Expanded Clinical Study of the Tendyne Mitral Valve System
Phase: NA
Conditions: Mitral Valve Regurgitation
Sponsor: Abbott Medical Devices

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CS-03 Version H 
 
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Expanded Clinical Study 
 
of 
Tendyne Mitral Valve System 
 
 
Clinical Investigation Protocol 
Protocol No. CS-03 
Version H 
20 February 2020 
 
 
 
 
 
 

Tendyne Holdings, Inc. 
 
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CRD_000 Tendyne EFS 
ABT-CIP-10337 Tendyne EFS CIP Version H 
20 February 2020 
Clinical Investigational Protocol 
CS-03 Version H 
 
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CONFIDENTAL INFORMATION 
No use or disclosure of information contained within this document is permitted  
without prior written authorization from Abbott. 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
Expanded Clinical Study of Tendyne Mitral Valve System 
Protocol No. CS-03 
Version H 
20 February 2020 
I have read this protocol and agree to adhere to the requirements.  I will provide copies of 
this protocol and all pertinent information to study personnel and my hospital Institutional 
Review Board (IRB)/ Ethics Committee (EC).  I will discuss this material with them and 
ensure they are fully informed regarding the Tendyne Bioprosthetic Mitral Valve System and 
the conduct of the study according to this protocol, applicable laws and regulatory 
regulations, including hospital IRB/EC requirements. 
 
 
Clinical Site Name 
 
 
_______________________________________________              
 
 
__________________________ 
Site Investigator Signature 
 
 
 
 
 
Date 
 
_______________________________________________    
Site Investigator Printed Name 

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Table of Contents 
Contact Information................................................................................................................. 8 
1 
Study Summary ................................................................................................................. 9 
2 
Introduction .................................................................................................................... 14 
2.1 
Executive Summary .......................................................................................................... 14 
2.2 
Anatomy of the Mitral Valve ............................................................................................ 14 
2.2.1 
Mitral Valve Disease Prevalence and Etiology ....................................................... 16 
2.2.2 
Mitral Stenosis ........................................................................................................ 16 
2.2.3 
Mitral Regurgitation ............................................................................................... 16 
2.3 
Pathophysiology of Untreated Mitral Regurgitation ........................................................ 18 
2.4 
Treatment of Mitral Regurgitation ................................................................................... 19 
2.4.1 
Treatment Guidelines and Guideline Adherence ................................................... 19 
2.4.2 
Treatment Methods for Mitral Regurgitation ....................................................... 21 
2.4.3 
Preclinical Evaluation of Percutaneous Mitral Valve Replacement ..................... 24 
2.5 
Therapeutic Need ............................................................................................................. 26 
3 
Device Description ....................................................................................................... 27 
3.1 
Intended Use .................................................................................................................... 27 
3.2 
Intended Clinical Performance ......................................................................................... 27 
3.3 
Identification .................................................................................................................... 27 
3.4 
Design ............................................................................................................................... 28 
3.4.1 
Valve ........................................................................................................................ 28 
3.4.2 
Valve Sizes and Models ........................................................................................... 30 
3.4.3 
Instrument Set ......................................................................................................... 32 
4 
Risk-Benefit Analysis ................................................................................................... 34 
4.1 
Risk Analysis ..................................................................................................................... 34 
4.1.1 
Risk Assessment ....................................................................................................... 34 
4.1.2 
Risk Mitigation ........................................................................................................ 34 
4.2 
Potential Benefits ............................................................................................................. 34 
4.3 
Study Participation Associated Risks ................................................................................ 35 
5 
Study Purpose ................................................................................................................ 36 
6 
Study Design ................................................................................................................... 36 
6.1 
Geographies and Centers ................................................................................................. 36 
6.2 
Duration ............................................................................................................................ 36 
6.3 
Sample Size ....................................................................................................................... 37 
6.4 
Eligibility Criteria .............................................................................................................. 37 

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6.4.1 
Inclusion Criteria .................................................................................................... 37 
6.4.2 
Exclusion Criteria .................................................................................................... 37 
7 
Objectives and Endpoints ........................................................................................... 39 
7.1 
Performance ..................................................................................................................... 39 
7.1.1 
Technical Success Definition (Exit from procedure room) .................................... 39 
7.1.2 
Device Success Definition (at 30 day and all post-procedural time points) ......... 39 
7.2 
Primary Effectiveness:  Individual Patient Success (1-year) ............................................. 40 
7.3 
Safety ................................................................................................................................ 40 
7.3.1 
Primary Safety Objective ........................................................................................ 40 
7.3.2 
Primary Safety Endpoints ....................................................................................... 40 
7.3.3 
Secondary Safety Objective ..................................................................................... 40 
7.3.4 
Secondary Safety Endpoints ................................................................................... 41 
7.4 
Valve System Usability ..................................................................................................... 41 
7.4.1 
Valve System Usability Objective ............................................................................ 41 
7.4.2 
Valve System Usability Data ................................................................................... 41 
7.5 
Additional Endpoints ........................................................................................................ 41 
8 
Analysis Plan and Sample Size Justification ........................................................ 42 
8.1 
Sample Size ....................................................................................................................... 42 
8.2 
Screen Failures and Point of Enrollment .......................................................................... 42 
8.3 
Baseline Demographics, Clinical Background, and Protocol Administration ................... 42 
8.4 
Handling Study Discontinuations ..................................................................................... 43 
8.5 
Evaluation of Primary Endpoints ...................................................................................... 43 
8.5.1 
Primary Performance Objective ............................................................................. 43 
8.5.2 
Primary Safety Objective ........................................................................................ 43 
8.5.3 
Valve System Usability Objective ............................................................................ 44 
8.6 
Evaluation of Secondary Endpoints .................................................................................. 44 
9 
Regulations ..................................................................................................................... 45 
10 Site Initiation Activities .............................................................................................. 45 
10.1 
Investigator and Site Selection ......................................................................................... 45 
10.2 
Initiation Requirements .................................................................................................... 45 
10.3 
Site Training ...................................................................................................................... 46 
11 Screening and Enrollment ......................................................................................... 46 
11.1 
Screening .......................................................................................................................... 46 
11.2 
Informed Consent ............................................................................................................. 46 
11.3 
Vulnerable Population ...................................................................................................... 47 
11.4 
Enrollment ........................................................................................................................ 48 
12 Methods ............................................................................................................................ 49 
12.1 
Overview........................................................................................................................... 49 
12.2 
Echocardiography ............................................................................................................. 50 

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12.3 
Angiography ..................................................................................................................... 51 
12.3.1 
Preoperative Cardiac Computerized Tomography (CT) ....................................... 51 
12.3.2 
Intraoperative Angiography................................................................................... 51 
12.4 
Intraoperative Hemodynamic Measurements ................................................................. 51 
12.5 
History and Physical Examination .................................................................................... 52 
12.6 
Clinical Status ................................................................................................................... 52 
12.7 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ........................................................ 52 
12.8 
Six-Minute Hall Walk ........................................................................................................ 52 
12.9 
Medications ...................................................................................................................... 52 
12.10 Clinical Laboratory Tests .................................................................................................. 52 
12.11 Electrocardiogram ............................................................................................................ 53 
12.12 Adverse Events ................................................................................................................. 53 
12.13 Vigilance Officer ............................................................................................................... 53 
13 Implant Procedure ....................................................................................................... 54 
13.1 
Requirements ................................................................................................................... 54 
13.2 
Preparation ....................................................................................................................... 54 
13.3 
Initial Data Acquisition ..................................................................................................... 54 
13.4 
Implant Procedure ............................................................................................................ 55 
13.4.1 
Valve Placement ...................................................................................................... 55 
13.4.2 
Valve Verification .................................................................................................... 55 
13.5 
Post-Operative Care ......................................................................................................... 56 
14 Follow-up Visits ............................................................................................................. 57 
14.1 
Pre-Discharge ................................................................................................................... 57 
14.2 
Scheduled Follow-up Visits ............................................................................................... 57 
14.3 
Study Exit .......................................................................................................................... 57 
14.4 
Unscheduled Follow-Up Visits .......................................................................................... 58 
14.5 
Lost to Follow-Up ............................................................................................................. 58 
14.6 
Withdrawals ..................................................................................................................... 58 
15 Reinterventions and Explants .................................................................................. 59 
16 Heart Transplants or Subject Death ....................................................................... 59 
17 Data Management ......................................................................................................... 60 
17.1 
Subject Identification ....................................................................................................... 60 
17.2 
Central Database .............................................................................................................. 60 
17.3 
Electronic Case Report Forms (eCRF) ............................................................................... 60 
17.4 
Protocol Deviations .......................................................................................................... 60 
17.5 
Centre Noncompliance ..................................................................................................... 60 
17.6 
Data Processing and Management .................................................................................. 60 
17.7 
Confidentiality and Protection of Study Files ................................................................... 61 
17.8 
Monitoring ........................................................................................................................ 61 

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18 Adverse Event Reporting ........................................................................................... 62 
18.1 
Adverse Event (AE) Review and Classification ................................................................. 62 
18.2 
Anticipated AEs ................................................................................................................ 63 
18.3 
Relationship of AEs to the Device or Procedure .............................................................. 63 
18.4 
Seriousness of AEs ............................................................................................................ 63 
18.5 
Device Deficiencies ........................................................................................................... 64 
19 Responsibilities ............................................................................................................. 64 
19.1 
Investigator Responsibilities ............................................................................................. 64 
19.2 
Sponsor Responsibilities ................................................................................................... 65 
19.3 
Echocardiography Core Laboratory .................................................................................. 65 
19.4 
Computed Tomography Core Laboratory ........................................................................ 65 
19.5 
Clinical Events Committee (CEC) ...................................................................................... 66 
19.6 
Data and Safety Monitoring Board (DSMB) ..................................................................... 66 
19.7 
Publications Committee ................................................................................................... 66 
20 Device Accountability .................................................................................................. 67 
21 Study Closure .................................................................................................................. 67 
21.1 
Suspension or Early Termination...................................................................................... 67 
21.2 
Routine Closeout .............................................................................................................. 67 
22 Appendix A ...................................................................................................................... 68 
23 Appendix B, Statistical Methodologies .................................................................. 76 
23.1 
Scope of Analysis .............................................................................................................. 76 
23.2 
Purpose ............................................................................................................................. 76 
23.3 
Hypotheses (HO, HA) for 30-day mortality ...................................................................... 76 
23.4 
Calculation of Sample Size for Mortality .......................................................................... 77 
23.5 
Criteria for Termination .................................................................................................... 77 
23.6 
Analysis Populations ......................................................................................................... 78 
23.7 
Calculation of Sample Size for Safety ............................................................................... 78 
23.8 
Planned Subgroup Analyses ............................................................................................. 79 
23.9 
Comparison of Tendyne 1.0 Valve and Tendyne Low Profile (LP) .................................... 79 
23.10 Handling Missing Data ...................................................................................................... 79 
24 Appendix C ....................................................................................................................... 80 
 
 
 

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List of Tables 
TABLE 1: CAUSES AND MECHANISMS OF MITRAL REGURGITATION1 ..................................................................... 17 
TABLE 2: TENDYNE MITRAL VALVE SIZES AND MODELS ...................................................................................... 31 
TABLE 3: STUDY PARTICIPATION ASSOCIATED RISKS .......................................................................................... 35 
TABLE 4: ASSESSMENTS AND DATA COLLECTION REQUIREMENTS ....................................................................... 49 
TABLE 5 ESTIMATED MORTALITY ..................................................................................................................... 77 
TABLE 6 SAMPLE SIZE, 95% CONFIDENCE INTERVAL ......................................................................................... 78 
List of Figures 
Figure 1. Human Heart Diagram .................................................................................................... 14 
Figure 2.  Normal Mitral Valve Leaflets Viewed from the Left Atrium .......................................... 15 
Figure 3. Long Axis View of Left Ventricle ..................................................................................... 15 
Figure 4.  The Inner Nitinol Frame ................................................................................................. 28 
Figure 5.  The Valve Inner .............................................................................................................. 28 
Figure 6. The Outer Nitinol Frame (top view). .............................................................................. 28 
Figure 7.  The Tendyne Mitral Valve (top view). ........................................................................... 28 
Figure 8.  The Tendyne Mitral Valve with Braided Tether and Apical Pad .................................... 29 
Figure 9. The Apical Pad ................................................................................................................ 29 
Figure 10.  The Tendyne Mitral Valve, with the Proud Anterior Element of Cuff on the Left....... 30 
Figure 11.  The Tendyne Mitral Valve in its Final Position within the Native Mitral Valve ........... 30 
Figure 12 Tendyne Mitral Valve dimensions: AP, anterior-posterior; IC, intercommissural; and 
perimeter. .............................................................................................................................. 31 
Figure 13.  Valve Design Differences Between Tendyne 1.0 Valve and LP .................................... 32 
 
 
 

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Contact Information 
 
Study Sponsor / Device Manufacturer 
Tendyne Holdings, Inc. (also doing business as Abbott Medical) 
A subsidiary of Abbott Vascular Inc.  
177 County Road B East 
St. Paul, Minnesota, 55117     
USA 
 
 
Authorized Representative 
Abbott Medical 
The Corporate Village 
Da Vincilaan 11 Box F1 
1935 Zaventem 
Belgium 
Tel: +32 2 774 68 11 
 
 
 

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1 Study Summary 
Protocol Title 
Expanded Clinical Study of Tendyne Mitral Valve System  
Investigational 
Device: 
Tendyne Bioprosthetic Mitral Valve System 
Purpose: 
The purpose of this expanded clinical study is to evaluate the 
performance and safety of the Tendyne Mitral Valve System in the 
treatment of severe mitral regurgitation in patents with functional 
disability greater than or equal to NYHA Class II, who are not suitable 
candidates for surgical replacement with otherwise available devices. 
The data gathered in this study will be used to support conformity 
requirements for CE Mark of the Tendyne Mitral Valve System, using an 
appropriately powered sample size to enable assessment of the study 
safety and performance endpoints of the Tendyne Mitral Valve System 
in the intended populations. 
This study will be continued after the CE Mark to collect long-term 
safety and performance data as part of the Tendyne post-market follow-
up program. All patients shall continue to be followed through 5 years 
in the post-market setting. 
Design: 
Nonclinical assessments, pre-clinical data, and acute clinical study data 
have been used to evaluate the Tendyne Bioprosthetic Mitral Valve 
System design concept.  This study is required to collect further data. 
This study is a single-arm, multicenter study designed in accordance 
with the MVARC 2015 guideline and standard ISO 5840-3:2013.  The 
subjects will be individuals who have symptomatic mitral valve 
regurgitation and meet eligibility criteria.  
Population: 
Subjects who are 18 years or older with a symptomatic mitral valve 
regurgitation may be invited to participate in this study. 
Sample Size: 
Up to 110 subjects will be enrolled into the study in support of the CE 
Mark.  Up to an additional 240 subjects (for an overall sample size of 
350) may be enrolled in the study to evaluate the long-term 
performance of the Tendyne Mitral Valve. Refer to Section 8, Analysis 
Plan and Sample Size Justification; and Appendix B, Statistical 
Methodology.   
Clinical Sites: 
Up to 40 centers will participate in the study, with an expected 
enrollment of 6 to 10 patients per site.  Enrollment is competitive and 
geographical expansion will allow overcoming the limitations of slow 
enrollment due to the stringent inclusion and exclusion criteria. Centers 
to be included in the study will meet study qualification requirements, 
have received necessary institutional review board/ethics committee 
and/or other approvals, be in countries in which the study has been 
approved as required by law, and be approved by the sponsor to 
participate.  Geographies being considered for the study include 
Australia, Canada, Europe, and the United States.  
Objective and 
Endpoints: 
Endpoints were selected to enable the sponsor, its safety committees, 
and regulatory agencies the ability to compare estimates obtained from 
this study to estimates from studies of other comparable procedures 
and devices.  Objectives and endpoints were selected based on input 
from medical advisors experienced in related procedures and studies of 
other replacement valves and devices used to treat mitral regurgitation.  

