodic report(s) as per local requirements. 
 
Additional information may be requested, when required, by the sponsor in order to support the reporting of AEs or DDs to regulatory authorities and to 
support AE or DD analysis. The investigator must notify the EC, if appropriate, in accordance with national and local laws and regulations, of the AEs and 
DDs reported to the sponsor. 
 
In case of disagreement between sponsor and investigator in the AE or DD assessment, then both assessments will be reported. 
7.4 
Patient Death 
7.4.1. Procedure for recording and reporting Patient Death 
7.4.2. All patient deaths are to be documented and reported to the sponsor maximum 3 calendar days after becoming aware of 
the event. Should death occur, the investigator is requested to record death information in the hospital records and 
immediately document the information on the Death Form. By completing the form the sponsor will be notified. Refer to 

          
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 and Appendix C: Data Collection Method. In case of EDC failure, notify Sponsor via Fax or via 
AdverseEvent@sjm.com. 
 
All efforts (including use of national death registries) should be made to identify, precisely 
characterize, and appropriately classify any death. 
 
Patient death is an outcome of a serious adverse event (SAE). All efforts to get SAE details should be 
made and the Adverse Event eCRF must be completed. 
 
If available, the explanted Portico valve should be returned to SJM per instructions provided in 
Appendix K: Explant, Return, and Analysis of Valve and Appendix L: Instructions for device return - 
Large and Small Kits. 
 
The patient’s death is an early conclusion of the patient’s participation in the investigation. Therefore, 
the investigator is requested to complete the termination form. The investigator must notify the 
EC/IRB, if appropriate, in accordance with national and local laws and regulations. 
7.5 
Criteria and procedures for patient withdrawal or discontinuation 
Each patient should remain in the investigation until completion of the required follow up period; 
however, a patient’s participation in the investigation may be discontinued. Should this occur, the 
reason for discontinuation must be documented in the source documents. 
Patients must be informed about their right to withdraw from the investigation at any time and for any 
reason without sanction, penalty or loss of benefits to which the patient is otherwise entitled and 
withdrawal from the investigation will not jeopardize their future medical care or relationship with the 
investigator. Patients will be asked to specify the reason for the termination, but have the right not to 
answer. 
The investigator may decide to withdraw a patient from the investigation at any time. 
The patient’s future care will not be influenced by a decision, voluntary or otherwise, to withdraw 
from the investigation. All reasonable efforts should be made to retain the patient in the clinical 
investigation until completion of the investigation. 
 
Reasons for patient’s withdrawal include, but are not limited to: 
• 
Patient refuses to continue participating in the investigation (refuse all subsequent 
testing/follow up) 
• 
Patient does not meet the inclusion/exclusion criteria prior to baseline procedure 
• 
Patient is deceased (cause must be documented) 
• 
Patient’s non-compliance 
• 
Patient’s participation is terminated by the PI or investigator, although the patient consented, 
since participation is no longer medically justified 
• 
Patient is ‘lost to follow up’: Patient does not adhere to the scheduled follow up visits but has 
not explicitly requested to be withdrawn from the clinical investigation. (This does not apply to 
missed visits). Site personnel should at all times make all reasonable efforts to locate and 
communicate with the patient in order to achieve patient compliance to the scheduled follow up 
visits. A patient will be considered ‘lost to follow up’ after 
• 
A minimum of 2 phone calls from a physician or delegate at the investigational site 
have been attempted to reach the patient. These 2 phone calls need to be documented 
in the patient’s hospital records. 
• 
And a certified letter has been sent to the patient’s last known address or general 
practitioner (GP). A copy of this letter should be maintained in the patient’s hospital 
records. If these attempts are unsuccessful, 
 
Note: If a patient misses one or more of the scheduled follow up visits, this will be considered as a 
missed visit. The patient may therefore still return for subsequent visits and will not be excluded from 
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If the patient misses two consecutive scheduled follow up visits and the above mentioned attempts to 
contact the patient or/and GP were unsuccessful, the patient will be considered ‘lost to follow up’ and 
patient’s termination form should be completed. The investigator ensures that all attempts are 
documented in the patient’s hospital records. 
 
7.6 
Document and data control 
7.6.1. Traceability of documents and data 
The investigator shall ensure accuracy, completeness, legibility and timeliness of the data reported to 
the sponsor on the eCRF's and in all required reports. Where copies of the original source document as 
well as print outs of original electronic source documents are retained, these shall be signed and dated 
by a member of the investigation site team with a statement that it is a true reproduction of the original 
source document. 
7.6.2. Definition of source data 
Investigators shall ensure that all source documents are accurate, complete, legible, up to date, 
original, attributable and capable of being audited. They shall not be obscured by correction fluid or 
have temporary attachments (such as removable self-stick notes). Photocopies of eCRF's are not 
considered acceptable source documents. Source documents are original records in which raw data are 
first recorded. These include, but are not limited to hospital/clinic/general practitioner records, charts, 
diaries, X-rays, laboratory results, printouts, pharmacy records, care records, ECG. Source documents 
should be kept in a secure, limited access area. 
7.6.3. Recording of data 
Source documents shall be created and maintained by the investigation site team throughout the 
clinical investigation. The data reported on the eCRF's shall be derived from, and be consistent with, 
these source documents. Attempts to clarify any conflicting information (discrepancy) shall be 
documented using the appropriate option in the Electronic Data Capture (EDC) system. The eCRF's 
shall be validated by the principal investigator or delegated investigator. Any change or correction to 
data reported on an eCRF shall be tracked. 
 
7.6.4. Review of data (source data verification) 
The clinical investigation will be monitored by reviewing the electronic eCRF's approved by the 
investigators. During monitoring visits, reported data are reviewed with regard to being accurate, 
complete, and verifiable from source data (Source Data Verification). All data reported on the eCRF’s 
should be supported by source data.  
 
The following activities will occur: 
• 
eCRFs will be reviewed for completeness and accuracy by sponsor. 
• 
The investigator, co-investigator and/or delegate will be notified regarding any missing or 
unclear/inconsistent data. 
• 
The investigator (co-investigator) and/or delegate will be requested to clarify or correct the 
inconsistency. 
7.7 
Monitoring  
On site-monitoring will be performed during the clinical investigation in order to guarantee adherence 
to all applicable regulations, the clinical investigation plan and the signed clinical investigation 
agreement. By monitoring, the sponsor can also verify the accuracy of data collected on the 
accompanying eCRF's throughout the duration of the clinical investigation.   

          
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Monitoring is necessary to ensure adequate protection of the rights and safety of human patients 
involved in the clinical investigation and the quality and integrity of the data obtained during the 
clinical investigation. The sponsor will at the same time assess the investigational site and clinical 
investigation team on staffing and facilities to ensure the clinical investigation can continue in a safe 
and effective fashion. 
During the monitoring visits, data reported on the eCRF shall be reviewed as specified in the 
monitoring plan. (Refer to section 7.7.2). 
7.7.1. Designated Monitors 
Only monitors qualified by education, training and experience, which have been trained on the CIP, 
device and its indication for use, eCRF content, use of eCRF guidelines, Monitoring Plan, relevant 
requirements and informed consent process will be allowed to perform monitoring activities during 
this clinical investigation. The monitor’s qualifications and training will be documented by the 
sponsor.  A list of monitors is available upon request. 
7.7.2. Monitoring Plan 
Prior to the start of the site monitoring activities for this clinical investigation, a project specific 
Monitoring Plan (MP) will be created and will be available upon request.  
At a minimum, the Monitoring Plan will include the following: 
• 
Frequency of monitoring visits 
• 
% of source data verification 
• 
Monitoring visit requirements 
• 
Action to be taken in case of serious site non-compliance 
• 
Monitoring report content and timelines  
• 
Close-out visit procedures 
 
The monitoring plan may be updated as appropriate.  All revisions will be tracked.  
7.7.3. National Competent Authority (NCA)/ National Regulatory Authority 
(NRA) Inspections 
The investigator and/or delegate should contact SJM immediately upon notification of a NCA/NRA 
inspection at the site. A clinical monitor will assist the investigator and/or delegate preparing for the 
audit. 
 