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Inclusion 
Criteria: 
Subjects must meet ALL of the following criteria: 
1. Severe mitral regurgitation of primary or secondary etiology 
according to MVARC (Mitral Valve Academic Research 
Consortium) 2015 defined as: 
• 
For Degenerative MR: EROA ≥ 40 mm2 or regurgitant 
volume ≥ 60ml 
• 
For Secondary MR: EROA ≥ 20 mm2 or regurgitant volume ≥ 
30ml 
2. New York Heart Association (NYHA) functional Class ≥ II while 
on guideline directed medical therapy (GMDT), including device 
therapy (CRT) if indicated.   
3. Heart team determines patient is not a suitable candidate for 
traditional surgical treatment according to valid guidelines. 
4. Age 18 years or older. 
Exclusion 
Criteria: 
Subjects will be excluded if any of the following criteria are met: 
1. Severe mitral annular calcification, severe mitral stenosis, 
valvular vegetation or mass. 
2. Left Ventricle (LV) or Left Atrium (LA) thrombus. 
3. Patient has a chest condition that prevents transapical access. 
4. Left ventricular ejection fraction (LVEF) less than 30% by 
echocardiogram. 
5. Left Ventricular End Diastolic Diameter (LVEDD) > 7.0 cm. 
6. Prior surgical or interventional treatment of mitral or aortic 
valves (e.g. valve repair or replacement, MitraClip, edge to edge 
repair, aortic balloon valvuloplasty, etc.). 
7. Any planned surgery or interventional procedure within the 
period of 30 days prior to 30 days following the implant 
procedure. 
 
This 
includes 
any 
planned 
concomitant 
cardiovascular procedure such as PCI, pulmonary vein ablation, 
left atrial appendage occlusion, septal defect repair, etc. 
8. Cardiac resynchronization therapy device or implantable pulse 
generator implanted within three months of planned implant 
procedure. 
9. Myocardial Infarction (MI) within 30 days of the planned 
implant procedure. 
10. Symptomatic, unresolved multi-vessel coronary artery disease 
(CAD) or unprotected left main coronary artery disease 
requiring stenting or Coronary Artery Bypass Grafting (CABG). 
11. Cerebrovascular accident (CVA) within six months of planned 
implant procedure. 
12. Unresolved severe symptomatic carotid stenosis (> 70% by 
ultrasound).  
13. Cardiogenic shock or hemodynamic instability requiring 
inotropes or mechanical support devices at the time of planned 
implant procedure. 
14. Severe tricuspid regurgitation, tricuspid valve disease requiring 
surgery or severe right ventricular dysfunction. 
15. Hypertrophic or restrictive cardiomyopathy, constrictive 
pericarditis or any other structural heart disease causing heart 

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failure other than dilated cardiomyopathy of either ischemic or 
non-ischemic etiology. 
16. Any 
of 
the 
following: 
 
leukopenia, 
acute 
anemia, 
thrombocytopenia, 
history 
of 
bleeding 
diathesis, 
or 
coagulopathy if cannot be adequately treated. 
17. History of endocarditis within six months of planned implant 
procedure. 
18. Active systemic infection requiring antibiotic therapy. 
19. Known hypersensitivity or contraindication to procedural or 
post-procedural medications (e.g., contrast solution, anti-
coagulation therapy) which cannot be adequately managed 
medically or hypersensitivity to nickel or titanium. 
20. Patient is undergoing hemodialysis due to chronic renal failure. 
21. Patient has pulmonary arterial hypertension (fixed PAS 
>70mmHg). 
22. Patient has COPD and is on home oxygen. 
23. Patient refuses blood transfusions. 
24. Pregnant, lactating, or planning pregnancy within next 12 
months. 
25. Participating or planning participation in an investigational 
drug or another device study. 
26. Patient or legal guardian unable or unwilling to give informed 
consent. 
27. Patient unable or unwilling to comply with study required 
testing and follow-up visits. 
28. Patients with non-cardiac co-morbidities that are likely to result 
in a life expectancy of less than one year. 
Primary Safety 
Objective: 
To evaluate one month procedural and device safety of the Tendyne 
Bioprosthetic Mitral Valve System. 
Primary Safety 
Endpoints: 
Device success and freedom from the following device- or procedure-
related serious adverse events (SAEs) at 30 days post implant, as 
classified by the Clinical Events Committee (CEC):  
 
Cardiovascular death 
 
Reintervention caused by valve-related dysfunction 
 
Disabling stroke 
 
Myocardial infarction (MI) 
 
Life-threatening bleeding  
 
Major Vascular Complications 
 
Renal failure requiring dialysis 
 
Other device-related SAEs 
 
Other procedure-related SAEs 
Stroke and MI classifications will be per the Valve Academic Research 
Consortium – 2 (VARC-2).  Life-threatening bleeding classifications will 
be per the Bleeding Academic Research Consortium (BARC) consensus 
(Type 2, 3, and 5). 

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Secondary 
Safety 
Objective: 
To evaluate long-term safety of the Tendyne Bioprosthetic Mitral Valve 
System. 
Follow-up for secondary endpoints will be continued for 2 years. 
Additional follow-up will be obtained for up to 5 years as recommended 
by most recent guidelines, to capture long-term data on less common or 
unanticipated adverse events, on adverse events which are time-related 
(e.g. structural deterioration, adverse effects on native valve anatomy) 
and on long-term performance.  
Secondary 
Safety 
Endpoints: 
Through two years post implant: 
 
Device success and, 
 
No device or procedure related SAEs 
Primary 
Performance 
Objective: 
To evaluate the performance of the Tendyne Mitral Valve System 
Endpoint definitions are derived from MVARC 2015 Guidelines. 
Technical 
Success 
Definition: 
Upon Exit from procedure room, alive with the following:  
 
Successful access, delivery and retrieval of the transcatheter valve 
delivery system, and 
 
Deployment and correct positioning of the correctly sized valve, and  
 
No need for additional emergency surgery or re-intervention 
related to the device or procedure. 
Device Success 
Definition: 
At 30 day and all post-procedural time points, alive with the following: 
 
Disabling stroke free, with 
 
Original intended device in place, and 
 
No additional surgical or interventional procedures related to 
access or the device, and 
 
Intended performance of the device: 
o No Device specific adverse events, such as migration, 
embolization, fracture, hemolysis, thrombosis or endocarditis, 
and 
o Maintenance of expected hemodynamic performance (e.g., 
central mitral regurgitation (MR) < 1+; mitral valve gradient < 6 
mmHg or effective orifice area (EOA) > 1.5 cm2) and,  
o No para-device complications (left ventricular outflow tract 
(LVOT) obstruction: >20 mmHg increase in LVOT gradient vs. 
baseline; paravalvular leak (PVL) > 1+; effects on coronary 
circulation or other heart structures, e.g., erosion or need for 
permanent pacemaker implantation. 
Primary 
Effectiveness: 
Individual 
Patient 
Success 
Individual patient success is defined as device success and all of the 
following at 1-year:  
• 
No re-hospitalizations or re-interventions for heart failure  
• 
Change in NYHA functional class 
o Improvement is defined as NYHA grade ≥ 1 compared to 
baseline 

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• 
Change in distance walked, six-minute hall walk 
o Improvement is defined as ≥ 50 meters compared to baseline 
• 
Change in Kansas City Cardiomyopathy Questionnaire scores 
o Improvement is defined as ≥ 10 compared to baseline 
Valve System 
Usability 
Objective: 
Gather and evaluate information on the usability of the Tendyne 
Bioprosthetic Mitral Valve System. 
Valve System 
Usability Data: 
Data will be implanters’ assessments of usability, especially as it relates 
to the ability to successfully deliver and deploy the Tendyne Mitral Valve 
in the desired anatomical location. 
Additional 
Endpoints: 
• 
Length of ICU stay 
• 
Length of hospital stay 
• 
30-day mortality  
• 
3-month mortality 
Imaging Core 
Laboratories 
SPH/UBC Cardiac CT Core Lab 
University of British Columbia, 6190 Agronomy Rd, 
Vancouver, British Columbia, V6T 1Z3, Canada 
Department of Radiology ‐ St. Paul’s Hospital 
Dr. Jonathon Leipsic jleipsic@providencehealth.bc.ca 
Dr. Philipp Blanke phil.blanke@gmail.com 
 
Boston/USA Echocardiography Core Lab 
Beth Israel Deaconess Medical Center, 
375 Longwood Ave, 3rd Floor, Boston, MA 02215, USA 
Michael Chaung mchuang@bidmc.harvard.edu 
 
 
 

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2 Introduction 
2.1 Executive Summary 
The purpose of this expanded clinical study is to evaluate the performance and safety of the 
Tendyne Mitral Valve System in the treatment of severe mitral regurgitation in patents with 
functional disability greater than or equal to NYHA Class II, who are not suitable candidates 
for surgical replacement with otherwise available devices.  The data gathered in this study 
will be used to support conformity requirements for CE Mark of the Tendyne Mitral Valve 
System, using an appropriately powered sample size to enable assessment of the study safety 
and performance endpoints of the Tendyne Mitral Valve System in the intended populations. 
This study will be continued after the CE Mark to collect long-term safety and performance 
data as part of the Tendyne Mitral Valve System post-market follow-up program.  All patients 
shall continue to be followed through 5 years in the post-market setting. 
2.2 Anatomy of the Mitral Valve 
The mitral valve (MV) is located in the heart at the atrioventricular (AV) junction between 
the left atrium (LA) and the left ventricle (LV).  The opening and closing of the MV is 
coordinated with the cardiac cycle to regulate the flow of blood from the lungs to the systemic 
circulation.  A properly functioning MV is open during ventricular diastole to allow 
oxygenated blood to enter the LV from the LA, and closed during ventricular systole to 
prevent backflow into the LA. 
The MV apparatus consists of the following: two leaflets, annulus, chordae tendinae, and 
papillary muscles (Figure 1).  These four parts acting in concert with the walls of the LA and 
LV are required for the normal valvular function.   
 
Figure 1. Human Heart Diagram 
The MV is also referred to as the bicuspid valve, because it consists of two leaflets: anterior 
and posterior (Figure 2).  The posterior leaflet extends around two-thirds of the AV junction.  

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The posterior leaflet has three indentations that form three scallops on the free edge that are 
labeled P1, P2 and P3.  The three corresponding segments of the anterior leaflet are A1, A2 
and A3.  Complete coaptation and correct apposition of the leaflets is required for the 
prevention of regurgitation. 
 
Figure 2.  Normal Mitral Valve Leaflets Viewed from the Left Atrium1 
The MV annulus is in contact with the AV junction.  The annulus is elliptical in shape, with the 
anteroposterior 
dimension/septal-lateral 
being 
shorter 
than 
the 
commissure-
commissure/inter-commissural dimension.  The anterior third of the annulus consists of 
fibrous connective tissue, which is shared with the aortic valve.  The posterior two-thirds of 
the annulus consists of cardiac muscle.  The annulus is pliable and changes shape throughout 
the cardiac cycle. 
Papillary muscles (PMs) are fingerlike projections from the wall of the left ventricle.  The 
chordae tendinae (CT) are inelastic fan-shaped cords that connect the PMs to the leaflets 
(Figure 3). 
 
Figure 3. Long Axis View of Left Ventricle 
Pathology that affects any part of the MV apparatus can lead to MV disease.  Therefore, 
understanding the normal interaction of these parts provides the backdrop for 
understanding MV disease processes, the associated outcomes, and the currently utilized 
medical therapies.2 

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2.2.1 Mitral Valve Disease Prevalence and Etiology 
Mitral valve disease can present in two general forms: (1) a narrowing of the valve, called 
mitral stenosis and (2) valvular insufficiency, which leads to mitral regurgitation.   
2.2.2 Mitral Stenosis 
Mitral stenosis (MS) is less prevalent than mitral regurgitation (MR).  In MS, the narrowing 
of the mitral valve is the result of the post-inflammatory changes to the leaflets, which 
become thickened, nodular, and fused at the commissures.  These leaflet changes can be 
accompanied by shortening of the CT and fibrosis of the PMs.  These changes typically 
progress over time and secondary calcification of the valvular apparatus can occur.  Fusion 
of the leaflets results in a funnel-shaped orifice.  Restricted leaflet motion during both diastole 
and systole may result.  This differs from secondary MR, in which the restricted leaflet motion 
normally only occurs during systole.3 
The primary cause of MS is rheumatic fever.  Although rheumatic fever is common in 
developing countries, it is comparably rare in developed countries due to the use of 
antibiotics for streptococcal infections.  In a study of school-age children, there was a 12-fold 
higher prevalence of rheumatic fever in developing compared to developed countries.3  Thus, 
MS is also less prevalent in developed countries.  In the Euro Heart Survey, which reviewed 
valvular heart disease across 25 European countries, only 27% of those patients who 
presented with isolated MV disease had MS.  In 85% of the MS patients, the primary cause 
was rheumatic fever.  Primary etiology accounted for most of the remaining MS cases,4 with 
the majority being older (>50 years of age).  Similarly, Nkomo et al., in study of the general 
population in the US found that MS occurred in 0.1% of all people with a slight increase to 
0.2% in persons ≥65 years of age.5 
As noted, MR is the more prevalent form of isolated MV disease and will be the focus of the 
remainder of this overview.   
2.2.3 Mitral Regurgitation  
2.2.3.1 Prevalence 
Two population-based studies in the US showed that mitral regurgitation (MR) is the most 
common heart valve disease.5,6  The Framingham Offspring Study used color Doppler 
echocardiography to assess for MR, which was detected in 90% of the subjects, albeit trace 
or mild in severity (not clinically significant) in the majority of cases.  However, 1.6% of 
subjects had moderate to severe MR.6  The most common factors associated with the 
presence of MR were older age, lower body mass index, heart failure, myocardial infarction 
(MI) and hypertension.   
Similarly, a population-based study by Nkomo et al. found moderate to severe MR occurring 
in approximately 1.7% of the US population with increasing prevalence among older 
individuals (7.3% of those ≥65 years of age).   The authors estimated that in the year 2000 
approximately 2 to 2.5 million people were affected by moderate to severe MR. With current 

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US demographic trends toward increasing population growth and increasing numbers of 
older Americans, the number of people with MR is expected to double by 2030.5 
Referral and treatment patterns for valvular heart disease were evaluated in the Euro Heart 
Survey of 92 centers over a 3 month period in 2001.7,8  Mitral regurgitation was identified as 
the second most common form of valvular heart disease after aortic stenosis.  The authors 
noted that the difference compared to the US studies may have been due to the nature of the 
survey, in which only those patients referred for at least moderate valve disease to tertiary 
centers were included.8  This suggests that patients with moderate or severe MR are not being 
properly referred for treatment, and important interventions are being delayed. 
2.2.3.2 Etiology 
There are two basic causes of MR: ischemic (e.g., subsequent to coronary artery disease) and 
nonischemic (all other causes).   
The mechanisms are broadly classified as secondary (e.g., secondary to ischemia or LV 
remodeling) or primary (e.g., intrinsic valve lesions).  The mechanisms can be further 
subdivided based on Carpentier’s functional types, which describe leaflet motion in relation 
to the mitral annular plane: 9 
• 
Type I.  Normal leaflet motion.  MR is due to leaflet perforation or annular dilatation, 
which is usually the result of LV disease.  
• 
Type II.  Excessive leaflet motion above the annular plane (leaflet prolapsed) into the 
LA. 
• 
Type III.  Restricted leaflet motion. 
o Type IIIa.  Restricted leaflet movement throughout the cardiac cycle (both 
systole and diastole). 
o Type IIIb.  Restricted leaflet movement in systole alone.  
The causes and mechanisms of MR are summarized, as follows, in Table 1. 
Table 1: Causes and Mechanisms of Mitral Regurgitation1 
CAUSE 
MECHANISM 
Primary 
Secondary 
Type I 
Type II 
Type IIIa 
Type I/Type IIIb 
Non-
ischemic 
• Endocarditis 
(perforation) 
• Degenerative 
(annular 
calcification) 
• Congenital 
(cleft leaflet) 
• Degenerative 
(billowing/flail 
leaflets) 
• Endocarditis 
(ruptured CT) 
• Traumatic 
(ruptured CT/PM) 
• Rheumatic (acute 
RF) 
• Rheumatic (chronic RF) 
• Iatrogenic 
(radiation/drug) 
• Inflammatory 
(anticardiolipin/ 
eosinohilic endocardial 
disease/lupus/ 
endomyocardial 
fibrosis) 
• Cardiomyopathy 
• Myocarditis 
• LV dysfunction 
(any cause) 
Ischemic 
 
• Ruptured PM 
 
• Functional 
ischemic 

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In developed countries, the most common etiologies for patients requiring surgical correction 
are primary (myxomatous), ischemic, rheumatic, and endocarditis.1,7,8  Primary MR 
represents approximately two-thirds of all surgical correction cases, with the most common 
form of primary MR being MV prolapse.  Prolapse can be moderate, with leaflet edges 
remaining in the ventricle; or severe, with eversion of the leaflets, usually the posterior 
leaflet, into the LA.  This severe eversion of the leaflets, also called flail leaflets, is usually the 
result of ruptured CT.  A less common form of primary MR is calcification of the annulus.   
Secondary MR accounts for approximately 20 to 25% of surgical correction cases.  Secondary 
MR may result from annular enlargement secondary to LV dilatation or PM displacement due 
to LV remodeling.10  Because CT are non-extensible, PM displacement exerts traction on 
leaflets through the CT resulting in tethered and apically displaced leaflets.  Changes in the 
annulus and the tethering of the leaflets, either alone or together, results in loss of coaptation 
that yields secondary MR.  
2.3 Pathophysiology of Untreated Mitral Regurgitation 
The pathophysiology of the disease is variable depending on the mechanism of MR. In 
significant primary MR, there is a volume overload of the left ventricle that results in LV 
hypertrophy to compensate for both the metabolic demands of the body (forward stroke 
volume) and regurgitant volume with each heartbeat.  There is also a compensatory gradual 
enlargement of the LA and increase in LA compliance.  This increased LA compliance allows 
for near normal drainage from the pulmonary veins.  This is the chronic, compensated phase 
of the disease during which patients may be asymptomatic and have normal exercise 
tolerances.   
Compensated MR may persist for many years.  At some point, however, the LV myocardium 
is no longer able to contract adequately to overcome the volume overload caused by MR. The 
reduced ability of the LV to contract results in a decreased stroke volume, which leads to 
decreased cardiac output, an increase in end systolic volume, increased LV filling pressures 
and increased pulmonary congestion.  In this stage, the patient displays signs of heart failure 
and exercise intolerance.  In an attempt to increase cardiac output, there is further dilatation 
of the LV, which leads to increasing dilatation of the MV annulus and increasingly more severe 
MR.  An additional complicating feature is that LA enlargement predisposes patients to AF 
and arterial thromboembolism.  Left untreated, patients may develop pulmonary 
hypertension and right-sided heart failure.1  
There is a population of patients who can tolerate mild MR without an impact to clinical status 
or mortality.  Approximately 50% of patients with primary MR have a normal life 
expectancy.11 At the other end of the spectrum, 20% are at high risk for progression to heart 
failure or death without surgical correction.  The predictors of this more severe course 
include moderate and severe MR and reduction in ejection fraction.11  
As noted above, secondary MR results from distortion of ventricular anatomy.  In this 
population where ventricular dysfunction occurs prior to MR, diagnosis can be more difficult 
and the clinical course is often worse than in primary MR.  The most common cause of 

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secondary MR is MI.  In one cohort study of 773 patients underwent echocardiograms at 30 
days post-MI.  In this population, MR was present in 50% with 12% being categorized as 
moderate/severe.12  Mitral regurgitation in this population increases atrial pressure, which 
leads to pulmonary hypertension and heart failure.  Despite the fact that MR could be severe, 
the combination of increased atrial pressure and low ventricular driving force will 
paradoxically cause the calculation of RVol to be low.  
Although there are no randomized controlled trials that have assessed the impact of 
secondary MR on heart chamber remodeling, clinical evidence strongly indicates that in 
patients with LV dysfunction, secondary MR worsens the prognosis.12,13,14,15,16  Grigioni et al. 
showed that patients with ischemic MR (IMR) had a significantly higher all-cause mortality 
and cardiac mortality incidence at 5 years when compared to a cohort of patients with 
ischemic heart disease and no MR.12  Their work further showed that revascularization 
therapy alone did not eliminate the poor prognosis for patients with MR.  A subgroup analysis 
of patients in the CADILLAC trial showed that MR was strongly associated with 30 day and 1 
year mortality patients undergoing percutaneous coronary intervention procedures for acute 
MI.12 More severe MR was associated with a higher mortality rates (1.4%, 3.7%, and 8.6% at 
30 days; 2.9%, 8.5%, 20.8% at 1 year for no, mild, and moderate/severe MR, respectively).  
DeServi et al. reported similar results in a younger patient cohort experiencing a first MI.15  
In this study, the 15-month mortality for patients with IMR was more than three times that 
of patients without IMR (9.8% versus 3.2%).  Furthermore, patients with IMR were more 
likely to develop heart failure at 15 months (20% versus 3%).   
Even though IMR is a strong predictor of poor outcomes following revascularization 
procedures, there are no guidelines for patient follow-up.16  Taken together, these data 
suggest that there is a substantial population of patients that could benefit from correction of 
IMR, which could lead to improved outcomes. 
2.4 Treatment of Mitral Regurgitation 
2.4.1 Treatment Guidelines and Guideline Adherence 
The American College of Cardiology/American Heart Association (ACC/AHA) and the 
European Society of Cardiology/European Association for Cardio-Thoracic Surgery 
(ESC/EACTS) have published guidelines for the management of valvular heart disease.17,18  In 
summary, the guidelines contain the following Class I recommendations.  
Primary MR 
• 
Symptomatic patients with severe primary MR and without severe LV dysfunction  
• 
Asymptomatic patients with severe primary MR and LV dysfunction  
• 
Repair is preferable to replacement when a successful and durable repair can be 
accomplished 
• 
Patients with chronic severe primary MR undergoing cardiac surgery for other 
indications (ACC/AHA Guidelines only) 

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Secondary MR 
• 
Patients with severe MR undergoing CABG and without severe LV dysfunction 
(ESC/EACTS only – there are no Class I recommendations for surgical intervention in 
the ACC/AHA Guidelines) 
Despite the existence of well-defined guidelines and the abundant literature that indicates 
that the 10 year survival rate for medically managed patients ranges from 20 to 
60%19,20,21,22,23,  several studies have shown that guideline adherence is poor, and many 
patients go without recommended treatment.24,25,26,27  An evaluation of surgical interventions 
in the Euro Heart Survey showed that only 193 of 396 (48.7%) of patients with severe 
symptomatic MR had a surgical valve procedure.  Multivariate analysis identified five factors 
that led to the decision not to operate: LV dysfunction, non-ischemic etiology, patient age, 
comorbidities, and grade 3 versus more severe grades of MR.  Specifically, these data showed 
that patients with LVEF between 30 and 60% accounted for 53% of the population that did 
not receive surgery, despite this level of LV dysfunction being a Class I recommendation in 
both the ACC/AHA and ESC/EACTS guidelines.26  Similarly, Bach et al. evaluated 300 patients 
identified in the University of Michigan database with significant MR.  Of these patients, 112 
had primary MR, but mitral surgery was performed on only 59 (53%) of the patients.  Of the 
patients who did not undergo surgical intervention, 39/53 (74%) met the guideline 
requirements for MV surgery.24  Toledano et al. published on the results of a questionnaire 
mailed to all cardiologists in Canada to identify causes of non-compliance to the published 
guidelines.  They found that only 57% of responding cardiologists correctly identified that an 
LVEF of 50 to 60% should trigger a referral for surgery.  Further, only 16% would correctly 
refer an NYHA Class II patient with severe MR and an LVEF >60%.27  
To evaluate longitudinal outcomes of isolated MV repair in older patients, Badhwar et al. 
performed an analysis of linked data from the Society of Thoracic Surgeons (STS) adult 
cardiac surgery database and claims data from the Centers for Medicare & Medicaid Service 
(CMS) covering a period from 1991 through 2007.  They identified over 14,000 isolated non-
emergent MV repair operations, and one of the findings was that most elderly patients came 
to surgery late as they were more likely to have NYHA Class III or IV heart failure and AF, and 
nearly all had severe MR.  Although the operative success rates were high and life expectancy 
for patients undergoing the MV repair procedure was restored to that of age-matched 
controls, the authors concluded that the practice of delayed referral, which is in conflict with 
the treatment guidelines, should be re-evaluated.25  
Methods for treatment of chronic functional and ischemic functional MR are less clear.  The 
guidelines for management of valvular heart disease recommend consideration of MV repair 
or replacement with preservation of the subvalvular apparatus.  However, no evidence was 
available for Class I or Class II regarding the best treatment approaches.  Some reports 
indicated that medical therapies directed at the underlying heart failure and LV dysfunction 
may have a beneficial effect on secondary MR in some patients.  Specifically, maximal therapy 
beta adrenergic blockers or angiotensin-converting enzyme inhibitors28,29,30 and cardiac 
resynchronization therapy31,32 have been shown to reduce MR severity.  As noted above, 

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patients with IMR have a worse prognosis than patients with MR from other causes.  The 
general belief has been that early reperfusion with percutaneous coronary intervention (PCI) 
or coronary artery bypass grafts (CABG) would reduce ischemic damage to the heart muscle 
and retard the process of LV remodeling, thereby preventing the development of MR.16  
However, treatment of the ischemia with PCI or CABG did not improve survival or result in 
the short-term or long-term improvement in the IMR severity.15,33,34 Some data suggest that 
MV repair or reduction of annular diameter with an annuloplasty ring concomitant with a 
CABG procedure may provide benefit.35,36,37,38  It should be noted; however, that surgical 
treatment of  secondary MR is evolving such that many patients will not receive repair or 
replacement unless the patient has concomitant surgical indications for revascularization or 
aortic valve replacement. 
2.4.2 Treatment Methods for Mitral Regurgitation 
Treatment methods for MR involve surgical or percutaneous interventions to repair or 
replace the mitral valve.  Surgical repair and surgical valve replacement have been used for 
many years.  Percutaneous methods are currently being developed and becoming 
increasingly more available.   
2.4.2.1 Surgical Repair 
Surgical repair for primary mitral valves can be traced to the technique developed by 
Carpentier, the “French correction”, which involved quadrangular resection of prolapsed 
leaflets, transposition of normal chords to other areas of the leaflet, as needed, and utilization 
of a ring annulus as part of a remodeling annuloplasty.9  The Carpentier method utilized a flat, 
rigid ring.  In the years since this original publication, variations of annuloplasty rings have 
been developed to mimic the more anatomically correct “saddle-shaped” structure and 
flexibility of the mitral annulus.  There are no conclusive data to suggest that these alternative 
ring forms enhance long-term clinical benefit.39,40,41,42  Using the Carpentier technique and 
associated variations, surgical repair and long-term outcomes were generally more favorable 
in patients with isolated posterior leaflet prolapse compared to anterior or bileaflet 
prolapse.43  In a 12-year post-MV repair follow-up, freedom from reoperation was 96±2%, 
88±4%, and 94±2% (p=0.019) for posterior, anterior and bileaflet prolapse, respectively.  
Freedom from >2+ MR at 12 years trended similarly, and anterior prolapse was an 
independent predictor of reoperation.   
For the treatment of secondary MR, annuloplasty bands to restrict annulus diameter to 
facilitate leaflet coaptation have been employed.44  Long term studies have shown that these 
bands become distorted over time, resulting in a recurrence of MR.  Based on further analysis 
of the recurrent MR, it was determined that the anterior-posterior dimension must be 
reduced in order to maintain valve coaptation.45 
Two additional techniques have been developed that differ from the fundamentals of those 
first introduced by Carpentier:  artificial chordae and edge-to-edge approximation.   
The artificial chordae technique replaces diseased chordae without the chord transposition 
or resection that was introduced as part of the Carpentier method.46  However Salvador et al. 

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published 15-year follow-up data on 608 patients who had MV repair with artificial chordae.  
These patients had an 84% survival rate, 92% freedom from reoperation, and 85% freedom 
from severe MR.47  Because of the association with other techniques, isolated evaluations of 
artificial chordae in the literature are rare.   
Edge-to-edge approximation also called the Alfieri technique.48  Edge-to-edge approximation 
consists of suturing the anterior and posterior leaflets together to create a double orifice MV.  
This technique in recommended for use in combination with an annuloplasty, as results of an 
isolated edge-to-edge repair have been suboptimal.  Edge-to-edge repair has, however, 
improved outcomes of patients with anterior leaflet prolapse.  A single-center study 
compared 133 patients undergoing edge-to-edge repair of anterior leaﬂet prolapse and 605 
patients undergoing quadrangular resection of the posterior leaﬂet with or without 
annuloplasty.  Over the follow-up period (mean 4.5±3.1 years), freedom from reoperation in 
the anterior group was not inferior (96±2% in the anterior leaﬂet prolapse group versus 
97±1% in the posterior leaﬂet prolapse group, p=0.37).49 
2.4.2.2 Surgical Replacement 
There are conditions where the valve is not amenable to repair including prolapsed leaflets 
associated with extensive annular calcification, prolapse of one leaflet with hypoplasia of the 
opposite leaflet, extreme fibroelastic deficiency, and extensive postendocarditis tissue 
destruction.50  In these cases, MV replacement is the most viable treatment option.  There are 
two basic types of prosthetic valves: mechanical prostheses and bioprostheses.  Mechanical 
prostheses require lifelong anticoagulation therapy but have longer durability, whereas 
bioprostheses do not require long-term anticoagulation but are subject to structural valve 
deterioration (SVD) over time.  A 20-year follow-up of 1285 patients with MV bioprostheses 
determined the estimated freedom from SVD at 5, 10, and 15 years to be 98±1%, 69±2, and 
32±4%, respectively.51  The choice of which type of valve prosthesis to use is largely related 
to patient life expectancy and risk of developing anticoagulant-related bleeding and 
thromboembolism.   
The ESC/EACTS Class I recommendations for mechanical prostheses include patients that 
have no contraindications for long-term anticoagulation, who are at increased risk for 
accelerated SVD (<40 years of age or hyperparathyroidism), or are already on 
anticoagulation due to a mechanical valve in another location.  The Class IIa 
recommendations include patients <65 years of age and/or those who have a reasonable life 
expectancy and for whom a reoperation would be contraindicated because of patient risk.   
The ESC/EACTS Class I recommendations for bioprostheses include patients with a high risk 
of bleeding or those that are having a reoperation for mechanical valve thrombosis.  The Class 
IIa recommendations include patients who are at low risk of future valve reoperation or are 
>70 years of age.52 
2.4.2.3 Comparison of Surgical Treatment Interventions 
 The Euro Heart Survey, which was conducted from April to July 2001, showed that the 
number of patients undergoing MV replacement versus repair were similar.  Of 155 patients 

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who underwent surgery for MR, slightly more than half (83/155) had a valve replacement, 
with the majority being mechanical prostheses (67/83).  O’Brien et al. showed similar trends 
using the Society of Thoracic Surgeons (STS) database for the period covering the years 2002 
to 2006.  Over 40,000 patients undergoing MV surgery were evenly divided between isolated 
MV replacement (21,229) and isolated MV repair (21,238).53 
Over time as knowledge and skills have increased, new techniques and devices have come 
into wider use to make surgical correction, rather than replacement, a viable option for 
increasingly greater numbers of patients. However, MV repair surgery tends to be more 
complex, requiring a surgical center that is experienced with repair techniques.  There are a 
limited number of centers with the necessary expertise.   
Despite important biases, the published guidelines for the management of valvular heart 
disease currently specify MV repair as the surgical intervention of choice.52,54  The 
recommendation is based largely on data that show a lower risk associated with MV repair 
over MV replacement.  Evidence suggests that repair is effective and is associated with 
reduced morbidity and mortality compared to replacement.18,54  In the STS risk model for 
valvular surgery, patients with valve replacements were more than three times more likely 
to die within 30 days of the surgery (5.7% to 1.6%), and more than twice as likely to 
experience the one or more major morbidity or morality events (26.7% to 12.7%).53  It should 
be noted however that the patient group receiving prosthetic valves were older and had more 
complex valve pathology.53, 55  Further, the valve replacement surgeries were often performed 
without sparing the valvular substructure, which has been shown to have a negative influence 
on outcomes.56,57,58,59 The apparent superiority of MV repair over replacement did not hold 
up to propensity matching analysis, which found no significant difference in mortality (at 5, 
10, and 15 years) nor in freedom from reoperation (at 5 and 10 years) between repair and 
replacement.55  
Until recently, there has been a lack of randomized controlled data comparing repair and 
replacement.  However, a recent report by Acker et al. of a randomized controlled trial that 
compared repair versus replacement in 251 patients with severe IMR showed that 
replacement had similar or better outcomes than repair.60  Specifically, there was no 
significant difference in 12-month mortality (14.3% for repair versus 17.6% for replacement) 
or change in LVESV index from baseline (-6.6 mL/m2 for repair versus -6.8 mL/m2 for 
replacement). In fact the rate of recurrence of moderate or severe MR was significantly 
greater in the repair group (32.6% versus 2.3%, p<0.001).  The authors concluded that 
“replacement provided a more durable correction of mitral regurgitation.”60  
Surgical interventions for MR are underutilized within the context of existing 
guidelines.24,25,26,27  An important goal in addressing the growing problem of MR is to raise 
awareness such that patients who would benefit from either MV repair or replacement are 
referred in a timely manner.   