An investigator who has authority to grant access shall permit authorized NCA/NRA employees, at 
reasonable times and in reasonable manner, to enter and inspect any establishment where devices are 
held (including any establishment where devices are used or where records or results are kept). 
 
An investigator, or any person acting on behalf of such a person with respect to the investigation, shall 
permit authorized NCA/NRA employees, at reasonable times and in reasonable manner, to inspect and 
copy all records relating to the investigation. 
 
An investigator shall permit authorized NCA/NRA employees to inspect and copy records that 
identify patients, upon notice that NCA/NRA has reason to suspect that adequate informed consent 
was not obtained, or that reports required to be submitted by the investigator, to the Sponsor or 
EC/IRB have not been submitted or are incomplete, inaccurate, false or misleading. 
7.8 
Investigation Termination 
The Sponsor reserves the right to stop the investigation at any stage, with appropriate written notice to 
the investigator. Possible reasons for early termination of the investigation by the sponsor, either at 
local, national or international level, may include, but are not limited to: 
 
• 
The device fails to perform as intended 

          
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• 
Occurrence of USADE which cannot be prevented in future cases 
• 
Sponsor’s decision 
• 
Request from regulatory bodies 
• 
Request of EC(s) 
 
The investigation will then be terminated according to applicable regulations. 
 
The investigator may also discontinue participation in the clinical investigation with appropriate 
written notice to the Sponsor.  
7.8.1. Investigation Conclusion 
The investigation will be concluded when: 
• 
A close-out visit has been performed at each participating site 
• 
The final report has been provided by sponsor 

          
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8 
 Risks and Benefits of the clinical investigation 
8.1 
Anticipated clinical benefits 
The information collected in this clinical investigation will be added to the current knowledge and 
understanding of treatment options for patients with severe symptomatic aortic stenosis who require a 
TAVI procedure. It is expected that patients implanted with a Portico Valve will have the same 
benefits as patients implanted with other transcatheter valves. 
8.2 
Anticipated Adverse Events and Adverse Device Effects 
Adverse events potentially associated with the use of transcatheter valves and their potential 
complications are documented in the Instructions for use. Instructions for use are available upon 
request. 
8.3 
Possible interactions with concomitant medical treatments 
There are no known interactions of the Portico Valve with concomitant medical treatment. Patients 
experiencing an adverse event shall be treated by their treating physician or per the standard of care at 
the investigation site. 
8.4 
Steps that will be taken to control or mitigate the risks 
Actions to control or mitigate risks at the clinical investigation site level will include the selection of 
qualified and experienced investigators and site personnel, investigators intensive device training, and 
strict adherence to the CIP. Data collected during this clinical investigation will include, but not 
limited to, echocardiography, ECG, and adverse event assessment. In addition, investigators shall be 
actively involved in the follow-up of the patients implanted with the transcatheter valves. 
 
Risks shall be minimized by careful assessment of each patient prior to, during and after implant of the 
Portico Valve. After implantation, patients in this clinical investigation shall be followed at regular 
intervals to monitor their condition. 
8.5 
Risk-to-Benefit Rationale 
The risks associated with the use of Portico Valve and transcatheter delivery system and valve loading 
system are anticipated to be comparable to those associated with the use of other currently available 
transcatheter valve and delivery systems. Patients participating in this clinical investigation are 
indicated for a TAVI procedure as part of their standard medical management and are subject to the 
risks associated with these devices. 
 
 
 

          
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9 
Statistical considerations 
9.1 
Analysis population 
All patients who have signed a PIC will be considered enrolled in the clinical investigation (refer to 
Section 4: Clinical investigation design). However, it is anticipated that there will be patients who are 
enrolled in the clinical investigation but will not be included in the analysis dataset.  
 
These patients are described as follow: 
• 
Patients who gave consent to participate in the clinical investigation but did not satisfy the 
inclusion and/or exclusion criteria before the index procedure (screen failure), or have been 
excluded from the study by the investigator before the index procedure. 
• 
Patients who have enrolled in the clinical investigation and started the procedure, but did not 
have the Portico Valve implanted and are procedural exclusions due to their anatomy, 
circumstances related to the procedure, or physician judgment. 
• 
Patient who died, were lost to follow-up or withdraw consent before the index procedure. 
 
Patients enrolled in the clinical investigation and implanted with a PORTICO valve for whom a 
deviation related to inclusion and/or exclusion criteria is identified, should be followed 
throughout the study. The statistical analysis plan, will further describe how the data of these 
patients will be handled.  
9.2 
Sample size estimation 
9.2.1 Cohort A 
The sample size estimation is based on the primary endpoint of this study, all-cause mortality at 1 year 
post implant for patients having received a Portico Valve. 
 
It is assumed that the expected mortality rate at 1 year post implant will be 22.1% 20), and the total 
recruitment period will be 2 years; at least 608 patients are required to be at risk at 1 year post implant, 
in order to establish a two sided 95% confidence limit (18.8%, 25.4%) using non-parametric survival 
analysis with Peto’s variance21. With a dropout rate of 10%, at least 866 patients need to be recruited. 
 
9.2.2 Cohort B 
The anticipated number of patients who participated to a SJM-sponsored Regulatory or First-In-
Human trial conducted in Europe and who will participate to the clinical investigation will be 
approximately 180. 
 
The total population to be enrolled in the clinical investigation is at least 866 for COHORT A, added 
up with any additional patients enrolled in Cohort B, to a maximum of 1046 patients in total. 
9.3 
Primary endpoint analysis 
The primary endpoint analysis will only include patients from Cohort A. 
 
Non-parametric survival analysis will be used to calculate the mortality rate at 1 year post index 
procedure and build its 95% confidence limit. The corresponding variance will be computed using 
Peto’s formula for survival analysis. The survival time will be calculated as the number of days 
between the implant date and the death date for the patients who die at 1 year (365 days) post implant. 
And for the patients who are considered as censored (loss to follow up, explanted, etc.), the survival 
times will be calculated as the number of days between the implant date and the last known adverse 
event or the last documented contact date before 1 year follow up. A Kaplan-Meier curve with the 
cumulative survival rate will also be presented. 
 

          
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A Cox regression model can be used for further explanatory analysis of the relationship of the 
prognostic factors and the mortality. These factors will include baseline factors such as age, gender, 
NYHA class etc., and other factors defined by steering committee can also be analyzed. 
 
9.4 
Secondary endpoint analysis 
The secondary endpoint analysis will include both cohorts but results will be presented separately. 
 
All safety secondary endpoints will be estimated using non-parametric survival analysis, and the data 
will be presented with the aid of Kaplan-Meier curve.  The time to event will be defined as from the 
implant date to the first occurrence of the event for the patients who experienced the event, or to the 
last documented contact date for the patients without the event. 
 
All safety secondary endpoints will be reported at 30 days, 1 year, 2 years, 3 years, 4 years and 5 years 
post implant, as recommended by VARC 2. 
Note: Safety events which occurred prior to the index procedure will be reported separately and will 
not be included in the safety secondary endpoints reporting. 
 
All continuous secondary endpoints will be summarized with the number of non-missing data, mean ± 
standard deviation, median and range (minimum – maximum). 
 
All categorical secondary endpoints will be tabulated with number of occurrence, and the percentage. 
 
Generalized linear mixed model will be used to assess the evolution of the NYHA class at baseline, 30 
days, 1 year, 2 years, 3 years, 4 years and 5 years post implant. 
 
General linear mixed model will be used to evaluate the improvement for the QOL at baseline, 30 
days, 1 year, 2 years, 3 years, 4 years and 5 years post implant. 
 
Other secondary endpoints analysis will be described in a separate statistical analysis plan. This 
document will be available upon request. 
9.5 
Interim reporting 
Interim reporting of primary and secondary endpoints will be performed, before the study’s 
conclusion, upon recommendation of the steering committee. 
Interim reporting of relevant data will also be performed for reimbursement purposes upon request of 
sponsor Health Economics and Reimbursement (HE&R) department. 
 