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2.4.2.4 Percutaneous Mitral Valve Repair 
Many MR patients, however, are not good surgical candidates.  Age and comorbidities may 
make them unsuitable for anesthesia and open-heart surgery with cardiopulmonary bypass.  
With the aim of providing lower-risk therapies to improve MR related mortality and 
morbidity, treatments through percutaneous methods are being developed.   
Percutaneous devices for MV repair have been evaluated in clinical trials and reported in 
peer-reviewed literature.  One such device, MitraClip, is based on the edge-to-edge 
technique.61,62,63,64,65,66,67,68,69 Other companies have performed preliminary clinical 
evaluations of annuloplasty devices that are intended to reshape the mitral annulus and 
thereby reduce MR.70,71 
The MitraClip device has been evaluated in a pilot trial61, in a randomized controlled trial 
against MV repair surgery63,66 and in several registry studies.63,64,65,66,67,68,69  In the randomized 
controlled trial, the MitraClip patients fared worse on the 12-month primary endpoint of 
freedom from death, surgery for MV dysfunction, and MR grade 3+ or 4+ than did the patients 
undergoing MV repair surgery (55% to 73%; p=0.007).62 The MONARC and CARILLON 
annuloplasty devices were evaluated in multicenter, single-arm studies in 72 and 48 patients, 
respectively.  Early clinical use has also been reported for the Cardioband device including a 
feasibility study on 29 patients with encouraging procedural success and patient clinical 
response. Whether any of these devices have a favorable risk-benefit profile is inconclusive, 
larger scale clinical studies and randomized controlled trials are required to further evaluate 
them.70,71,72 
2.4.2.5 Percutaneous Mitral Valve Replacement 
Transcatheter aortic valve replacement (TAVR) has become a therapeutic option for high risk 
and extreme surgical risk patients with symptomatic calcific aortic stenosis73 and is now 
being studied for intermediate risk, failed bioprosthetic valves, bicuspid aortic stenosis and 
aortic insufficiency.  Several valves for TAVR are commercially available in Europe and The 
United States and more newly designed valves undergoing development.72 
The success of transcather valves for aortic stenosis have paved the way for transcatheter 
mitral valve replacements, but the mitral valve has been a much more elusive target.  
Transcatheter mitral valve replacement (TMVR) faces challenges arising from not only the 
heterogeneity of mitral valve pathology but also from its complete intracardiac positioning.  
The mitral annulus, leaflets and subvalvular apparatus offer significant obstacles to valve 
delivery.74 
These challenges have not deterred industry and physician inventors from pursuing TMVR 
devices.  There is a parade of devices from both start-up and mature companies active in this 
field.76   Several pre-clinical and clinical publications have emerged in recent years.  
2.4.3 Preclinical Evaluation of Percutaneous Mitral Valve Replacement 
Development and preclinical evaluation of candidate devices for MV replacement has focused 
in two general areas: devices that can be stably implanted within the native mitral valve 

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apparatus and devices that can be implanted within valves or rings that were surgically 
implanted in previous procedures (e.g., valve-in-valve).   
The first literature reports of off-pump, percutaneous MV valves were in 2005 by Ma et al. 
and Boudjemline et al.75,76  Ma et al. utilized a “double-crown” stented valve.  This valve was 
implanted at the mitral location through the transatrial route and centered on the mitral 
annulus that was previously marked with clips.  
The Lutter group has performed the most extensive series of transapical mitral valve 
implantation in animal studies.73,77 ,78,79,80,81,82  Early device prototypes utilized self-expanding 
stent with a star-shaped atrial element that was designed to prevent migration into the left 
ventricle, and ventricular fixation system consisting of four individual neo-chordae attached 
to the ventricular rim of the stent .  This group reported on four acute/short term studies on 
variations of the star-shaped prototype.76,77,78,79,80  
Gillespie et al. reported on the on-pump implant of a sutureless mitral valve device delivered 
via atrial access in ten sheep.  In this acute study, the authors reported that the implanted 
valves displayed normal hemodynamic properties, no paravalvular leakage, and mild central 
regurgitation in three animals.83 
Several investigators have reported on preclinical evaluations of percutaneous valve-in-
valve84,85,86 and valve-in-ring replacements.87,88,89,90  The impetus behind evaluating MV 
replacement into existing devices is to treat those patients that have had previous surgical 
implants at the mitral position, are having a recurrence of MR, and are at high risk of 
undergoing a repeat surgical procedure.  The benefit of implanting into pre-existing valve or 
ring implants is that there is a structure by which to anchor the replacement valve.  With the 
exception of Zou et al. who utilized a custom-made MV in four animals, the procedures 
utilized currently marketed aortic valves, Edwards Sapien and Medtronic Melody as the 
replacement devices.   
In general, evaluations of MV replacement into native structures and existing implanted 
valves and rings have shown to be feasible and able to be performed off-pump.  As the 
requirement for cardiopulmonary bypass is significant source of operative risk, this is a 
desirable procedural characteristic.  Some early studies, utilized rapid ventricular pacing to 
assist with valve placement, which again would not be desirable for high-risk patients, but 
later studies were performed without the aid of pacing.   
This series of studies indicates that beating heart procedures with transseptal, transatrial, 
and transapical access have all been shown to be feasible.  Stented valves placed into the 
native valve structure have shown stability and functionality.  Short deployment times, high 
success in deployment and good functional characteristics make these valves good 
candidates for pilot clinical evaluations. 
The first published clinical use of a TMVR was the acute implantation of a Tendyne Mitral 
Valve. Two patients were treated under clinical protocol prior to receiving surgical mitral 
valve replacement.91  They reported safe implantation and reduction of severe MR with 

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immediate improvement in hemodynamics.  In-hospital outcomes for the chronic 
implantation of the Tendyne Mitral Valve were subsequently reported in three patients.   
Implantation was safe resulting in elimination of severe MR in 2 of 3 patients (with trivial PV 
leak in the third) and all patients being discharged to their own home.92 
Neovasc has reported short-term clinical results of the Tiara valve in two patients.  The 
experience demonstrated feasibility with safe implantation and excellent hemodynamic 
results and valve function through 2 months.93 
In addition to the percutaneous application of devices that are designed specifically for the 
MV, some surgical centers are now using percutaneous application of aortic replacement 
valves in the MV position.  Most often these procedures are valve-in-valve implants for older 
patients with bioprosthetic valve dysfunction.  These are poor candidates for reoperation and 
have limited life expectancy.  Cheung and Al-Lawati reported encouraging data on 36 patients 
who underwent transcatheter mitral valve-in-valve implantation.  Thirty-day mortality was 
7.5%, and surviving patients had a decrease in MR severity from 3+ and 4+ to 1+ or 0.74  
These data provide evidence that percutaneous MV replacement can be successfully utilized 
in high surgical risk patients.   
2.5 Therapeutic Need 
Although the guidelines for management of valvular heart disease suggest that surgical 
correction of symptomatic MR is preferred over surgical replacement, more recent evidence 
indicates that replacement is not inferior and represents a viable first line treatment option 
for many patients.  Additionally, there is a large patient population that has limited treatment 
options.  Specific populations of patients with limited options include those who are not 
suitable surgical candidates, because they considered high risk for peri-procedural morbidity 
and mortality and those with secondary MR.   
These populations could benefit from a less invasive approach that does not require an open-
heart procedure nor cardiopulmonary bypass.  Therefore, transcatheter mitral valve 
implantation has the potential to be a viable alternative to traditional mitral valve surgery.  
 
 

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3 Device Description 
3.1 Intended Use 
The Tendyne Bioprosthetic Mitral Valve System is intended for transapical, beating heart, 
mitral valve replacement in patients with a diseased, damaged, or malfunctioning mitral 
valve.   
The Tendyne Mitral Valve is implanted through the apex of the left ventricle via a left mini-
thoracotomy while the heart remains beating.  Compared to open-heart valve replacement 
surgery, access is less invasive and the risks of cardiopulmonary bypass are avoided.  Thus, 
the Tendyne Mitral Valve System is designed to provide a mitral valve replacement 
alternative 
for 
patients 
who 
are 
not 
suitable 
candidates 
for 
surgical 
replacement/transcatheter valve repair.   
Implantation of the Tendyne Mitral Valve does not involve concomitant surgical removal or 
revision of the failed native mitral valve.  It is implanted within the native mitral valve, using 
minimally invasive techniques, such that the mitral apparatus is preserved.  Preservation of 
the native structures has been shown to improve clinical outcomes in mitral valve 
replacement17,  as they are essential for maintaining normal left ventricular shape, volume 
and function. 
The Tendyne Mitral Valve can be repositioned and/or retrieved intraoperatively.  These 
features are designed to allow optimization of the valve position following deployment and 
use of an alternative valve size if the initial valve does not have adequate performance.  
3.2 Intended Clinical Performance  
The Tendyne Mitral Valve is intended to reduce mitral regurgitation.  Reduced mitral 
regurgitation may lead to favorable left ventricular remodeling, improved quality of life, 
fewer patient symptoms, and/or reduced hospitalizations for heart failure. 
3.3 Identification 
The Tendyne Bioprosthetic Mitral Valve System consists of the Tendyne Mitral Valve and an 
instrument set to facilitate placement of the valve.   
The Tendyne Mitral Valve System is manufactured by Tendyne Holdings, Inc, a subsidiary of 
Abbott Vascular Inc. (also doing business as Abbott Medical).    
The Tendyne Mitral Valve is supplied in a 0.6% solution of glutaraldehyde for sterile 
packaging and preservation of porcine tissue components.  The instrument set is supplied 
sterile and for single use only.   
The Tendyne Mitral Valve is available in several sizes to accommodate differing cardiac 
anatomies.  Each valve size is described by major (AP, anterior-posterior) and minor (ICD, 
inter-commissural dimension) dimensions, see Section 3.4.1 for more information. 

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3.4 Design 
3.4.1 
Valve 
The Tendyne Mitral Valve has three porcine pericardial tissue leaflets sewn onto a circular 
frame that is referred to as the valve inner.  The inner frame is made from nitinol, a nickel-
titanium alloy that has self-expanding properties and is radiopaque.  See Figure 4 and Figure 
5. 
 
   
Figure 4.  The Inner Nitinol Frame 
 
Figure 5.  The Valve Inner   
 
The porcine pericardial tissue is cross-linked before being sutured to the inner and outer 
frames.   
The valve inner is sutured to an outer nitinol frame that is covered in porcine pericardium 
with a PET (polyethylene terephthalate) fabric cuff that provides the sealing surface within 
the native annulus.  See Figure 6 and Figure 7. 
 
 
Figure 6. The Outer Nitinol Frame (top 
view). 
 
Figure 7.  The Tendyne Mitral Valve 
(top view). 

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Together the valve inner and outer form a self-expanding prosthetic, which is connected to a 
braided fiber tether made of polyethylene.  
The tether is intended to stabilize the valve by passing through the left ventricular 
myocardium near the apex, where it is fastened to a pad on the epicardium.  During 
implantation, the tether is used to adjust tension and optimize the position of the valve within 
the mitral annulus. The apical pad is a PEEK (polyether ether ketone) button covered in PET 
fabric, designed to promote ingrowth.  See Figure 8 and Figure 9. 
 
 
 
Figure 8.  The Tendyne Mitral Valve 
with Braided Tether and Apical Pad 
 
 
Figure 9. The Apical Pad

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The outer frame is formed into a D-shaped body, which helps seat the valve in the mitral 
annulus.  The cuff is raised, or, proud along the straight leg of the D-shape.  The valve is 
intended to be oriented such that the proud element of the cuff rests upon the aortic-mitral 
continuity.  This aspect of the cuff is thereby aligned with the anterior portion of the native 
mitral valve.  See Figure 10.      
The Tendyne Mitral Valve is intended to rest on the floor of the left atrium, to provide counter 
traction to the tether force to prevent migration of the valve into the left ventricle and 
resistance to forward paravalvular leak.  Figure 11 shows the Tendyne Mitral Valve as 
intended for permanent placement.  The tether connects the valve to the apex of the ventricle 
where it is fastened by the apical pad.  
 
Figure 10.  The Tendyne Mitral Valve, 
with the Proud Anterior Element of Cuff 
on the Left. 
 
Figure 11.  The Tendyne Mitral Valve in 
its Final Position within the Native 
Mitral Valve 
3.4.2 
Valve Sizes and Models 
The Tendyne Mitral Valve is available in several sizes to accommodate differing cardiac 
anatomies. Available valve sizes and models are shown in Table 2 below.  
Each valve size is described by the anterior-posterior (AP) and inter-commissural (IC) 
dimensions. Imaging techniques are used by the Core Laboratory to determine valve size 
based on the patient’s mitral valve dimensions. The valve size is chosen to provide the proper 
fit for paravalvular sealing and device stability. 
The inner valve sizes for all valve numbers are the same: The Tendyne 1.0 valve has an EOA 
of 3.2cm2 and the low profile or LP valve has an EOA of 2.0cm2. 

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Table 2: Tendyne Mitral Valve sizes and models  
Valve 
Number 
AP  
(mm) 
IC  
(mm) 
Perimeter 
(mm) 
01 
32.5 
34.5 
113 
02 
32.5 
37.5 
118 
03 
32.5 
40.5 
124 
    04** 
32.5 
43.5 
130 
05 
32.5 
46.5 
136 
09 
34.5 
45.5 
138 
10 
34.5 
48.5 
144 
    14** 
36.5 
46.5 
144 
15 
36.5 
49.5 
150 
19 
38.5 
47.5 
150 
20 
38.5 
50.5 
156 
23 
40.5 
47.5 
154 
24 
32.5 
50.5 
144 
25 
34.5 
51.5 
150 
26 
36.5 
52.5 
156 
  27* 
29.0 
42.5 
119 
*    Size available in LP only 
**   Size available in standard profile and LP 
 
Figure 
12 
Tendyne 
Mitral 
Valve 
dimensions: 
AP, 
anterior-posterior; 
IC, 
intercommissural; and perimeter. 
 
 
AP dimension 
IC dimension 
Perimeter 
The Tendyne 1.0 valve was introduced in clinical trials in the year 2014. During these trials 
it was recognized that approximately 20-30% of clinically suitable candidates were excluded 
from the study due to anatomical limitations, in particular the potential left ventricular 
outflow tract (LVOT) produced by the valve outer sealing frame.   

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The Tendyne LP valve was introduced into the clinical investigation in mid-2016 (protocol 
Rev 5.0 and higher). The LP design was created to potentially allow implantation in subjects 
with small ventricles where the Tendyne 1.0 valve could result in LVOT obstructions. These 
subjects typically have primary MR. This valve has already passed the early feasibility stage, 
with more than 20 implantations in patients.  
The differences between the Tendyne 1.0 valve and the LP valve are described in the 
following figure. 
Figure 13.  Valve Design Differences Between Tendyne 1.0 Valve and LP 
 
 
 
 
 
 
 
 
 
 
The assessment of patient suitability for Tendyne Mitral Valve treatment and the decision to 
implant the Tendyne 1.0 valve or the LP valve is based on 3D modeling of the LVOT created 
by implant of the valve. All assessments are carried out by the Core Laboratories (see 
protocol Section 19.3). 
Typical anatomical scenarios that make the Tendyne LP valve more suitable include Primary 
MR and/or subjects with smaller ventricles. 
3.4.3 
Instrument Set 
The instrument set included in the Tendyne Mitral Valve System includes (1) an access 
system that can be configured multiple ways and (2) an apical pad tool.  
The instrument sets are identical for the two valve models. 
3.4.3.1 Access System 
The access system is designed to facilitate Tendyne Mitral Valve implantation using standard 
transapical access methods.  The system is designed to facilitate gradual, controlled 
deployment of the valve and proper seating within the mitral annulus.  It is also designed to 
facilitate intraoperative repositioning, if necessary, to achieve optimal orientation within the 
annulus.  The system allows intraoperative retrieval, if necessary, to pull the valve out.  An 
alternate Tendyne Mitral Valve may then be implanted. 
Decreased area of the leaflets 
from ES0526-xxx resulting in a 
smaller diameter of the inner 
valve frame on ES1066-xx. 
Decreased height of the valve 
outer sealing frame on ES1066-
xx (also referred to as sealing 
height) as compared to 
ES0526-xx of the same size. 

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The access system includes instrumentation that may be configured for alignment, loading, 
delivery, repositioning, or retrieval.  The access system has the following features:   
• 
Precise alignment guide and needle access 
• 
Mechanisms to ensure device does not traverse in between chordae tendinae or 
leaflet cusps preventing future device entanglement 
• 
Consistent, controlled manner to collapse the implant prior to delivery 
• 
Atraumatic radiopaque tip introducer with dilator 
• 
Mechanism for controlled advancement and retraction of the valve 
• 
Fine-positioning mechanism for precise deployment and capture of the valve 
• 
Flush ports for removing air from the system 
• 
Graduated retrieval dilator system to ensure proper collapse of the device prior to 
retrieval 
• 
Ability to release the pad locking mechanism if previously deployed and adjustments 
to positioning are necessary 
The access system is identical for the two valve models. 
 
3.4.3.2 Apical Pad Tool 
The apical pad tool is designed to fasten the apical pad to the braided tether, at the epicardial 
surface.  It has an articulating head to facilitate proper angulation, and a cam rotator that 
drives a pin through the braided tether.  The cam rotator allows for unlocking and relocking 
of the pin in case the tether tension needs to be adjusted. 
The apical pad is identical for the two valve models. 
 
 

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4 Risk-Benefit Analysis 
4.1 Risk Analysis 
4.1.1 Risk Assessment 
In conducting the risk analysis, the concepts of risk estimation, risk acceptability, risk control 
and overall risk evaluation were applied in accordance with ISO 14971.  The intended use 
and implantation procedures were taken into consideration along with the materials and 
mechanical features of the Tendyne system.  Based on an evaluation of residual risk 
acceptability, it was concluded that the overall residual risk did not exceed the criteria for 
acceptable risk.   
4.1.2 Risk Mitigation 
A major risk is potential damage to the left atrial and ventricular structures during 
implantation of the Tendyne Mitral Valve.  Damage to the subvalvular apparatus is mitigated 
by the delivery system that is designed to cross the mitral valve with minimal risk of 
entanglement in the chordae tendinae.  Damage to the atrium is mitigated by controlling valve 
deployment.  The delivery instrument employs a fine ratcheting system, allowing the valve to 
exit the delivery sheath gradually.  Damage to the atrium is further mitigated by employing a 
soft, flexible tip dilator and delivery sheath to introduce the device.   
Transapical techniques have been used for many years.  Transapical aortic valve implantation 
is done through a similar access, and left ventricular assist devices are traditionally attached 
at the apex.  Nevertheless, puncture of the left ventricular apex and subsequent closure may 
cause bruising and scar tissue, with the potential for impaired cardiac function.  The apex, 
however, contributes minimally to the overall ventricular contraction.  Damage at the apex is 
mitigated by a relatively low-profile delivery system to make the puncture as small as 
possible.   
The residual risks are disclosed in the labeling of the device (IFU) and are counterbalanced 
by the potential benefits of the therapy in the target patient population, as discussed in 
Section 4.2.   
The mini-thoracotomy required for apical access is the same opening in which drainage tubes 
would be placed following mitral valve surgery.  Therefore, the mini-thoracotomy does not 
add to the morbidity risks compared to surgical repair or replacement. 
Not all risks may be known at this time.  To see a list of anticipated adverse events, please see 
Section 0. 
4.2 Potential Benefits  
Patients who are contraindicated for mitral valve replacement surgery may benefit from 
receiving the Tendyne Mitral Valve because there are currently no other nonsurgical 
replacement options.  Currently all prosthetic mitral valves for replacement within the native 
valve must be implanted surgically. 

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Unlike contemporary replacement mitral valves, the Tendyne Mitral Valve does not require 
open-heart surgery.  The benefits here are twofold.  First, less invasive access leads to lower 
operative risk.  Second, the use of cardiopulmonary bypass carries several risks, including 
abnormal bleeding, acute respiratory distress syndrome, air embolism, atelectasis, blood 
clotting, capillary leak syndrome, hemolysis, pancreatitis, postperfusion syndrome, renal 
dysfunction and neurologic deficits in elderly, which can be substantial. 
The Risk/Benefit analysis performed in accordance with ISO 14971 showed that the Tendyne 
Bioprosthetic Mitral Valve System has the same risks of the other mitral valve prosthetic 
devices currently used in clinical practice or in clinical studies. The benefit that the Tendyne 
Bioprosthetic Mitral Valve System can give to patients suffering of severe mitral regurgitation 
are important, considering that the system can give opportunities for therapy to elderly 
patients that are excluded by the surgical option.  The clinical benefit of the device is balanced 
against the residual risk associated with the treatment. 
4.3 Study Participation Associated Risks 
The risks associated with study participation (Table 3) are those associated with standard 
clinical diagnostic und evaluative practices procedures: 
Table 3: Study Participation Associated Risks 
Study Procedures 
Risks 
History, Clinical Status, QOL 
Survey, 6-Minute Walk & Physical 
Exam 
None, Minimal 
Laboratory testing 
Usual risks associated with phlebotomy 
Concomitant Medication 
Physician use and risk information in accordance with 
usual clinical practice and type of medication. 
ECG 
None, Minimal 
Echocardiography TTE 
None, Minimal 
Echocardiography TEE 
Written informed consent consistent with clinic policy 
Angiography (LV 
Ventriculogram) / 
Hemodynamics 
Written informed consent consistent with clinic policy 
Computerized tomography 
angiography (CTA) 
Written informed consent consistent with clinic policy  
The obtainment of patient informed consent for study procedures determined to require 
prospective informed consent will be undertaken in accordance with the procedural 
informed consent procedures and documentation content defined by participating hospital 
policy. The procedures required per study protocol are consistent with standard of practice 
procedures given the indication for the associated intervention.  
 

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5 Study Purpose 
The purpose of this expanded clinical study is to evaluate the performance and safety of the 
Tendyne Mitral Valve System in the treatment of severe mitral regurgitation in patents with 
functional disability greater than or equal to NYHA Class II, who are not suitable candidates 
for surgical replacement with otherwise available devices. The data gathered in this study 
will be used to support conformity requirements for CE Mark of the Tendyne system, using 
an appropriately powered sample size to enable assessment of the study safety and 
performance endpoints of the Tendyne System in the intended populations. 
This study will be continued after the CE Mark to collect long-term safety and performance 
data as part of the Tendyne post-market follow-up program. All patients shall continue to be 
followed through 5 years in the post-market setting. 
6 Study Design 
Nonclinical assessments, pre-clinical data, and acute clinical study data have been used to 
evaluate the Tendyne Bioprosthetic Mitral Valve System design concept.  This study is 
required to collect further data. 
This study is a single-arm, multicenter study, designed in accordance with the MVARC 2015 
guideline and standard ISO 5840-3:2013.94,95,96,97  The subjects will be individuals who have 
symptomatic mitral valve regurgitation and meet eligibility criteria.  
6.1 Geographies and Centers 
Up to 110 subjects will be enrolled into the study in support of the CE Mark.  Up to an 
additional 240 subjects (for an overall sample size of 350) may be enrolled in the study to 
evaluate the long-term performance of the Tendyne Mitral Valve. Refer to Section 8; and 
Appendix B, Statistical Methodology. 
Up to 40 centers will participate in the study, with an expected enrollment of 6 to 10 patients 
per site.  Enrollment is competitive and geographical expansion will allow overcoming the 
limitations of slow enrollment due to the stringent inclusion and exclusion criteria. Centers 
to be included in the study will meet study qualification requirements, have received 
necessary institutional review board/ethics committee and/or other approvals, be in 
countries in which the study has been approved as required by law, and be approved by the 
sponsor to participate.  Geographies being considered for the study include Australia, Canada, 
Europe, and the United States. 
6.2 Duration 
The EFS and Expanded study have enrolled approximately 90 subjects to date. The objective 
of this study is to enroll a maximum of 350 patients to allow evaluation of the primary 
endpoint as well as pre-planned subgroup analyses. 

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The enrollment phase is anticipated to take up to 36 months. All subjects will be followed out 
to two years for secondary endpoints. Therefore, the anticipated duration is less than 5 years. 
During this timeframe, the Tendyne Mitral Valve System may achieve CE Mark certification 
when adequate data are available to achieve the primary endpoints and demonstrate 
conformance with the safety and performance requirements of the Medical Devices Directive, 
See Appendix B, Statistical Methodology. 
The cohort of patients included in pre-market clinical investigations shall continue to be 
followed through 5 years in the post-market setting, as appropriate to capture long-term data 
on less common or unanticipated adverse events, on adverse events which are time-related 
(e.g. structural deterioration, adverse effects on native valve anatomy) and on long-term 
performance.  Thus, it is anticipated that the overall study duration will be nine years 
(including the pre-market and post-market phase). 
6.3 Sample Size 
Up to 350 subjects will be enrolled in the study. Subjects shall be recruited by up to 40 clinical 
sites based upon availability of appropriate subjects.  Enrollment shall be competitive and 
enrollment will be closed once a sufficient number of subjects have been included.  
6.4 Eligibility Criteria 
Candidates will have symptomatic mitral valve regurgitation and meet all eligibility criteria. 
6.4.1 Inclusion Criteria  
 
Subjects must meet ALL of the following criteria: 
1. Severe mitral regurgitation of primary or secondary etiology according to MVARC 
(Mitral Valve Academic Research Consortium) 2015 defined as: 
• 
For Degenerative MR: EROA ≥ 40 mm2 or regurgitant volume ≥ 60ml 
• 
For Secondary MR: EROA ≥ 20 mm2 or regurgitant volume ≥ 30ml 
2. New York Heart Association (NYHA) functional Class ≥ II while on guideline directed 
medical therapy (GMDT), including device therapy (CRT) if indicated.   
3. Heart team determines patient is not a suitable candidate for traditional surgical 
treatment according to valid guidelines. 
4. Age 18 years or older. 
6.4.2 Exclusion Criteria  
 
Subjects will be excluded if any of the following criteria are met: 
1. Severe mitral annular calcification, severe mitral stenosis, valvular vegetation or 
mass. 
2. Left Ventricle (LV) or Left Atrium (LA) thrombus. 

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3. Patient has a chest condition that prevents transapical access. 
4. Left ventricular ejection fraction (LVEF) less than 30% by echocardiogram. 
5. Left Ventricular End Diastolic Diameter (LVEDD) > 7.0 cm. 
6. Prior surgical or interventional treatment of mitral or aortic valves (e.g. valve repair 
or replacement, MitraClip, edge to edge repair, aortic balloon valvuloplasty, etc.). 
7. Any planned surgery or interventional procedure within the period of 30 days prior 
to 30 days following the implant procedure.  This includes any planned concomitant 
cardiovascular procedure such as PCI, pulmonary vein ablation, left atrial 
appendage occlusion, septal defect repair, etc. 
8. Cardiac resynchronization therapy device or implantable pulse generator implanted 
within three months of planned implant procedure. 
9. Myocardial Infarction (MI) within 30 days of the planned implant procedure. 
10. Symptomatic, unresolved multi-vessel coronary artery disease (CAD) or 
unprotected left main coronary artery disease requiring stenting or Coronary Artery 
Bypass Grafting (CABG). 
11. Cerebrovascular accident (CVA) within six months of planned implant procedure. 
12. Unresolved severe symptomatic carotid stenosis (> 70% by ultrasound).  
13. Cardiogenic shock or hemodynamic instability requiring inotropes or mechanical 
support devices at the time of planned implant procedure. 
14. Severe tricuspid regurgitation, tricuspid valve disease requiring surgery or severe 
right ventricular dysfunction. 
15. Hypertrophic or restrictive cardiomyopathy, constrictive pericarditis or any other 
structural heart disease causing heart failure other than dilated cardiomyopathy of 
either ischemic or non-ischemic etiology. 
16. Any of the following:  leukopenia, acute anemia, thrombocytopenia, history of 
bleeding diathesis, or coagulopathy if cannot be adequately treated. 
17. History of endocarditis within six months of planned implant procedure. 
18. Active systemic infection requiring antibiotic therapy. 
19. Known hypersensitivity or contraindication to procedural or post-procedural 
medications (e.g., contrast solution, anti-coagulation therapy) which cannot be 
adequately managed medically or hypersensitivity to nickel or titanium. 
20. Patient is undergoing hemodialysis due to chronic renal failure. 
21. Patient has pulmonary arterial hypertension (fixed PAS >70mmHg). 
22. Patient has COPD and is on home oxygen. 
23. Patient refuses blood transfusions. 
24. Pregnant, lactating, or planning pregnancy within next 12 months. 
25. Participating or planning participation in an investigational drug or another device 
study. 
26. Patient or legal guardian unable or unwilling to give informed consent. 

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27. Patient unable or unwilling to comply with study required testing and follow-up 
visits. 
28. Patients with non-cardiac co-morbidities that are likely to result in a life expectancy 
of less than one year. 
7 Objectives and Endpoints 
Endpoints were selected to enable the sponsor, its safety committees, and regulatory 
agencies the ability to compare estimates obtained from this study to estimates from studies 
of other comparable procedures and devices.  Objectives and endpoints were selected based 
on input from medical advisors experienced in related procedures and studies of other 
replacement valves and devices used to treat mitral regurgitation.  
7.1 Performance  
Provide initial insight into the performance of the Tendyne Mitral Valve System by measuring 
technical and device success. 
7.1.1 Technical Success Definition (Exit from procedure room) 
Alive with the following: 
• 
Successful access, delivery and retrieval of the transcatheter valve delivery system, 
and 
• 
Deployment and correct positioning of the correctly sized valve, and 
• 
No need for additional emergency surgery or re-intervention related to the device or 
access procedure. 
7.1.2 Device Success Definition (at 30 day and all post-procedural time points) 
Alive with the following: 
• 
Disabling stroke free, with 
• 
Original intended device in place, and 
• 
No additional surgical or interventional procedures related to access or the device, 
and 
• 
Intended performance of the device: 
o No Device specific adverse events, such as migration, embolization, fracture, 
hemolysis, thrombosis or endocarditis, and 
o Maintenance of expected hemodynamic performance (e.g., central mitral 
regurgitation (MR) < 1+; mitral valve gradient < 6 mmHg or effective orifice area 
(EOA) > 1.5 cm2) and,  
o No para-device complications (left ventricular outflow tract (LVOT) obstruction: 
>20 mmHg increase in LVOT gradient vs. baseline; paravalvular leak (PVL) > 1+; 
effects on coronary circulation or other heart structures, e.g., erosion or need for 
permanent pacemaker implantation. 