          
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10 Data Management 
 
Overall, the sponsor will be responsible for the data handling. The sponsor and/or its affiliates will be 
responsible for compiling and submitting all required reports to governmental agencies. 
Investigational data will be analyzed by the sponsor and may be transferred to the sponsor’s locations 
outside of Europe and/or any other worldwide regulatory authority in support of a market-approval 
application. 
 
St. Jude Medical respects and protects personally identifiable information that we collect or maintain. 
As part of our commitment, SJM is certified to the U.S. - European Union Framework and U.S. – 
Swiss Safe Harbor Framework Agreements regarding human resources and patient clinical trial 
personal information. 
10.1 Data Management Plan 
 
eCRF data will be entered in a validated electronic database using Oracle Clinical. The investigator or 
designee is required to enter the data through an electronic data capture system (EDC) system. 
 
The Data Validation Procedure (DVP), which is part of the Data Management Plan (DMP), describes 
all the computerized data cleaning checks (validation rules) as programmed at the time of database set-
up. However, these validation rules may change and be updated throughout the course of the 
investigation. 
Manual review and Data Cleaning Convention (DCC) will be used in addition to computerized data 
cleaning checks, to check for discrepancies and to ensure consistency of the data. 
More information will be provided in the DMP which may be updated as appropriate. All revisions 
will be tracked and include an effective date. The DMP will be available upon request. 
 

          
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11 Document Retention 
 
The principal investigator (PI) shall maintain all essential clinical investigation documents from prior, 
during and (as specified) after the clinical investigation on file at the site for a minimum of 15 years 
after the termination of this investigation, or longer as per local laws, or when it is no longer needed to 
support a marketing application, whichever is later.   
The PI must contact the sponsor prior to destroying or archiving off-site any records and reports 
pertaining to this investigation to ensure that they no longer need to be retained on-site. 
All original patient files must be stored for the longest possible time permitted by the regulations at the 
hospital, research institute, or practice in question. If archiving can no longer be maintained at the site, 
the investigator will notify the sponsor.  
 
All data and documents shall be made available on request of the relevant authorities in case of an 
audit. 
 
The sponsor will archive and retain all essential clinical investigation documents from prior, during 
and (as specified) after the clinical investigation as per requirements.  
 

          
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12 Amendments to Clinical Investigation Plan  
 
The CIP, CRFs, informed consent form and other patient information, or other clinical investigation 
documents shall be amended as needed throughout the clinical investigation, and a justification 
statement shall be included with each amended section of a document. Proposed amendments to the 
CIP shall be agreed upon between the sponsor and principal investigator, or the coordinating 
investigator. The amendments to the CIP and the patient’s informed consent shall be notified to, or 
approved by, the EC and regulatory authorities, if required. The version number and date of 
amendments shall be documented. 
 
The amendment will identify the changes made, the reason for the changes and if it is mandatory or 
optional to implement the amendment. 
 
Any amendment affecting the patient requires that the patient be informed of the changes and a new 
consent be signed and dated by the investigator and patient prior to the patient’s next follow up. 
 
Changes to, or formal clarifications of, the CIP will be documented in writing and provided to the 
investigators. This information will be incorporated when an amendment occurs. 
 

          
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13 Publication Policy 
 
The results of the clinical investigation will be submitted, whether positive or negative for publication.  
 
A publication agreement will be signed between the principal investigator of each participating site 
and the sponsor. 
 
If such a publication agreement is not signed by both parties as a separate agreement it may be part of 
the overall clinical investigation agreement.  A publication committee may also be selected and a 
study specific charter may be developed.   
 
For more information on publication guidelines, please refer to the International Committee of 
Medical Journal Editors (ICMJE) on www.icmje.org. 
 
 
 

          
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14 Investigation Organization 
14.1 Investigation Management/Sponsor 
The organization which takes responsibility for the initiation, implementation and coordination of the 
clinical investigation is SJM International, Inc., with offices located at: 
 
St. Jude Medical Coordination Center BVBA 
Corporate Village 
Da Vincilaan 11, Box F1 
B-1935 Zaventem 
Belgium 
Tel: +32 2 774 69 37 
Fax: +32 2 774 69 46 
 
The SJM safety department can be reached at: 
 
SJM International, Inc. 
Clinical Safety Department 
Corporate Village 
Da Vincilaan 11, Box F1 
B-1935 Zaventem 
Belgium 
Fax: +800 2546 2546 
Email: AdverseEvent@sjm.com 
 
14.1.1 Sponsor Responsibilities 
Sponsor’s responsibilities are in accordance with applicable guidelines. This includes but is not limited 
to the following activities: 
• 
Sign off the clinical investigational plan before the start of the investigation or after 
modifications to the protocol. 
• 
Develop the database. 
• 
Select the clinical investigators. 
• 
Train the clinical investigational sites. 
• 
Activate the sites after receipt of the required documentation. 
• 
Monitor the participating centers by reviewing collected data and investigation documentation 
for completeness and accuracy. 
• 
Perform the data analysis. 
• 
Ensure that all adverse events, adverse device effects and device deficiencies are reported and 
reviewed with the clinical investigator(s) and where appropriate that all serious adverse events, 
serious adverse device effects and device deficiencies that could have led to a serious adverse 
device effect are reported to the relevant authorities and EC(s) and/or safety monitoring 
committee(s). 
• 
Maintain an updated list of principal investigators, investigational sites and institutions. This 
list will be available upon request. 
 
SJM retains the right to terminate the participation of an investigator for any of, but not limited to, the 
following reasons: 
• 
Concern for patient safety and welfare. 
• 
Failure to secure PIC prior to any investigational activity. 
• 
Failure to report unanticipated adverse device effects within 72 hours to SJM. 

          
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• 
Failure to report unanticipated adverse device effects to the EC 
• 
Repeated non-compliance with this CIP or the clinical investigation agreement. 
• 
Inability to successfully implement this CIP. 
• 
Violation of the Declaration of Helsinki 2008 (refer to Appendix B). 
• 
Violation of applicable national or local laws and regulations. 
• 
Falsification of data, or any other breach of ethics or scientific principles. 
14.2 Clinical Investigators 
This clinical investigation will be conducted by qualified investigators who have experience with: 
• 
TAVI procedures. 
• 
Management of patients with severe aortic stenosis and associated co-morbidities. 
• 
Conduct of clinical investigations. 
14.2.1 Investigator’s responsibilities 
By agreeing to this CIP, the investigators accept to allow monitoring, audits (internal or external), EC 
review, and regulatory inspections that are related to the clinical investigation. They also agree to 
provide authorized individuals with direct access to source data and documentation as well as the right 
to copy records, provided such activities do not violate patient consent and patient data confidentiality.  
 
A principal investigator should have experience in and/or will be responsible for: 
• 
Providing signed clinical investigation agreement and appropriate appendices. 
• 
Providing the sponsor with copies of any clinical-investigation-related communications 
between the Principal Investigator and the EC. 
• 
Screening and selecting appropriate patients. 
• 
Providing appropriate EC approved informed consent. 
• 
Collecting and archiving of source data obtained prior to implant, during implant, at follow-up 
examinations and after the investigation has been completed. 
• 
Strict adherence to the CIP investigational requirements to provide for optimal safety and 
efficacious use of the device under clinical investigation. 
• 
Adequate safety reporting. 
• 
Maximizing the quality of data entered in the eCRF’s. 
• 
Supporting the monitor, and auditor, if applicable, in their activities to verify compliance with 
the CIP, to perform source data verification and to correct the eCRF where inconsistencies or 
missing values are identified. 
 
It is acceptable for the principal investigator to delegate one or more functions to an associate or co-
investigator, however, the principal investigator remains responsible for the proper conduct of the 
clinical investigation, complying with the investigational plan and collecting all required data. This 
delegation of specific functions shall be documented on the signature and delegation list (provided by 
Sponsor). The investigation is not transferable to other implant centers attended by the investigator 
unless prior approval is obtained from SJM. 
 