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7.2 Primary Effectiveness:  Individual Patient Success (1-year) 
Individual Patient success is defined as device success and all of the following:  
 
No re-hospitalizations or re-interventions for heart failure  
 
Change in NYHA functional class 
o Improvement is defined as NYHA grade ≥ 1 compared to baseline 
 
Change in distance walked, six-minute hall walk 
o Improvement is defined as ≥ 50 meters compared to baseline 
 
Change in Kansas City Cardiomyopathy Questionnaire scores 
o Improvement is defined as ≥ 10 compared to baseline 
7.3 Safety  
Provide insight into the safety profile of the Tendyne Mitral Valve System and procedure. 
7.3.1 Primary Safety Objective 
To evaluate one month procedural and device safety of the Tendyne Bioprosthetic Mitral 
Valve System. 
7.3.2 Primary Safety Endpoints  
Device success and freedom from the following device- or procedure-related serious adverse 
events (SAEs) at 30 days post implant, as classified by the Clinical Events Committee:  
• 
Cardiovascular death 
• 
Reintervention caused by valve-related dysfunction 
• 
Disabling Stroke 
• 
Myocardial infarction (MI) 
• 
Life-threatening bleeding (BARC Type 2, 3, and 5)  
• 
Major Vascular Complications 
• 
Renal failure requiring dialysis 
• 
Other device-related SAEs 
• 
Other procedure-related SAEs 
Stroke and MI classifications will be per the VARC-2.  Life-threatening bleeding classifications 
will be per the Bleeding Academic Research Consortium (BARC) consensus. Criteria are 
provided in Appendix A. 
7.3.3 Secondary Safety Objective 
To evaluate long-term safety of the Tendyne Bioprosthetic Mitral Valve System. 
Follow-up for secondary endpoints will be continued for 2 years. Additional follow-up will be 
obtained for up to 5 years as recommended by most recent guidelines, to capture long-term 

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data on less common or unanticipated adverse events, on adverse events which are time-
related (e.g., structural deterioration, adverse effects on native valve anatomy) and on long-
term performance. 
7.3.4 Secondary Safety Endpoints  
Through two years post implant: 
 
Device success, and 
 
No device or procedure related SAEs 
 
7.4 Valve System Usability  
7.4.1 Valve System Usability Objective 
Gather and evaluate information on the usability of the valve system. 
7.4.2 Valve System Usability Data 
Data will be implanters’ assessments of usability, especially as it relates to the ability to 
successfully deliver and deploy the Tendyne Mitral Valve in the desired anatomical location. 
7.5 Additional Endpoints 
 
Length of ICU stay 
 
Length of hospital stay 
 
30 day mortality  
 
3-month mortality 
 
 

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8  Analysis Plan and Sample Size Justification 
Descriptive statistics for each variable will be calculated which will include measures of 
central tendency, variation, a frequency histogram and a count of the number of missing 
values. 
When the arithmetic mean is found not to be an appropriate measure of central tendency, 
alternative statistics will be considered (e.g., median). When the distribution of a variable 
does not support the use of parametric statistics, nonparametric approaches or data 
transformations may be implemented. If data transformations are used, they will be specified 
in the final clinical report. 
The anticipated primary safety endpoint will be reported in the range of 80 to 90% (device 
success and freedom from the CEC adjudicated device- or procedure-related serious adverse 
events (SAEs) through 30 days post implant.  If we conservatively estimate the scenario that 
the freedom from safety rate is 80%, a sample size of 94 subjects will yield precision (defined 
as distance from point estimate to lower 95% confidence limit) of 9%.  If we allow up to 15% 
attrition, a sample size of 110 subjects would need to be enrolled to achieve a minimum 
precision level of at least 9% provided the safety rate is 80% or better. 
8.1 Sample Size  
Up to 110 subjects will be enrolled into the study in support of the CE Mark.  Up to an 
additional 240 subjects (for an overall sample size of 350) may be enrolled in the study to 
evaluate the long-term performance of the Tendyne Mitral Valve. Refer to Section 8; Analysis 
Plan and Sample Size Justification, and Appendix B, Statistical Methodology. 
8.2 Screen Failures and Point of Enrollment 
The number and percentage of subjects screened, screen failure, enrolled, treated, and 
completed will be summarized. Screen failure percentage is calculated from number of 
screened subjects and other percentages are calculated among number of enrolled subjects.  
The point of enrollment is the time at which a subject signs and dates the informed consent 
form, in accordance with ISO 14155. Statistics will be calculated in the intent to treat (ITT) 
population (all subjects in whom the Tendyne Mitral Valve System is introduced into the 
body); and Implanted Patient Populations (IPP) (all subjects in whom the Tendyne Mitral 
Valve implant is completed).   
8.3 Baseline 
Demographics, 
Clinical 
Background, 
and 
Protocol 
Administration 
Descriptive statistics will be used to present the data and summarize the results. The study 
population will be summarized using descriptive statistics for baseline demographics, 
disease characteristics, echocardiography parameters, procedural characteristics, and 
follow-up data collected. Continuous variables will be summarized by reporting the number 

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of observations (N) mean, standard deviation, median, minimum and maximum values.  
Categorical variables will be summarized using frequency distributions and cross 
tabulations, incidence and event rate.  Compliance with the protocol will be evaluated by 
summarizing the number of subjects enrolled, implanted, and completing study required 
follow-ups.  Patients terminating the study early will be listed along with the reason for 
termination.   
8.4 Handling Study Discontinuations  
Study drop-outs will be listed along with the reason for termination per Section 8.1 of the 
protocol. Drop-outs will be censored from the analysis with no data imputation. Deviations 
from the protocol will also be summarized by deviation type as well as total. The primary 
statistical analysis will be based on subject counts.  A subject with more than one deviation 
will be counted only once toward the rate based on the total number of subjects with protocol 
deviations.   
8.5 Evaluation of Primary Endpoints 
8.5.1 Primary Performance Objective 
The primary performance objective is to estimate the proportion of subjects with MR grade 
≤ 2 at 30 days post-implant.   
Subjects included in the analysis:  All subjects in whom the Tendyne Mitral Valve 
implant is completed.  
Endpoint:  Percentage of subjects with MR grade ≤ 2 at 30 days post-implant.    
Data analysis:  The number and percent of subjects associated with each MR grade 
at baseline and 30 days post implant will be summarized.  The number and 
proportion of subjects with MR grade ≤ 2 at 30 days will be calculated along with the 
95% confidence interval for that proportion. 
8.5.2 Primary Safety Objective 
The primary safety objective is to evaluate one-month procedural and device safety of the 
Tendyne Bioprosthetic Mitral Valve System.  
Subjects included in the analysis:  All subjects in whom the Tendyne Mitral Valve 
System is introduced into the body. 
Endpoint:  Each of the individual primary safety endpoints will be evaluated (see list 
in 7.3.2 above).  Additionally, composite endpoints may be estimated and evaluated 
for comparison to the literature.   
Data analysis:  The number of events and the number and percent of patients 
affected by individual primary safety events and if desired composite endpoints 
within 30 days of the procedure will be summarized along with the exact 95% 
confidence interval. 

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8.5.3 Valve System Usability Objective 
The valve system usability objective is to evaluate information on the usability of the Tendyne 
Bioprosthetic Mitral Valve System. 
Data included in the analysis:  All usability data gathered from implanters will be 
analyzed.  Data will be implanters’ assessments of usability, especially as it relates to 
the ability to successfully deliver, position, and deploy the Tendyne Mitral Valve in 
the desired anatomical location.  Data will also include information on retrievability, 
if available. 
Data Analysis:  Continuous variables will be summarized by reporting the mean, 
standard deviation, median, minimum and maximum.  Categorical variables will be 
summarized by reporting the number and percent in each category. 
8.6 Evaluation of Secondary Endpoints 
A complete list of secondary safety and performance endpoints is provided in Section 7 above.  
Secondary study endpoints are collected for the purpose of further evaluation of the device 
performance and to aid in the design of future studies.  Standard statistical methods will be 
used to provide estimates along with their 95% confidence intervals. 
 
 

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9 Regulations 
This study will be conducted under good clinical practices, ISO 14155:2011(E) and ISO 5840-
3:2013(E), and when not in contradiction to local standards, laws or requirements, also in 
alignment with the United States Food and Drug Administration Code of Federal Regulations 
Title 21 Parts 11, 50, 54, 56, 58, and 812. 
The study shall be conducted consistent with the ethical principles of the Declaration of 
Helsinki. 
Prospective review and approval of this study shall be undertaken consistent with the legal 
and regulatory requirements of those countries in which the program is to be undertaken.  
The Study Protocol and associated essential documents, as well as any subsequent 
Amendments, shall require the prospective review and approval of the Competent Authority 
and responsible Ethics Committee consistent with applicable regulatory requirements. 
The applicable laws and regulations and the communicated requirements of the Competent 
Authorities and Ethics Committee shall be respected during the conduct of the clinical study. 
Clinical Study Insurance consistent with the laws and regulations in the countries of conduct 
shall be provided by the Study Sponsor. 
10 Site Initiation Activities 
10.1 Investigator and Site Selection 
The sponsor will assess potential investigators to ensure that they are experienced and have 
the necessary expertise.  Investigators must also have the ability to enroll an adequate 
number of subjects.   
The sponsor will also assess the site to ensure that it is equipped with adequate facilities for 
the study.  The sponsor will ensure that qualified personnel are available to conduct the 
study, including a designated research coordinator and a procedural heart team.  At a 
minimum, the procedural heart team will be composed of an interventional cardiologist, a 
cardiac surgeon experienced in transapical procedures, a sonographer, and an experienced 
cardiac anesthesiologist. 
Investigators must agree to comply with this protocol, all ethics committee requirements, and 
all applicable laws and regulations.   
10.2 Initiation Requirements  
Investigative sites may begin enrolling subjects after all initiation requirements are met and 
the sponsor has given notice of approval to start.  Initiation requirements include: 
institutional review board/ethics committee approval of this protocol and the informed 
consent; training of all participating site personnel; a site initiation visit by the sponsor; 

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training by the echo core lab; and submission of all required documents to the sponsor.  
Required documentation includes: institutional review board/ethics committee approvals; 
curricula vitae (CVs); signed investigator agreements with conflict of interest/financial 
disclosure statements; documentation of site training; and any other documents requested 
by the sponsor. 
10.3 Site Training  
On-site training of investigators and site study personnel will be conducted by the sponsor as 
part of the initiation activities.  Training sessions may be tailored to fit site personnel’s roles 
in the study.  The sponsor will ensure adequate training is provided on the following: 
 
Investigational device, principle of operation and system components 
 
Protocol 
 
IFU 
 
Data collection and eCRFs 
 
Investigator responsibilities 
 
Device accountability 
 
Implantation procedure 
 
Imaging and data acquisition 
 
Echo protocol 
 
CT protocol 
11 Screening and Enrollment 
11.1 Screening 
Patients with symptomatic mitral regurgitation are to be evaluated to determine if they meet 
the eligibility criteria based on standard of care tests and procedures. All cases should be 
screened by a heart team. 
11.2 Informed Consent 
Once it is determined that a patient provisionally meets the eligibility criteria the investigator 
must: explain the nature, purpose, and consequences of study participation to the patient; 
answer any questions the patient may have; and provide the patient with the approved 
consent form to read.  The oral informed consent process shall include: an overview of all 
aspects of the written patient information document with specific attention to the voluntary 
nature of participation; an overview of study obligations; risks associated with the study 
device implantation; study procedures; and alternative treatment modalities.  In addition, the 
possibility to discontinue participation without impact upon on usual care shall be reviewed 
including requirements for routine clinical follow-up evaluations.  The informed consent 

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form must be approved by the sponsor and the reviewing institutional review board/ethics 
committee.  The investigator will inform the patient with new information, if applicable. 
In the event a patient has limited or absent legal competence, the process for obtainment of 
informed consent defined by law involving the documented consent of the patient’s legal 
representative shall be strictly observed and undertaken. Insofar as such a patient, 
independent of legal competence status, is able to understand the nature, purpose and 
consequences of study participation and to make his/her will known, such patient informed 
consent is mandatory, independent of any consent provided by his/her legal representative. 
Minors, as well as pregnant or nursing women, or women intending to become pregnant in 
the ensuing 12 months are specifically excluded from participation. 
In order to participate in the study, the patient and person performing the consent process 
must sign and date the informed consent form.  Subjects may also be asked to consider signing 
a supplemental consent form pertaining to heart donation to the sponsor in the event of a 
transplant.  Analysis of an in situ device would provide valuable histological information. 
Insofar as additional institutional patient information documents for the following study 
procedures are implemented, such institutional standard documents shall be executed in 
conformance with institutional policy: 
• 
Echocardiography 
• 
Angiography 
• 
Computerized Tomographic Angiography (CTA) 
All applicable laws, regulations, and ethics committee requirements must be followed during 
the consent process.   
11.3 Vulnerable Population 
A vulnerable subject is defined as an individual whose willingness to volunteer in a clinical 
investigation could be unduly influenced by the expectation, whether justified or not, of 
benefits associated with participation or of retaliatory response from senior members of a 
hierarchy in case of refusal to participate.  
EXAMPLES: Individuals with lack of or loss of autonomy due to immaturity or through mental 
disability, persons in nursing homes, children, impoverished persons, subjects in emergency 
situations, ethnic minority groups, homeless persons, nomads, refugees, and those incapable 
of giving informed consent. Other vulnerable subjects include, for example, members of a 
group with a hierarchical structure such as university students, subordinate hospital and 
laboratory personnel, employees of the sponsor, members of the armed forces, and persons 
kept in detention. 
Individuals who fulfill these criteria shall not be approached for participation in the study. 

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11.4 Enrollment 
The point of enrollment is the time at which a subject signs and dates the informed consent 
form, in accordance with ISO 14155. 
Study subjects who are implanted with a permanent Tendyne Mitral Valve will be followed 
through two years and annually thereafter until study closure.  Subjects who have any part 
of the Tendyne Mitral Valve System introduced into the body, but who do not end up with an 
implanted Tendyne Mitral Valve will be followed through one month or until any procedure 
or device related adverse event is resolved, whichever comes later.  Subjects will then be 
exited from the study.  Subjects who do not have any part of the Tendyne Mitral Valve System 
introduced into the body will be exited from the study immediately. 
 
 

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12 Methods 
12.1 Overview 
Study methods include testing and collection of data for evaluating the study endpoints, in 
accordance with the clinical data requirements described in ISO 5840. Table 4, that follows, 
outlines the study requirements. 
Table 4: Assessments and Data Collection Requirements  
 
 
Exams, Tests and 
Data Collection 
Screening
/ Baseline 
Procedure 
Pre-
discharge 
1 
Month
1 
3 
Months 
6 
Months 
1 
year2 
2 
years 
Annual 
visits 
up to 5 
yrs 
Visit Window 
 
Before and 
After 
Implant 
24 hours 
prior to 
discharge
3 
-2 days  
+10 days 
±14 
days 
±30 
days 
±45 
days 
±60 
days 
±60 
days 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Screening 
X 
 
 
 
 
 
 
 
 
Medical history 
with Demographics 
X 
 
 
 
 
 
 
 
 
Physical Exam 
including Vital Signs 
while sitting 
X 
 
 
X 
X 
X 
X 
X 
X 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EuroSCORE II 
X 
 
 
 
 
 
 
 
 
STS Risk Score 
X 
 
 
 
 
 
 
 
 
CCS Angina class 
X 
 
 
 
 
 
 
 
 
NYHA class 
X 
 
 
X 
X 
X 
X 
X 
X 
Six Minute Hall 
Walk Test 
X 
 
 
X 
X 
X 
X 
X 
X 
KCCQ 
X 
 
 
X 
X 
X 
X 
X 
X 
CLINICAL LABORATORY TESTS 
 
Pregnancy Test4 
X 
 
 
 
 
 
 
 
 
Creatinine 
X 
 
X5 
X 
X 
X 
X 
X 
X 
Plasma–free 
Hemoglobin 
X 
 
 
X 
X 
X 
X 
X 
X 
LDH (lactate 
dehydrogenase) 
X 
 
 
 
 
 
 
 
 
NT pro-BNP 
X 
 
 
X 
X 
X 
X 
X 
X 
International 
Normalized Ratio 
(INR) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Creatinine Kinase-
MB (CK-MB) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Troponin (Type I or 
T) 
X 
 
X 
X 
X 
X 
X 
X 
X 
INTRAOPERATIVE HEMODYNAMICS (NOT LIMITED TO)9 
 
CO 
 
X 
 
 
 
 
 
 
 
PA Pressures 
 
X 
 
 
 
 
 
 
 
PCWP 
 
X 
 
 
 
 
 
 
 
LV Pressures 
 
X 
 
 
 
 
 
 
 

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12.2 Echocardiography 
Transesophageal echocardiography (TEE) is required intraoperatively to guide the 
implantation of the Tendyne Mitral Valve and to assess performance before and after 
placement.  Transthoracic (TTE) echocardiography should be used at all follow-up visits. 
The sponsor will identify an independent echocardiography core laboratory to analyze the 
echo studies.  To ensure quality imaging and facilitate standardized analyses, echo protocols 
for both TEE and TTE have been established.  These protocols outline modes of operation and 
imaging views to be obtained. 
This study requires TEE 3D imaging of the mitral apparatus.  Transthoracic imaging will be 
2D for assessing mitral, tricuspid, and aortic valves with and without color Doppler and will 
include spectral imaging of these valves as well as the pulmonary veins.  Spectral imaging of 
the left ventricular outflow track (LVOT) and images needed to assess left ventricular 
volumes and central venous pressures will also be acquired.  
The echocardiography core lab will extract indices that include the following: 
• 
MR grade 
• 
MR volume and fraction 
• 
Mitral valve dimensions  
EXAMS AND TESTS 
 
Coronary 
Angiogram 
X6 
 
 
 
 
 
 
 
 
Cardiac CT 
X11 
 
 
X12 
 
 
 
 
 
ECG (12-Lead) 
X7 
X8 
X 
 
 
 
 
 
 
TEE9 
X11 
X 
 
 
 
 
 
 
 
TTE9 
X11 
 
X 
X 
X 
X 
X 
X 
X 
Angiography: LV 
Gram 
 
X10 
 
 
 
 
 
 
 
OTHER 
 
Device Deficiencies 
 
X 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
Protocol 
Deviations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CCS = Canadian Cardiovascular Society      CTA = Computerized Tomography Angiography     CO = Cardiac Output    ECG = 
Electrocardiogram       eGFR = estimated Glomerular Filtration Rate      NT-proBNP = N-terminal of the prohormone Brain Natriuretic 
Peptide     PA = Pulmonary Arterial     PCWP = Pulmonary Capillary Wedge Pressure         STS= Society of Thoracic Surgeons    TEE = 
Transesophageal Echocardiography     TTE = Transthoracic Echocardiography 
 
1 A month equals 30 days 
2 A year equals 365 days 
3 If prolonged hospitalization occurs data for this visit may be collected within 10 days after the implant procedure. 
4 Urine or blood test if subject of child bearing potential 
5 When possible measure 48 hours post implant 
6 Within the last 6-months of scheduled procedure if clinically indicated 
7 Less than or equal to 7 days from Baseline 
8 Before and after implant 
9 LVEF and LVEDD 
10  Optional for subjects with stage 3, 4 or 5 chronic kidney disease (eGFR < 60 mL/min/1.73 m2) 
11 Date of image/testing should be considered clinically relevant per PI 
12 Optional if indicated per standard of care at the hospital 

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• 
LV and LA dimensions 
• 
Effective regurgitant orifice area (EROA) 
• 
Mitral valve gradient 
• 
LVEF 
• 
Cardiac output  
• 
LVOT dimensions and gradient 
 
12.3 Angiography 
The subject’s coronary artery disease status usually will be known in advance, via a routine 
diagnostic angiogram done as part of the work-up for cardiac surgery or transcatheter mitral 
valve repair if clinically indicated.  Any stenting treatment should be administered prior to 
the implantation of the Tendyne Mitral Valve as outlined in the patient eligibility criteria in 
section 6.4 above.  No simultaneous therapeutic procedures should be planned in conjunction 
with the Tendyne Mitral Valve implantation. 
12.3.1 Preoperative Cardiac Computerized Tomography (CT) 
Cardiac CT is performed as standard of care for transcatheter valve implantation; therefore, 
all subjects will have a Cardiac CT performed at baseline to evaluate cardiac dimensions 
relevant to valve sizing and aid in procedural planning.  If a cardiac CT is obtained per non-
research clinical practice at any follow-up, it should be provided to the study sponsor.   
Additionally, a follow-up cardiac CT should be performed at the 1 Month visit, if tolerable by 
the patient. 
12.3.2 Intraoperative Angiography 
Subjects will undergo left-heart catheterization with radiographic imaging as per standard-
of-care.  Imaging will include a left ventriculogram before and after the Tendyne Mitral Valve 
is placed, for radiographic assessment of LV and mitral valve competence.  Care must be taken 
to minimize the amount of contrast media injected into subjects with compromised renal 
function.  Therefore, left ventriculogram procedures described in this protocol are optional 
for subjects with stage 3, 4 or 5 chronic kidney disease. 
Tendyne will provide specific instruction on intraoperative imaging requirements as part of 
investigator training. 
12.4 Intraoperative Hemodynamic Measurements 
Subjects will also undergo right-heart catheterization to measure hemodynamics 
intraoperatively.  Cardiac output (CO), pulmonary arterial (PA), aortic and right arterial (RA) 
pressures will be measured before and after the Tendyne Mitral Valve is placed via the right 
heart catheter.  LV pressures should be measured via a pigtail catheter.  LV pressures should 
be measured simultaneously and recorded digitally for post-processing analysis if possible. 

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12.5 History and Physical Examination 
At baseline, a standard physical examination and complete medical history must be taken 
including co-morbidities and co-existing medical conditions; previous cardiovascular and 
peripheral vascular interventions; symptoms and diagnosis of mitral insufficiency. 
12.6 Clinical Status 
Clinical status including vital signs and NYHA functional classification must be evaluated at 
baseline and each scheduled follow-up visit.  Vital signs include sitting pulse, sitting blood 
pressure and body temperature.   
12.7 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The KCCQ is a heart failure specific measure of health status and quality of life.  It is a 12-item 
questionnaire that quantifies physical function, symptoms, social function, self-efficacy and 
quality of life for patients with heart failure.  The KCCQ is self-administered and takes 
approximately 5 minutes to complete.  It must be given to subjects at baseline and each 
scheduled follow-up visit. 
12.8 Six-Minute Hall Walk 
A six-minute hall walk test must be done at baseline and each scheduled follow-up visit.  
Subjects will be asked to walk as far as they can for six minutes, and the distance they cover 
is to be recorded.  If a subject has a non-cardiovascular limitation such as an orthopedic 
restriction or hemiplegia, this must be noted.  If a subject is non-ambulatory due to heart 
failure status, a score of 0 will be recorded.  
12.9 Medications 
All cardiovascular medications must be documented at baseline, and any changes in 
medications must be documented at each scheduled follow-up visit.  Cardiovascular 
medications include anticoagulants, antiplatelet agents, ACE inhibitors, angiotensin II 
receptor blockers or inhibitors, beta blockers, calcium channel blockers, diuretics, digitalis 
preparations, and any medication that may increase the risk of bleeding. 
12.10 Clinical Laboratory Tests 
Blood laboratory analyses must be done at baseline and each scheduled follow-up visit.  
Assessments include: NT-proBNP, plasma free hemoglobin, serum creatinine, and 
International Normalized Ratio (INR). Creatinine kinase-MB (CK-MB) and/or Troponin (Type 
I or T) should also be collected according to standard of care at the clinical site. Additionally, 
serum creatinine, INR, CK-MB/Troponin must be assessed at pre-discharge. 

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12.11 Electrocardiogram  
A 12-lead ECG must be recorded at baseline, intraoperatively both before and after implant 
and at pre-discharge.  
12.12 Adverse Events 
All adverse events (AEs) that occur to any subject during study participation must be 
documented on an AE case report form (CRF).  Refer to Section 0 below for further reporting 
requirements.   
12.13 Vigilance Officer 
The following Vigilance Officer should be contacted in regard to serious adverse events by all 
activated centers in the study. 
Vigilance Officer 
Tendyne Holdings, Inc.  
A subsidiary of Abbott Vascular Inc. 
177 County Road B East 
St. Paul, Minnesota, 55117 
USA 
 
Vigilance Officer: 
Allison Genereau 
Sr. Safety Specialist 
6820 Wedgwood Rd 
Maple Grove, MN 55369 
Tel: +1 651-756-5436 
E-mail: CS03safety@abbott.com 
 
 
 

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13 Implant Procedure 
13.1 Requirements 
The implant should be performed by the procedural heart team (See Section 10.1).  The 
cardiac surgeon should be the primary operator.  
The following equipment is required for implantation: 
• 
Standard cardiac catheterization lab equipment 
• 
Fluoroscopy equipment appropriate for use in cardiac interventions 
• 
Transesophageal echocardiographic equipment 
• 
Angiographic equipment 
For backup purposes, the following are needed: 
• 
Circulatory support 
• 
Temporary pacing equipment 
• 
Defibrillator 
 
13.2 Preparation 
The Tendyne Mitral Valve implant procedure is to be performed without cardiopulmonary 
bypass, however, it must be available for backup support if needed. 
Prepare the subject for the implant procedure as follows: 
• 
Administer general anesthesia. 
• 
Attach a 12-lead ECG (if not obtained immediately prior). 
• 
Prepare the subject for a left mini-thoracotomy. 
• 
Prepare the subject for TEE. 
• 
Prepare the subject for right- and left-heart catheterization. 
The subject must be on anticoagulant typical for transcatheter therapeutic interventions.  
Activated clotting time (ACT) is to be maintained at >250 seconds for the duration of the 
procedure. 
 
13.3 Initial Data Acquisition 
Tendyne will provide specific instruction on intraoperative imaging and data acquisition 
requirements as part of investigator training.  A brief overview is provided here. 
Using cardiac catheters, obtain the required measurements, including the following: 
• 
Cardiac output using thermodilution method 

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• 
Intracardiac and vascular pressures 
Perform the intraoperative TEE protocol to obtain views and measurements pertaining to the 
mitral valve and left ventricular function.  
13.4 Implant Procedure 
An overview of the recommended Tendyne Mitral Valve implant procedure is provided here.  
Refer to the Instructions for Use for additional detail.   
13.4.1 Valve Placement 
1. Ensure that all components are fully de-aired to avoid introducing air emboli into 
the heart, and continue to flush them with isotonic saline throughout the procedure. 
2. Thoroughly rinse the valve with heparinized isotonic saline. 
3. Compress and load the valve into the instrument, ensuring that the proud anterior 
segment is properly aligned with the corresponding marker on the instrument. 
4. Determine the proper trajectory from the patient’s left ventricular apex to the mitral 
valve.  Puncture the apex and insert a standard .035” guidewire. 
5. Ensure a path clear of entanglement in the chordae. 
6. Advance the instrument over the guidewire to achieve access to the left ventricle.  
Further advance it across the mitral valve and into the left atrium.   
7. Deploy the valve, while observing the deployment using echo and/or fluoroscopic 
imaging.   
8. Pull the valve proximally into the mitral annulus ensuring that the proud anterior 
cuff is oriented toward the aortic-mitral continuity. 
9. Using echo and/or fluoroscopic imaging, confirm that the valve is oriented correctly. 
a) If the valve needs to be repositioned, use the instrument to partially recapture the 
valve, push it up into the left atrium, reorient, and pull it back into position. 
b) If the valve is the wrong size or otherwise needs to be withdrawn, use the 
instrument to fully recapture the valve and pull it out through the apical access.  If 
desired, an alternative valve can be deployed. 
10. Once proper orientation has been confirmed, adjust tension using the apical pad tool 
to attain proper seating of the valve for mechanical stability and optimal 
paravalvular sealing. 
11. Once stability is achieved and valve function is determined to be acceptable, remove 
the instrument and fasten the apical pad to the tether.   
13.4.2 Valve Verification 
1. Monitor the function of the implanted valve with periodic TEE. 
2. Measure the cardiac output and cardiac index. 
3. Measure transmitral pressure gradient (mean and peak). 
4. Measure aortic and right arterial (RA) pressures. 
5. Optionally perform a left ventriculogram. 

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6. Perform an ECG. 
7. Trim the tether proximal to the apical pad. 
8. Close the surgical incision in the usual manner. 
 
13.5 Post-Operative Care  
In the immediate post-operative period, the subject’s blood pressure is to be closely 
monitored and maintained below 135 mmHg systolic if possible.   
Subjects are required to be on anticoagulation therapy, warfarin with a target INR range of 
2.5 to 3.5, for a minimum of three months.  Antiplatelet therapy may also be administered 
during this timeframe.  Thereafter, subjects should be on aspirin alone or in combination with 
anticoagulation therapy.  
 
 

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14 Follow-up Visits 
14.1  Pre-Discharge 
Pre-discharge data collection is to be done within 24 hours prior to discharge (or, in the event 
of prolonged hospitalization, within 10 days after the implant procedure).  Pre-discharge 
requirements include clinical status, medications, an ECG, and documentation of any peri-
operative AEs.  It is recommended that serum creatinine be assessed at approximately 48 
hours post implant.   
An Implant card will be delivered to the patient when required by National regulation per 
specific Tendyne instructions for implant card distribution and completion, as applicable. 
14.2 Scheduled Follow-up Visits 
Follow-up data must be documented using the appropriate eCRFs and image data must be 
submitted in electronic format.   
Follow-up visits must occur at the following time points following implantation: 
 
Pre-discharge  Within 24 hours prior to discharge or up to 10 days post-procedure, 
whichever occurs first 
 
One month  
28 - 40 days 
 
Three months  90 ± 14 days 
 
Six months  
180 ± 30 days 
 
One year  
365 ± 45 days 
 
Two years  
730 ± 60 days  
 
Annually thereafter until 5 years. 
Subjects who have any part of the Tendyne Mitral Valve System introduced into the body but 
who do not end up with an implanted Tendyne Mitral Valve only need to be followed through 
one month or until resolution of any procedure or device related adverse event and then 
exited from the study.  Subjects who are not exposed to the Tendyne Mitral Valve System will 
be exited from the study immediately.  Documentation for subjects exited from the study 
must be completed using the appropriate CRF. 
14.3 Study Exit 
After the 2-year study visit, subjects should be followed annually until study completion and 
closure.  Consistent with ongoing, interim communication with each patient’s community 
care physician/cardiologist, upon study completion, each patient will be returned to the full 
care of such patient-identified physicians. The clinical study team shall remain available to 
each patient’s community care physician in the event of any specific follow-up evaluations 
and consultations. 

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14.4 Unscheduled Follow-Up Visits 
If a subject presents for an unscheduled visit due to an AE that is serious (SAE) and/or device- 
or procedure-related, the following are required: clinical status; medication changes; and 
documentation of the AE using the appropriate eCRFs.   
14.5 Lost to Follow-Up 
If a subject fails to comply with follow-up schedule, the site must make repeated attempts (at 
least three) to contact the patient.  If a patient cannot be contacted anymore, the investigator 
should contact a third person (normally the patient's general practitioner) to get information 
about the patients' health. The permission and the contact details are stated in the Informed 
Consent form of the subject. Each attempt and the method used (e.g., telephone) must be 
documented in the patient’s records.  A subject who is lost to further follow-up must be 
reported to the sponsor using the appropriate eCRF. 
14.6 Withdrawals 
A subject may voluntarily withdraw from the study at any time.  A subject may also be 
withdrawn from the study at the discretion of the investigator.  In the event of withdrawal 
from the study, the investigator must ensure that the reason for the withdrawal is 
documented.  If the subject had an AE, the subject must be followed until it is resolved, if 
possible, or until the investigator determines that the condition is stable.  Withdrawn subjects 
will not be replaced. 
All withdrawals must be reported to the sponsor using the appropriate eCRF. 
 
 

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15 Reinterventions and Explants 
In the event that a subsequent procedure related to the Tendyne Mitral Valve is required at 
any time during a subject’s study participation, the physician should obtain image data and 
otherwise attempt to characterize the valve in situ, to the extent feasible. 
If an open-chest procedure is performed, then photographs should be taken.  Photographs 
should be taken of the valve and/or native tissues before and after any modification or 
explant is done.  The sponsor is particularly interested in understanding host response to the 
implanted valve (tissue ingrowth) and other device-host interfaces such as potential damage 
to native tissues including native leaflets, subvalvular structures and myocardium.   
If a valve is explanted, the valve should immediately be placed in 10% neutral buffered 
formalin and returned to the sponsor for analysis.  The valve must be handled carefully and 
as little as possible to prevent damage and preserve its integrity.  The sponsor must be 
contacted for shipping and packaging materials and to arrange for transport. 
All relevant data pertaining to the reintervention or explant must be documented on the 
appropriate eCRF.  The physician should dictate an operative report and submit it to the 
sponsor along with any image data and photographs. 
16 Heart Transplants or Subject Death 
In the event of subject death or heart transplant, histological and engineering analyses of the 
in situ valve would provide valuable information.  Therefore, a supplemental consent form 
may be used to authorize explant and donation of the heart to the sponsor.  The sponsor must 
be contacted for shipping and packaging materials and to arrange for transport. 
 