          
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14.2.2 Clinical Coordinating Investigators 
In addition to the responsibilities of the investigators, the Clinical Coordinating Investigators and 
National will: 
• 
Sign off the final version of the investigational protocol and any amendment to the protocol; 
• 
Act as main contact for all investigators in case of medical questions related to the conduct of 
the investigation. 
• 
Be a member of the study steering committee (SC). 
 
The following investigators have been appointed by the Sponsor as Clinical Coordinating 
Investigators: 
 
 
 
 
14.2.3 Source Data and Patient Files 
The investigator has to keep a written or electronic patient files for every patient participating in the 
clinical investigation including the screening failures. In this hospital file, the available demographic 
and medical information of a patient has to be documented, in particular the following:  
• 
Name 
• 
Patient identification code 
• 
Age on consent date 
• 
Gender 
• 
Height 
• 
Weight 
Prof L. Søndergaard 
Prof F. Maisano 
Prof S. Worthley 
Dr. J. Rodes 
 
 
Rigshospitalet 
Copenhagen University 
Hospital 
University Hospital 
Zurich  
 
St Andrews Hospital 
 
Institut Universitaire De 
Cardiologie Et De 
Pneumologie de Québec 
(ICUPQ) 
 
Kardiologisk Klinik B 
Cardiac Surgery 
Dept Cardiology 
 
 
Blegdamsvej 9 
Ramisstrasse 100 
350 
South 
Terrace 
Adelaide 
 
2725 ch Sainte-Foy, 
2100 Copenhagen 
Zurich CH-8091 
SA, 5000 
 
Québec, QC  
G1V 4G5 
 
Denmark 
Switzerland  
Australia 
 
Canada 
 
Tel: +45 35452018 
Tel:  +41 (0)44 255 33 81 
Fax: +41 (0)44 255 44 67 
 
 
Tel: +61 8 8223 4288 
 
Tel: +1 418 656 8711 
Fax: +1 418 656 4544 
 

          
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• 
Medical history 
• 
Concomitant diseases 
• 
Concomitant medication (including changes during the course of the clinical investigation) 
• 
Clinical investigation identification 
• 
Date of informed consent 
• 
All clinical investigation visit dates including the unscheduled visits 
• 
Predefined performed examinations and clinical findings 
• 
Heart team recommendations 
• 
Observed AEs, and DDs that led to an AE 
• 
Reason for withdrawal from the clinical investigation, if applicable. 
All data recorded on the eCRF must also be part of the patient’s source data. 
 
It should be possible to verify the inclusion and exclusion criteria for the investigation from the 
available data in this file. It must be possible to identify each patient by using this patient file. 
Additionally, any other documents with source data have to bear at least the patient identification and 
the printing date printed by the recording device to indicate to which patient and to which 
investigational procedure the document belongs. The medical evaluation of such records should be 
documented as necessary and signed/dated by the investigator.  
14.3 Boards 
14.3.1 Steering Committee 
The SC will be championed by the clinical coordinating investigators (CCI) Prof L. Søndergaard and 
Prof F. Maisano. The National Principal Investigators Prof. Worthley and Dr. Rodes will be part as 
well. 
 
This committee will be actively involved in the clinical investigation, and review its progress at 
regular intervals. At any time, this committee may request that the investigation is being put on hold or 
even terminated for safety, ethical or other reasons. 
A specific charter will be established for the steering committee member’s activities and will be 
available upon request. 
14.3.2 Clinical Event Committee  
An independent clinical events committee will be established for this clinical investigation. The CEC 
will include, at a minimum, an interventional cardiologist or a cardiologist, and a cardiothoracic 
surgeon whose main objective is to review and adjudicate specific adverse events which will occur 
throughout the duration of this trial, as specified in a separate CEC charter. The CEC will adjudicate 
these safety related events according to the VARC 2 criteria. 
The CEC charter will be established for the CEC member’s activities and will be available upon 
request. 
14.4 Outsourcing of duties and functions 
The sponsor may transfer any or all of the duties and functions related to the clinical investigation, 
including monitoring, to an external organization (such as a CRO or individual contractor), but the 
ultimate responsibility for the quality and integrity of the clinical investigation shall reside with the 
sponsor. All requirements applying to the sponsor shall also apply to the external organization 
inasmuch as this organization assumes the clinical-investigation-related duties and functions of the 
sponsor. 
14.4.1 Power of Attorney 
The POA delegates sponsor’s responsibility for specified tasks to the country entities involved in the 
clinical project. The POA is signed and dated by appropriate parties. The POA can consist of, but is 
not limited to: 

          
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• 
Ensure that the clinical investigation agreements are prepared appropriately, comply with legal 
obligations and are signed/dated by all parties. 
• 
Ensure that essential documents to activate the center are collected and maintained in the ISB. 
• 
Activate the centers and manage the centers throughout the duration and close of the 
investigation. 
• 
Report Adverse Events to relevant authorities. 
• 
Ensure that patient data relevant to the investigation is referenced in the hospital records, 
collected and provided to Sponsor  

          
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15 Bibliography  
 
1. Alec Vahanian et al. Guidelines on the management of valvular heart disease (version 2012) 
The Joint Task Force on the Management of Valvular Heart Disease of the European Society 
of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) 
Eur Heart J. 2012 Oct;33(19):2451-96. 
2. Iung B, Vahanian A. Epidemiology of valvular heart disease in the adult. Nat Rev Cardiol 
2011;8:162-72. 
3. Bonow RO, Carabello BA, Chatterjee K, et al, American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines. 2008 focused update incorporated into 
the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a 
report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of 
patients with valvular heart disease). Endorsed by the Society of Cardiovascular 
Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of 
Thoracic Surgeons. J Am Coll Cardiol 2008;52:e1-142. 
4. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic 
stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714-20. 
5. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic 
valve prosthesis for calcific aortic stenosis: first human case description. Circulation 
2002;106:3006-8. 
6. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement 
in high-risk patients. N Engl J Med 2011;364:2187–98. 
7. Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve replacement 
in selected high-risk patients with aortic stenosis. Circulation 2007;116:755-63. 
8. Grube E, Schuler G, Buellesfeld L, et al. Percutaneous aortic valve replacement for severe 
aortic stenosis in high-risk patients using the second- and current third-generation self-
expanding CoreValve prosthesis: device success and 30-day clinical outcome. J Am Coll 
Cardiol 2007;50:69-76. 
9. Ussia GP, Mulè M, Barbanti M, et al. Quality of life assessment after percutaneous aortic 
valve implantation. Eur Heart J 2009;30:1790-6. 
10. Gotzmann M, Hehen T, Germing A, et al. Short-term effects of transcatheter aortic valve 
implantation on neurohormonal activation, quality of life and 6-minute walk test in severe and 
symptomatic aortic stenosis. Heart 2010;96:1102-6. 
11. Buellesfeld L, Gerckens U, Schuler G, et al. 2-Year follow-up of patients undergoing 
transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am Coll 
Cardiol 2011;57:1650-7. 
12. Gotzmann M, Bojara W, Lindstaedt M, et al. One-year results of transcatheter aortic valve 
implantation in severe symptomatic aortic valve stenosis. Am J Cardiol 2011;107:1687-92 
13. Gurvitch R, Wood DA, Tay EL, et al. Transcatheter aortic valve implantation: durability of 
clinical and hemodynamic outcomes beyond 3 years in a large patient cohort. Circulation 
2010;122:1319-27. 
14. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic valve replacement for 
inoperable severe aortic stenosis. N Engl J Med 2012;366:1696 –704. 
15. Kodali S, Williams M, Smith CR, et al. Two year outcomes after transcatheter or surgical 
replacement in high risk patients with aortic stenosis. N Engl J Med 2012;366:1686 –95. 
16. Gotzmann M, Lindstaedt M, Mügge A. From pressure overload to volume overload: Aortic 
regurgitation after transcatheter aortic valve implantation. Am Heart J 2012;163:903-11 
17. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic 
valve implantation in high-risk patients with severe aortic stenosis: The U.K. TAVI (United 
Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol 
2011;58:2130–8. 
18. Gilard M, Eltchaninoff H, Iung B, et al. Registry of Transcatheter Aortic-Valve Implantation 
in High-Risk Patients. N Engl J Med 2012;366:1705-15. 

          
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19. A. Pieter Kappetein, Stuart J. Head, Philippe Genereux, Nicolo Piazza, Nicolas M. van 
Mieghem, Eugene H. Blackstone, Thomas G. Brott, David J. Cohen, Donald E. Cutlip, Gerrit-
Anne van Es, Rebecca T. Hahn, Ajay J. Kirtane, Mitchell W. Krucoff, Susheel Kodali, 
Michael J. Mack, Roxana Mehran, Josep Rodes-Cabau, Pascal Vranckx, John G. Webb, 
Stephan Windecker, Patrick W. Serruys, and Martin B. Leon. Updated standardized endpoint 
definitions for transcatheter aortic valve implantation: the Valve Academic Research 
Consortium-2 consensus document. European Heart Journal (2012) 33, 2403–2418 
20. Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K, Smith C, Serruys PW, 
Kappetein P, Leon MB. Clinical Outcomes After Transcatheter Aortic Valve Replacement 
Using Valve Academic Research Consortium Definitions. JACC 2012;59:2317-26. 
21. Alan B cantor , SAS survival analysis techniques for medical research. 
22. Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, 
Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip 
DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for 
cardiovascular clinical trials: a consensus report from the Bleeding Academic Research 
Consortium. Circulation 2011;123: 2736–2747. 
23. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 
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24. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, 
Kop WJ, Burke G, McBurnie MA. Frailty in Older Adults: Evidence for a Phenotype. Journal 
of Gerontology 2001; 56A:M146–M156. 
25. ATS Statement: guidelines for the Six-Minute Walk Test. AM J Respir Crit Care Med vol 
2002;166:111-117.  
26. Willson JT, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, Bone I. Improving the 
assessment of outcomes in stroke: use of a structured interview to assign grades on the 
Modified Rankin Scale. Stroke; 33:2243-2246 
27. Sinning JM, Hammerstingl C, Vasa-Nicotera M, Adenauer V, Lema Cachiguango SJ, Scheer 
AC, Hausen S, Sedaghat A, Ghanem A, Müller C, Grube E, Nickenig G, Werner N. Aortic 
regurgitation index defines severity of peri-prosthetic regurgitation and predicts outcome in 
patients after transcatheter aortic valve implantation. J Am Coll Cardiol. 2012 Mar 
27;59(13):1134-41. 

          
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Appendix A: Abbreviations 
 
Abbreviation 
Term 
6MWT 
ACS 
ADE 
AE 
AS 
ASADE 
AVR 
BARC 
BMI 
CAD 
CATD 
CCI 
CEC 
CHF 
CIP 
CBP 
CRF 
DCC 
DD 
DMP 
DVP 
EC 
ECG 
eCRF 
EDC 
EROA 
HE&R 
FCS 
GP 
ICMJE 
IFU 
IRB 
ISB 
ISO 
LBBB 
LVEF 
MI 
MP 
MSCT 
NAP 
NCA 
NRA 
NYHA 
PI 
PIC 
POA 
PIL 
QoL 
RBC 
RDC 
6 Minute Walk Test 
Acute Coronary Syndrome 
Adverse Device Effect 
Adverse Event 
Aortic Stenosis 
Anticipated Serious Adverse Device Effect 
Aortic Valve Replacement 
Bleeding Academic Research Consortium 
Body Mass Index 
Coronary Artery Disease 
Cardiovascular and Ablation Technologies Division 
Clinical Coordinating Investigator 
Clinical Event Committee 
Congestive Heart Failure 
Clinical Investigational Plan 
Cardio Pulmonary Bypass 
Case Report Form 
Data Cleaning Convention 
Device Deficiency 
Data Management Plan 
Data Validation Procedure 
Ethics Committee 
Electrocardiogram 
Electronic Case Report Form 
Electronic Data Capture 
Effective Regurgitant Orifice Area 
Health Economic and Reimbursement 
Field Clinical Specialist 
General Practitioner 
International Committee of Medical Journal Editors 
Instructions For Use 
Institutional Review Board 
Investigator Site Binder 
International Organization for Standardization 
Left Bundle Branch Block 
Left Ventricular Ejection Fraction 
Myocardial Infarction 
Monitoring Plan 
Multi Slice Computed Tomography 
Not Applicable 
National Competent Authority 
National Regulatory Authority 
New York Heart Association 
Principal Investigator 
Patient Informed Consent 
Power of Attorney 
Patient Identification Log 
Quality of Life 
Red Blood Cell 
Remote Data Capture 

          
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RIFLE 
SADE 
SAE 
SC 
SJM 
TAVI 
TEE 
TIA 
USADE 
VARC 
WMA 
Risk Injury Failure Loss End-Stage Kidney Disease 
Serious Adverse Device Effect 
Serious Adverse Event 
Steering Committee 
St. Jude Medical 
Transcatheter Aortic Valve Implantation 
Trans-Esophageal Echocardiography 
Transient Ischemic Attack 
Unanticipated Serious Adverse Device Effect 
Valve Academic Research Consortium 
World Medical Association 
 

          
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Appendix B: Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble                                                                                                                                                      
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including research on 
identifiable human material and data.                                                                                                    
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs.                                                                             
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving human 
subjects to adopt these principles.                                                                                                           
General Principles                                                                                                                                    
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics declares that, 
“A physician shall act in the patient's best interest when providing medical care.”                                                             
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty.                                                                                  
5. 
Medical progress is based on research that ultimately must include studies involving human 
subjects.                                                                                                                                                              
6.  
The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and therapeutic 
interventions (methods, procedures and treatments). Even the best proven interventions must be 
evaluated continually through research for their safety, effectiveness, efficiency, accessibility and 
quality.                                                                                                                                                           
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights.                                                                                                              
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can 
never take precedence over the rights and interests of individual research subjects.                                
9.         It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of 
research subjects. The responsibility for the protection of research subjects must always rest with the 
physician or other health care professionals and never with the research subjects, even though they 
have given consent.                                                                                                                                  
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and 
standards. No national or international ethical, legal or regulatory requirement should reduce or 

          
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eliminate any of the protections for research subjects set forth in this Declaration.                         
11.       Medical research should be conducted in a manner that minimizes possible harm to the 
environment.                                                                                                                                                 
12. 
Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other 
health care professional.                                                                                                                   
13.       Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research.                                                                                                                   
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic 
value and if the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects.                                                                          
15.       Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured.        
Risks, Burdens and Benefits                                                                                                                         
16.       In medical practice and in medical research, most interventions involve risks and burdens.                                   
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects.                                                                 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison 
with foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation.                                                                                                                                      Meas
ures to minimize the risks must be implemented. The risks must be continuously monitored, assessed 
and documented by the 
researcher.                                                                                       18.       Physicians may not be 
involved in a research study involving human subjects unless they are confident that the risks have 
been adequately assessed and can be satisfactorily managed.                                                                                              
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.                                                                                                                                                    
Vulnerable Groups and Individuals                                                                                                        
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood 
of being wronged or of incurring additional 
harm.                                                                                     All vulnerable groups and individuals 
should receive specifically considered protection.                              20. Medical research with a 
vulnerable group is only justified if the research is responsive to the health needs or priorities of this 
group and the research cannot be carried out in a non-vulnerable group. In addition, this group should 
stand to benefit from the knowledge, practices or interventions that result from the research.                                            
Scientific Requirements and Research Protocols                                                                              
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected.                                                                                     
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research 
protocol.                                                                                           The protocol should contain a 
statement of the ethical considerations involved and should indicate how the principles in this 
Declaration have been addressed. The protocol should include information regarding funding, 

          
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sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study.                                                              In clinical 
trials, the protocol must also describe appropriate arrangements for post-trial provisions.                                                  
Research Ethics Committees                                                                                                                    
23.       The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be transparent 
in its functioning, must be independent of the researcher, the sponsor and any other undue influence 
and must be duly qualified. It must take into consideration the laws and regulations of the country or 
countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this 
Declaration.                                                                                                                            The 
committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment 
to the protocol may be made without consideration and approval by the committee. After the end of 
the study, the researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions.                                  
Privacy and Confidentiality                                                                                                         
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information.                                                                   
Informed Consent                                                                                                              
25.       Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, 
no individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees.                                                                                                                                            
26.       In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, post-study provisions and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well as to the methods used 
to deliver the information.                                                                                                                            
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed 
consent, preferably in writing. If the consent cannot be expressed in writing, the non-written consent 
must be formally documented and 
witnessed.                                                                                                              All medical research 
subjects should be given the option of being informed about the general outcome and results of the 
study.                                                                                                                                       
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship.                                                                             
28.       For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended to promote 
the health of the group represented by the potential subject, the research cannot instead be performed 

          
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with persons capable of providing informed consent, and the research entails only minimal risk and 
minimal burden.                                                                                                                                 
29.       When a potential research subject who is deemed incapable of giving informed consent is able 
to give assent to decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected.                                                                                                                         
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents 
giving informed consent is a necessary characteristic of the research  group. In such circumstances the 
physician must seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a condition that 
renders them unable to give informed consent have been stated in the research protocol and the study 
has been approved by a research ethics committee. Consent to remain in the research must be obtained 
as soon as possible from the subject or a legally authorized representative.                                                                        
31.       The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to withdraw from 
the study must never adversely affect the patient-physician relationship.                                              
32.       For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research. In such situations the research may be done 
only after consideration and approval of a research ethics committee.                                                                                 
Use of Placebo                                                                                                                        
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances:                              
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or                
Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention                                                                                                        
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven 
intervention.                                                                                                             Extreme care must be 
taken to avoid abuse of this option.                                                         
Post-Trial Provisions                                                                                                                   
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as 
beneficial in the trial. This information must also be disclosed to participants during the informed 
consent process.                                                                           
Research Registration and Publication and Dissemination of Results                                      
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject.                                                                               
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to make 
publicly available the results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports. All parties should adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive as well as positive results must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be 

          
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declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication.                    
                                                                                                  
Unproven Interventions in Clinical Practice                                                                                 
37.       In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an unproven intervention if in 
the physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. 
This intervention should subsequently be made the object of research, designed to evaluate its safety 
and efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

          
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Appendix C: Data Collection Method 
 
Sponsor/Investigators are required to prepare and maintain adequate an accurate case histories 
designed to record all observations and other data pertinent to the investigation on each subject 1:1. 
Source documents include all original records from which eCRF’s derive their data. 
 
Worksheet might be provided. The purpose of these worksheets is to aid investigators in the capture of 
clinical investigational data and ensure all protocol required data, which is not captured in medical 
records, is recorded to support data for the investigation. These worksheets will not be a copy of the 
eCRF’s, but will contain entry blanks for clinical investigation required data not routinely collected by 
the investigators. 
All documentation pertaining to clinical assessments and medical evaluations should be signed and 
dated by the appropriate clinical personnel. 
 
Electronic Data Capture (EDC) will be used for this investigation, therefore, please find below 
instructions on how to access and use the eCRF application. 
 
Access to eCRF application 
The eCRF application is accessed through the internet and requires the use of a personal user account 
and password. 
 
The following documents and information are required prior to receipt of personnel user account and 
password: 
• 
Current signed and dated CV 
• 
Completed Signature and Delegation List 
• 
Documented training 
• 
Email address and telephone 
 
Personal user account and password are provided via email. User account and password are 
confidential and personal. They are not to be shared with other people. 
The first time the application is accessed, the password will need to be changed. 
If the password is forgotten and/or lost, a new password can be provided via email by following the 
instructions on the webpage. 
 
Each center must be authorized to start enrolling patients in the investigation before access privileges 
to the application is made available. 
Access privileges are based on the tasks assigned on the Signature and Delegation List and will be 
either: 
• 
Data entry and review 
• 
Data entry, review and sign off 
 
All eCRF’s have to completed, saved (‘save complete’) and approved by an investigator in a timely 
manner. 

          
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Appendix D: VARC 2 Endpoints Definitions 19 
 
Mortality 
 
(VARC 2) 
Cardiovascular Mortality: 
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 non-structural valve dysfunction 
or other valve-related adverse event. 
• 
Sudden or witnessed death. 
• 
Death of unknown cause. 
 
Non-Cardiovascular mortality: 
• 
Any death in which the primary cause of death is clearly related to another 
condition (e.g. trauma, cancer, suicide) 
Myocardial  
Infarction 
 
(VARC 2) 
Peri-procedural MI (≤ 72 h after the index procedure) 
New ischemic symptoms (e.g., chest pain or shortness of breath), or new ischemic 
signs (e.g. ventricular arrhythmias, new or worsening heart failure, new ST-segment 
changes, hemodynamic instability, new pathological Q-waves in at least two 
contiguous leads,  imaging evidence of new loss of viable myocardium or new wall 
motion abnormality),  
Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index 
procedure AND   consisting of at least one sample post-procedure with a peak value 
exceeding 15× as the upper reference limit for troponin or 5× for CK-MB. If cardiac 
biomarkers are increased at baseline (>99th percentile), a further increase in at least 
50% post-procedure is required AND 
the peak value must exceed the previously stated limit. 
Spontaneous MI (>72 h after the index procedure) 
Any 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. 

          
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Stroke and TIA 
 
(VARC 2) 
Diagnostic criteria 
• 
Acute episode of a focal or global neurological deficit with at least one of the 
following: change in level of consciousness, hemiplegia, hemiparesis, numbness 
or sensory loss affecting one side of the body, dysphasia or aphasia, haemianopia, 
amaurosis fugax, or other neurological signs or symptoms consistent with stroke. 
• 
Stroke: duration of a focal or global neurological deficit ≥24h; OR <24h, if 
available neuroimaging documents a new hemorrhage or infarct; OR the 
neurological deficit results in death. 
• 
TIA: duration of a focal or global neurological deficit <24h, any variable 
neuroimaging does not demonstrate a new hemorrhage or infarct. 
• 
No other readily identifiable non-stroke cause for the clinical presentation (e.g. 
brain tumor, trauma, infection, hypoglycaemia, peripheral lesion, 
pharmacological influences) to be determined by or in conjunction with the 
designated neurologista. 
• 
Confirmation of the diagnosis by at least one of the following: 
o Neurologist or neurosurgical specialist 
o Neuroimaging procedure (CT scan or brain MRI), but stroke may be 
diagnosed on clinical grounds alone. 
Stroke classification 
• 
Ischaemic: an acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by infarction of the central nervous system tissue. 
• 
Haemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction 
caused by intraparenchymal, intraventricular, or subarachnoid haemorrhage. 
• 
A stroke may be classified as undetermined if there is insufficient information to 
allow categorization as ischaemic or haemorrhagic. 
Stroke definitionsb 
• 
Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least 
one mRS category from an individual’s pre-stroke baseline. 
• 
Non-disabling stroke: an mRS score of <2 at 90 days or one that does not result in 
an increase in at least one mRS category from an individual’s pre-stroke baseline 
a Patients with non-focal global encephalopathy will not be reported as a stroke 
without unequivocal evidence based upon neuroimaging studies (CT scan or Brain 
MRI) 
bModified Rankin Score assessments should be made by qualified individuals 
according to a certification process.  
Bleeding 
 
(VARC 2) 
 
Life-threatening or disabling bleeding 
• 
Fatal bleeding (BARC(22) 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 ≥ 5 g/dl or whole blood or 
packed red blood cells (RBCs) transfusion ≥ 4 Unitsa (BARC type 3b). 
aGiven 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 

          
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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) 
Stage 1  
Increase in serum creatinine to 150% - 199% (1.5 to 1.99 X increase compared with 
baseline) OR increase of ≥ 0.3 mg/dl (≥26.4 mmol/l) OR 
Urine output <0.5 mL/kg/h for >6h but <12h 
Stage 2  
Increase in serum creatinine to 200% -299% (2.0 to 2.99 X increase compared with 
baseline)  OR 
Urine output <0.5 mL/kg/h for >12h but <24h 
Stage 3  
Increase in serum e 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/h for ≥24h OR 
Anuria for ≥12h 
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 bleedinga, 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 ischaemia or neurological impairment OR 
• 
Any new ipsilateral lower extremity ischaemia 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, pseudoaneuysms, hematomas , percutaneous 
closure device failure) not leading to  death, life-threatening or major bleedinga, 
visceral ischaemia, 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 

          
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• 
Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
• 
 
Percutaneous close device failure 
• 
Failure of a closure device to achieve haemostasis at the arteriotomy site leading 
to alternative treatment (other than manual compression or adjunctive 
endovascular ballooning) 
aRefers to VARC 2 bleeding definitions 

          
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Other 
TAVI-
related 
complications 
 
(VARC 2) 
Conversion to open surgery 
• 
Conversion to open sternotomy during the TAVI procedure secondary to any 
procedure-related complications 
Unplanned use of cardiopulmonary bypass (CPB) 
• 
Unplanned use of CPB for haemodynamic support at any time during the TAVI 
procedure 
Coronary obstruction 
• 
Angiographic or echocardiographic evidence of a new, partial or complete, 
obstruction of a coronary ostium, either by the valve prosthesis itself, the native 
leaflets, calcifications, or dissection, occurring during or after the TAVI 
procedure 
Ventricular septal perforation 
• 
Angiographic or echocardiographic evidence of a new septal perforation during 
or after the TAVI procedure 
Mitral valve apparatus damage or dysfunction 
• 
Angiographic or echocardiographic evidence of new damage (chordae papillary 
muscle, or to the leaflet) to the mitral valve apparatus or dysfunction (e.g. 
restrictions due to the THV) of the mitral valve during or after the TAVI 
procedure 
Cardiac tamponade 
• 
Evidence of a new pericardial effusion associated with haemodynamic instability 
and clearly related to the TAVI procedure 
Endocarditis 
Any one of the following 
• 
Fulfilment of the Duke endocarditis criteria (23) 
• 
Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary 
to infection by histological or bacteriological studies during a re-operation 
• 
Findings of abscess, pus, or vegetation involving a repaired or replaced valve 
during an autopsy 
Valve thrombosis 
• 
Any thrombus attached to or near an implanted valve that occludes part of the 
blood flow path, interferes with valve function, or is sufficiently large to warrant 
treatment. Note that valve-associated thrombus identified at autopsy in a patient 
whose cause of death was not valve-related should not be reported as valve 
thrombosis 
Valve malpositioning 
• 
Valve migration : After initial correct positioning, the valve prosthesis moves 
upwards or downwards, within the aortic annulus from its initial position, with or 
without consequences 
• 
Valve embolization: The valve prosthesis moves during or after deployment such 
that it loses contact with the aortic annulus 
• 
Ectopic valve deployment : Permanent deployment of the valve prosthesis in a 
location other than the aortic root 
TAV-in-TAV deployment 
• 
An additional valve prosthesis is implanted within a previously implanted 
prosthesis because of suboptimal device position and/or function, during or after 
the index procedure 
Potential 
failure modes of 
prosthetic valve 
Dysfunction 
 
(VARC) 
Aortic stenosis 
• 
Stent creep 
• 
Pannus 
• 
Calcification 
• 
Support structure deformation (out-of-round configuration), under-expansion, 

          
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fracture, or trauma (cardio-pulmonary resuscitation, blunt chest trauma) 
• 
Mal-sizing (prosthesis-patient mismatch) 
• 
Endocarditis 
• 
Prosthetic valve thrombosis 
• 
Native leaflet prolapse impeding prosthetic leaflet motion 
Aortic regurgitation 
• 
Pannus 
• 
Calcification 
• 
Support structure deformation (out-of-round configuration), recoil, under-
expansion, fracture, insufficient radial strength, or trauma (cardio-pulmonary 
resuscitation, blunt chest trauma) 
• 
Endocarditis 
• 
Prosthetic valve thrombosis 
• 
Malposition (too high, too low) 
• 
Acute mal-coaptation 
• 
Leaflet wear, tear/perforation, prolapse, or retraction 
• 
Suture breakage or disruption 
• 
Native leaflet prolapse impeding prosthetic leaflet motion 
Prosthetic 
Valve Stenosis  
 
In conditions of 
normal or near 
normal stroke 
volume (50–70 
ml). 
 
(VARC 2) 
 
Parameter  
Normal 
Mild Stenosis 
Moderate/Sever
e Stenosis 
Quantitative parameters (flow-dependent) 
Peak velocity (m/s) < 3m/s 
3–4m/s 
> 4m/s 
Mean gradient (mm 
Hg) 
< 20mmHg 
20–40 mmHg 
> 40  mmHg 
Doppler velocity 
index 
For LVOT >2.5 cm, 
significant stenosis 
criteria is <0.20. 
> 0.35 
0.35–0.25 
< 0.25 
Quantitative parameters (flow-independent) 
Effective orifice 
area (cm2) 
Use in setting of 
BSA ≥1.6 cm2 
> 1.1cm2 
1.1–0.8 cm2 
< 0.80 cm2 
Effective orifice 
area (cm2) 
Use in setting of 
BSA <1.6 cm2. 
> 0.9 cm2 
0.9 – 0.6 cm2 
< 0.6 cm2 
Prosthesis–
patient 
mismatch 
(PPM) 
 
(VARC 2) 
Parameter 
Insignificant 
Moderate 
Severe 
Indexed effective 
orifice area 
(cm2/m2) 
Use in setting of 
BMI <30 kg/ cm2. 
>0.85 cm2/m2  
0.85–0.65 cm2/m2 
< 0.65 cm2/m2 
Indexed effective 
orifice area 
(cm2/m2) 
Use in setting of 
BMI ≥30 kg/ cm2. 
>0.90 cm2/m2 
0.90–0.60 cm2/m2 
< 0.60 cm2/m2 
Prosthetic 
Parameter 
Mild 
Moderate 
Severe 

          
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Valve 
Regurgitation  
 
(VARC 2) 
Semi quantitative parameters 
Diastolic flow 
reversal in the 
descending aorta—
PW 
Absent or brief early 
diastolic  
Intermediate  
Prominent, 
holodiastolic 
Circumferential 
extent of prosthetic 
valve paravalvular 
regurgitation (%) 
Not well-validated 
and may 
overestimate the 
severity compared 
with the 
quantitative 
Doppler. 
<10% 
10–29% 
≥30% 
Quantitative parameters 
Regurgitant volume 
(mL/beat) 
<30 mL  
30–59 mL 
≥60 mL 
Regurgitant fraction 
(%) 
<30%  
30–49% 
≥50% 
EROA (cm2) 
0.10 cm2  
0.10–0.29 cm2 
≥0.30 cm2 
Device Success 
 
(VARC 2) 
• 
Absence of procedural mortality AND 
• 
Correct positioning of a single prosthetic heart valve into the proper anatomical 
location AND 
• 
Intended performance of the prosthetic heart valve (no prosthesis–patient 
mismatcha and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, 
AND no moderate or severe prosthetic valve regurgitationa) 
Early Safety (at 
30 days) 
 
(VARC 2) 
• 
All-cause mortality 
• 
All stroke (disabling and non-disabling) 
• 
Life-threatening bleeding 
• 
Acute kidney injury—Stage 2 or 3 (including renal replacement therapy) 
• 
Coronary artery obstruction requiring intervention 
• 
Major vascular complication 
• 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
Clinical efficacy 
(after 30 days) 
 
(VARC 2) 
 
• 
All-cause mortality 
• 
All stroke (disabling and non-disabling) 
• 
Requiring hospitalizations for valve-related symptoms or worsening congestive 
heart failureb 
• 
NYHA class III or IV 
• 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9–1.1 
cm2(c) and/or DVI <0. 35 m/s, AND/OR moderate or severe prosthetic valve 
regurgitationa 
Time-related 
valve safety 
 
(VARC 2) 
 
• 
Structural valve deterioration 
• 
Valve-related dysfunction (mean aortic valve gradient 
• 
≥20 mmHg, EOA ≤0.9–1.1 cm2cand/or DVI <0.35 m/s, AND/OR moderate or 
severe prosthetic valve regurgitationa) 
• 
Requiring repeat procedure (TAVI or SAVR) 
• 
Prosthetic valve endocarditis 
• 
Prosthetic valve thrombosis 
• 
Thrombo-embolic events (e.g. stroke) 

          
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• 
VARC bleeding, unless clearly unrelated to valve therapy (e.g. trauma) 
 
arefers to VARC definitions 
bAs a basis for calculation of ‘days alive outside the hospital’ endpoint. 
Supplementary appendix of Leon et al. Includes heart failure, angina, or syncope due 
to aortic valve disease requiring intervention or intensified medical management; 
clinical symptoms of CHF with objective signs including pulmonary oedema, 
hypoperfusion, or documented volume overload AND 
administration of IV diuresis or inotropic therapy, performance of aortic 
valvuloplasty, institution of mechanical support (IABP or ventilation for pulmonary 
oedema) or haemodialysis for volume overload; clear documentation of anginal 
symptoms AND 
no clinical evidence that angina was related to CAD or ACS; documented loss of 
consciousness not related to seizure or tachyarrhythmia. 
cDepending on the body surface area. 
 
 
 
 
 
 
 
 

          
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Appendix E: Surgical Risk Assessment Tools 
 
This clinical investigation requires the use of three (3) surgical risk assessment tools which are 
available online: 
 
o Logistic Euro SCORE I 
• 
http://euroscore.org/calcold.html 
o Logistic Euro SCORE II 
• 
http://euroscore.org/calc.html 
o The Society of Thoracic Surgeons’ (STS) risk calculation tools, Version 2.73 
• 
http://riskcalc.sts.org/STSWebRiskCalc273/de.aspx 
 
 
 
 
 
 
 

          
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Appendix F: Frailty Assessment 
 
Frailty assessment will be performed according to the VARC 2 guidelines. Frailty components have to 
be assessed concomitantly. 
 
5 meters walking time: Patients will be requested to walk for 5 meters. The time the patient takes to 
walk this distance, with or without a walking aid will be measured.  
 
Walk Time, stratified by gender and height (24). 
Gender 
Height 
Cutoff values for Time to Walk 5 meters criterion for frailty 
 
 
 
Male 
 ≤ 173 cm 
≥ 7sec 
Male 
 > 173 cm 
≥ 6sec 
 
 
 
Female 
≤159 cm 
≥ 7sec 
Female 
> 159 cm 
≥ 6sec 
 
Grip strength: Patients will be requested to squeeze a hand-held dynamometer. Patients 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. The best of three attempts will be 
used. 
 
Grip Strength, stratified by gender and body mass index (BMI) quartiles (24) 
Gender 
BMI 
Cutoff for grip strength (Kg) criterion for frailty 
 
 
 
Male 
≤24 
≤29 
Male 
 24.1–26 
≤30 
Male 
26.1–28 
≤31 
Male 
>28 #32 
≤32 
 
 
 
Female 
≤ 23 
≤17 
Female 
23.1–26 
≤17.3 
Female 
26.1–29 
≤18 
Female 
>29 
≤21 
 
 
Wasting and malnutrition: The following parameters will be determined for each patient 
 
Parameters 
Cutoff values for criterion for frailty 
Weight Loss (unintentional) 
>5Kgs/year 
BMI 
<20kg/m2 
Serum albumin 
< 3.5g/dL 
 
Cognitive impairment or dementia: The mini–mental state examination (MMSE) will be performed. 
 
 
 
 
 
 

          
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Appendix G: ATS Guidelines25 for the 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  
o 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.  
o 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.  
o 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.  
o 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.  
o If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or as 
directed by a physician or a protocol. 
 
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable 
dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
 
Technicians must be trained to recognize these problems and the appropriate responses. If a test is 
stopped for any of these reasons, the patient should sit or lie supine as appropriate depending on the 
severity or the event and the technician's assessment of the severity of the event and the risk of 
syncope. The following should be obtained based on the judgment of the technician: blood pressure, 
pulse rate, oxygen saturation, and a physician evaluation. Oxygen should be administered as 
appropriate.  
 
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the previous 
month and myocardial infarction during the previous month. Relative contraindications include a 
resting heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, and a diastolic 
blood pressure of more than 100 mm Hg.  
 
Patients with any of these findings should be referred to the physician ordering or supervising the test 
for individual clinical assessment and a decision about the conduct of the test. The results from a 
resting electrocardiogram done during the previous 6 months should also be reviewed before testing. 
Stable exertional angina is not an absolute contraindication for a 6MWT, but patients with these 
symptoms should perform the test after using their antiangina medication, and rescue nitrate 
medication should be readily available. A deviation from the Clinical Investigation Plan will need to 
be collected if the patient is unable to complete this test. 
 
LOCATION 

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

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

          
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2. Record the additional distance covered (the number of meters in the final partial lap) using the 
markers on the wall as distance guides. Calculate the total distance walked, rounding to the 
nearest meter, and record it on the worksheet.  
3. Congratulate the patient on good effort and offer a drink of water. 
 
 

          
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Appendix H: Structured Interview for the Modified Rankin Scale (mRS) 
 
The modified Rankin Scale (mRS) score is to be determined and graded by a certified rater. 
 
The determination of the scale should be made from 5 to 0, i.e., the order presented.  
 
The purpose of the mRS is to record whether the patient is dead, severely, moderately, or slightly 
disabled and if not dead or disabled, whether the patient is performing all usual activities without 
symptoms or not.  
 
Because patients 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 
rater may ask questions but must assess the disability whether or not in agreement with the patient or 
family (26).  
 
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 (ADL), 
but not requiring constant care.  
 
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking?  
 
3: Moderate disability; need for assistance with some instrumental ADL but not basic ADL.  
 
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, but independent for ADL.  
 
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 I: Peri-procedural instructions 
 
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 PVL; <10% = mild (I), 10-
29% = moderate (II), >30% = severe (III-IV). 
 
Hemodynamic assessment: the AR index will be calculated as described by Sinning et al (27). 
 
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 periAR. 
 
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 J: Recommendation for paced rhythm assessment in patients with a TAVI related 
implantation of permanent pacemaker 
 
This recommendation will apply for patients who received a new pacemaker, due to any degree of 
AV-block, within 30 days after their TAVI procedure. 
 
This testing is aimed to determine whether the patient is pacemaker dependent; it will be performed 
twice, at the 30 days visit and further following routine control. 
 
The patient will have a 12-lead ECG, if the latter shows a “pace rhythm”, then the pacemaker will be 
set to 30 bpm (VVI or DDD) for and another 12-lead ECG will be performed to see if there is still a 
“pace rhythm”. 
 
Afterwards the pacemaker will be programmed back to its normal setting. 
 
 
 
 

          
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Appendix K: 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:  SJM requests that all valves 
that are explanted or recovered be returned to SJM as follows: 
 
o Contact the SJM Clinical Manager(s) for this study as soon as it is learned that a valve will 
be explanted, or recovered during an autopsy. The Clinical Representative(s) will obtain a 
RA# (used for returning products to SJM), and then send a St. Jude Medical 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, in situ photographs, and operative/autopsy notes via courier to the 
following address: 
 
Attn: FER Lab 
177 East County Road B 
St. Paul, MN  55117 USA 
 
St. Jude Medical’s Responsibilities for the Analysis of an Explanted and Returned Device: 
 
Portico Valve that are explanted or recovered at autopsy and returned will, upon receipt at St. Jude 
Medical, Inc., be evaluated according to documented SJM procedures. 
 

          
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Appendix L: Instructions for device return - Large and Small Kits 
 
Instructions for Packaging and Returning Products to St. Jude Medical from US and Outside of US 
Locations 
 
St. Jude Medical 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: 
 
 
St. Jude Medical 
ATTN: Reliability Analysis Laboratory 
14901 DeVeau Place 
Minnetonka, MN 55345 
USA