 

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17 Data Management 
17.1 Subject Identification 
Each subject will be assigned a unique identification code (ID) for the purpose of identity 
protection.  Any subject names that may inadvertently appear on study documents submitted 
to the sponsor will be redacted upon receipt. 
17.2 Central Database 
All study documentation will be collected and compiled in a central database.  Appropriate 
quality control measures will be established to ensure accurate and complete transfer of 
information from the study documentation to the central database. 
17.3 Electronic Case Report Forms (eCRF) 
Electronic case report forms are designed to capture study data.  The investigator is 
responsible for completing all appropriate sections of the eCRFs and submitting them to the 
sponsor in a timely manner.  The investigator is also responsible for responding to queries 
(e.g., data clarification forms) from the sponsor to clarify any pending questions about the 
data. 
17.4 Protocol Deviations 
The investigator must document any deviation to this protocol using the appropriate eCRF.  
Study monitoring will include review for protocol deviations.  Under emergency 
circumstances, deviations from the Study Protocol to protect the rights, safety and well-being 
of human subjects may proceed without prior approval of the sponsor and the EC. Such 
deviations shall be documented and reported to the sponsor and the EC as soon as possible. 
An investigator must notify the sponsor and the reviewing institutional review board/ethics 
committee as soon as possible of any deviation from this protocol that was done to protect 
the life or physical well-being of a subject. 
17.5 Centre Noncompliance 
Protocol deviations will be closely monitored.  If unacceptable deviations, repeated 
deviations, or other compliance problems are noted, the sponsor reserves the right to 
suspend study enrollment at that site until a sufficient system is in place to reduce further 
deviations and ensure compliance. 
17.6 Data Processing and Management 
Data will be reviewed manually and electronically for accuracy and completeness.  Standard 
checks such as range checks will be incorporated into the central database.  Data clarification 
Forms (DCFs) will be issued to resolve data discrepancies.  Study monitoring will be 
conducted to ensure that the site is submitting complete and accurate data, and to verify 
source data. 

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17.7 Confidentiality and Protection of Study Files 
All information and data concerning subjects and their participation in this study will be 
considered confidential.  Only authorized personnel will have access to confidential files.  
Passwords will be issued for sponsor personnel to ensure confidentiality and protection of 
electronic data.  Hard copy data will be stored in a locked file.  No data will show subject 
names. 
When required by law, consistent with the specifications of Annex VII of Council Directive 
93/42/EEC, patient identification information, patient consent, individual patient clinical 
course documentation, as well as documentation of regulatory compliance with clinical study 
legal requirements shall be retained by the investigational site for a minimum period of 15 
years (implantable medical devices).  Original clinical data documentation provided for study 
analysis, as well as such documentation of regulatory conformance with legal requirements 
shall be retained by the study sponsor for a period of 15 years. The secure retention of site 
copies of clinical data documentation provided for study analysis may be delegated for 
appropriate third party storage in collaboration between sponsor and investigational site. 
17.8 Monitoring 
The sponsor will be responsible for monitoring at each site to ensure adequate protection of 
the rights and safety of study subject, and to verify the quality and integrity of the data 
collected and submitted.  The sponsor will identify and train qualified personnel to conduct 
monitoring visits.  Monitoring will consist of review of subject records, source documents, 
and other required documentation, including institutional review board/ethics committee 
approvals and correspondence.   
Monitors will conduct site visits to ensure accuracy of data, timeliness of data submission, 
adequate patient enrollment, compliance with applicable laws and regulations, compliance 
with this protocol, compliance with the signed investigator agreement, and compliance with 
institutional review board/ethics committee conditions and guidelines.  Any noncompliance 
with these items that is not adequately addressed by the investigator is cause for the sponsor 
to put the investigator on probation or withdraw the investigator or site from the study.   
The site staff must be available to meet with the monitor or other sponsor representative 
during monitoring visits.  The investigator must allow monitoring by the sponsor and its 
authorized representatives and any other local governmental body to review the study 
subjects’ medical records, including any test or laboratory data. 
Frequency of monitoring will be based on enrollment, study duration, site compliance, and 
any suspected inconsistency in data that requires investigation. 
 
 

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18 Adverse Event Reporting 
An adverse event (AE) is defined as any untoward medical occurrence in a study subject, 
which does not necessarily have to have a causal relationship with study treatment.  An AE 
can be an unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease, temporary or permanent, whether or not related to the prosthetic valve 
implantation or procedure.  Refer to 22 for further AE definitions. 
Reportable AEs are any that occur from the time a subject becomes enrolled through the 
subject’s exit from the study.  Any AE that occurs to any subject during the study must be 
documented on an AE electronic case report form.  Information collected includes: date of 
onset of first observation; description of the event; seriousness; causal relationship to the 
device; causal relationship to the procedure; treatment required; and outcome or status of 
the event. 
Serious Adverse Events (SAE) require reporting without delay to the Competent Authorities. 
In such cases, the investigator will inform the Sponsor immediately, but not later than 3 
calendar days after learning of the event and shall provide the required documentation to the 
Sponsor for assessment and regulatory reporting without delay. 
Pre-existing conditions must be documented so that related AEs can be correctly reported.  
An event that is a continuation of an unresolved AE must be reported as ongoing, not as a new 
AE.  Worsening of a pre-existing condition must be reported.  Complications and 
hospitalizations must also be reported. 
The sponsor and principal investigators must comply with all reporting requirements of the 
ethics committees and applicable laws and regulations. 
18.1 Adverse Event (AE) Review and Classification 
All AEs will be reviewed and classified by a Clinical Events Committee (CEC).  In addition, a 
Data and Safety Monitoring Board (DSMB) may review AE data as it relates to their role.  Refer 
to Sections 19.5 and 19.6 for more information. 
 
 

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18.2 Anticipated AEs 
Anticipated AEs are those that may be reasonably expected to occur in association with a 
surgical or transcatheter valve procedure.  Anticipated AEs include, but are not limited to, 
those listed here; those reported in the risk analysis report; those reported in the IFU; and 
those reported in the literature associated with valve procedures: 
 
Adverse foreign body response 
 
Adverse reaction to anesthesia 
 
Allergic reaction  
 
Anemia 
 
Annular dissection 
 
Aortic insufficiency  
 
Atrial or ventricular injury  
 
Bioprosthetic valve dysfunction  
 
Bleeding complications 
 
Blood loss which may require transfusion 
 
Cardiac arrest 
 
Cardiac perforation 
 
Conduction defect with or without need for 
pacemaker 
 
Cardiac arrhythmia, Atrial or Ventricular 
 
Damage to cardiac tissue and/or structures 
 
Death 
 
Decreased LV function and/or cardiac output 
 
Device embolism 
 
Device erosion, migration or malposition 
 
Device thrombosis 
 
Embolism (device, air, blood clot, tissue, etc.) 
 
Endocarditis 
 
Esophageal irritation, stricture or perforation 
 
Foreign Body Response 
 
Fever 
 
Heart Failure, new or worsening 
 
Hematoma 
 
Hemolysis 
 
Hypotension 
 
Infection / Sepsis 
 
Liver failure 
 
Mitral valve injury 
 
Mitral valve prolapse / stenosis 
 
Myocardial infarction 
 
Obstruction 
 
Pain 
 
Pleural effusion 
 
Pulmonary embolism 
 
Pulmonary hypertension 
 
Paravalvular leak 
 
Pericardial effusion / tamponade 
 
Renal insufficiency or failure 
 
Respiratory difficulty, insufficiency or 
failure 
 
Stroke or transient ischemic attack 
 
Tear or damage to device  
 
Vascular and access-related 
complications 
 
Worsening of mitral regurgitation  
 
18.3 Relationship of AEs to the Device or Procedure 
The investigator must specify whether an AE has a causal relationship to either the device or 
the implant procedure.   
The Clinical Events Committee will have final classifications.  In addition to categorizing the 
causal relationship, the probability will also be specified as definitely, possibly, or not related 
to the device or procedure by the Clinical Events Committee.   
Refer to 22 for AE definitions. 
18.4 Seriousness of AEs 
The investigator must categorize each AE as either serious (SAE) or non-serious, according 
to the definition in 22.  Final classifications will be made by the CEC.   

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18.5 Device Deficiencies 
All failures and malfunctions of the investigational device must be documented and 
communicated to the sponsor as soon as possible, preferably within 24 hours of knowledge 
of the event.  If a failed or malfunctioning Tendyne Mitral Valve is explanted, it should be 
returned to the sponsor as biohazardous material without re-sterilization and reuse.  
Procedures for returning explanted devices are detailed in Section 15.  All other device 
deficiencies should be reported to the sponsor on the appropriate eCRF as technical 
observations.   
19 Responsibilities 
This study will be performed in conformance with this protocol and all applicable laws and 
regulations. 
19.1 Investigator Responsibilities 
The investigator is responsible for ensuring the study is conducted according to all signed 
agreements, this protocol, the reviewing ethics committee, and all applicable laws and 
regulations.  Investigator responsibilities include, but are not limited to, the following: 
 
Assume responsibility for proper conduct of the clinical study. 
 
Disclose potential conflicts of interest, including financial, that may interfere with the 
conduct of the study or interpretation of results, and promptly update this 
information if any relevant changes occur during the course of the study. 
 
Submit this protocol and the sponsor-approved informed consent form (ICF) to the 
reviewing ethics committee, and obtain written approval before beginning study 
participation. 
 
Fulfill any conditions of approval imposed by the institutional review board/ethics 
committee, such as regular reporting. 
 
Provide the sponsor with copies of approvals and reports. 
 
Comply with the informed consent procedures, using the approved ICF. 
 
Ensure that the investigational device is used solely by authorized users for purposes 
of conducting the study in accordance with this protocol and the IFU. 
 
Maintain accurate, complete, and current records relating to the conduct of the study. 
 
Report study data and any protocol deviations to the sponsor promptly. 
 
Report adverse events, device deficiencies and device malfunctions to the sponsor 
(and to the institutional review board/ethics committee as required) promptly. 
 
Make available, at the sponsor’s request, all study-related data (including source 
documentation) and study-related documentation (including institutional review 
board/ethics committee approvals and correspondence) for monitoring or auditing 
purposes. 
 

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19.2 Sponsor Responsibilities 
Tendyne is the sponsor of this study.  Sponsor responsibilities include, but are not limited to, 
the following: 
 
Select and qualify investigative sites and principal investigators. 
 
Provide training to investigators and investigative site staff. 
 
Ensure approval/permission from regulatory body as required by geography. 
 
Select qualified monitors and ensure that adequate monitoring of clinical data occurs 
at the investigative sites.  
 
Retain ownership of all data generated in this study, and control the use of the data 
for appropriate purposes only.   
 
Collaborate with investigators on publishing study results. 
19.3 Echocardiography Core Laboratory 
The sponsor will contract with an echocardiography core lab to manage and evaluate the 
echocardiogram studies.  Interpretation of echocardiograms will be done by experienced 
personnel with appropriate expertise.  The echocardiography core lab will provide 
independent analysis of echocardiogram images and will maintain a database in accordance 
with their established standard operating procedures.  The data will then be transferred to 
and reported by the sponsor. 
 
Boston/USA Echocardiography Core Lab 
Beth Israel Deaconess Medical Center, 
375 Longwood Ave, 3rd Floor, Boston, MA 02215, USA 
Michael Chaung 
mchuang@bidmc.harvard.edu 
 
19.4 Computed Tomography Core Laboratory 
The sponsor will contract with a computed tomography core lab to manage and evaluate the 
tomographic studies.  Interpretation of tomographic images will be done by experienced 
personnel with appropriate expertise.   The computed tomography core lab will provide 
independent analysis of computed tomography images and will maintain a database in 
accordance with their established standard operating procedures.  The data will then be 
transferred to and reported by the sponsor. 
 
SPH/UBC Cardiac CT Core Lab 
University of British Columbia, 6190 Agronomy Rd, 
Vancouver, British Columbia, V6T 1Z3, Canada 
Department of Radiology ‐ St. Paul’s Hospital 
Dr. Jonathon Leipsic: jleipsic@providencehealth.bc.ca 
Dr. Philipp Blanke: phil.blanke@gmail.com 
 
It is a responsibility of the Core Laboratories to evaluate whether a subject is suitable for 
treatment with the Tendyne Mitral Valve and select the most suitable valve model and size 

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based on the imaging evaluation of the individual’s mitral valve by multiple modalities 
including echocardiography and computed tomography.  The anatomy of the mitral valve is 
complex and highly variable between subjects. For this reason, it is not possible to determine 
generic criteria applicable to all subjects, and an in-depth evaluation must be performed in 
every single candidate by the Echo and CT Core Labs using dedicated software programs. 
Mitral valve modeling is performed with the aid of special software:  Circle cardiovascular 
imaging software, www.circlecvi.com as recently published by the core lab;98 and Mimics 
(biomedical.materialise.com/mimics) for medical image segmentation and engineering on 
anatomy. The anatomical suitability is documented in each subject, see example in the IB 
(Appendix 2, Pre-procedural plan example). 
19.5 Clinical Events Committee (CEC) 
An independent Clinical Events Committee (CEC) will be established.  The CEC will consist of 
clinicians who are not investigators in the study and who do not have any significant 
investment in the sponsor or its competition.  At least three clinicians will serve on the CEC. 
The CEC will be responsible for reviewing and classifying all serious adverse events, device-
related adverse events, and deaths.  Refer to 22 for AE definitions.    
The CEC will meet periodically throughout the study.  CEC operations will be determined 
early in the study and formalized in a CEC charter. 
19.6 Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will be established.  Members will 
not have any significant investment in the sponsor or its competition.  The DSMB will consist 
of one statistician and at least two physicians.   
The role of the DSMB will be to monitor the overall conduct of the study, the rights, safety, 
and welfare of the study participants, and to evaluate interim data to determine if there are 
any specific safety concerns.  The DSMB will be responsible for communicating any safety or 
scientific concerns or perceived problems with the study to the sponsor as soon as possible.  
At the conclusion of each DSMB meeting, a recommendation will be made to the sponsor on 
whether to continue, suspend, modify, or stop the study. 
The DSMB will meet periodically throughout the study.  DSMB operations will be determined 
early in the study and formalized in a DSMB charter.  DSMB activities and members may 
overlap with the CEC as appropriate. 
19.7 Publications Committee 
The sponsor may form a publications committee to make decisions regarding authorship and 
content of publications.  The publications committee’s mission would be to construct a plan 
for topics and journals to target.  Any investigator intending to publish should inform the 
sponsor and attempt to collaborate.   
 
 

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20 Device Accountability 
The investigator or delegate must maintain a log to document the status/location of each 
investigational device provided by the sponsor for use in the study.  The log will include the 
following as applicable:  date of receipt, lot number, subject ID, disposition, reason, quantity 
and date of return to sponsor.  Devices allocated to a site must be stored in a secured area 
until used.  All explanted devices must be returned to the sponsor.   
Procedures for returning explanted devices are provided in Section 15.  At study closeout, the 
sponsor will collect all unused devices. 
21 Study Closure 
21.1 Suspension or Early Termination  
The entire study or any individual site may be suspended or terminated prematurely by the 
sponsor based on recommendation from the DSMB or if otherwise deemed necessary.  In the 
event of suspension or early termination, the sponsor will promptly inform principal 
investigators and ensure that institutional review boards/ethics committees are notified of 
the stoppage and the reason for it in line with Medical Device Directive 93/42/EEC Article 
15.7 and national regulations.  Subjects must continue to be followed per the protocol unless 
there is other direction from the sponsor. 
21.2 Routine Closeout 
At the end of the study, routine closeout activities will be conducted to ensure site records 
are complete, study data are complete and accurate, remaining study materials and 
investigational devices are returned to the sponsor, arrangements are made for record 
retention, and institutional review boards/ethics committees are notified.  
 
 

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22 Appendix A 
 
Normative References 
 
ISO 14155  
 ISO 14155:2011(E). Clinical investigation of medical devices for human 
subjects — Good clinical practice. 
 
ISO 5840-3  ISO 5840-3:2013(E). Cardiovascular implants — Cardiac valve prostheses — 
Part 3: Heart valve substitutes implanted by transcatheter techniques. 
 
 
Adverse Device Effect (from ISO 14155) 
Adverse event related to the use of an investigational medical device. 
 
Adverse Event  
Events that fall under the definition of Adverse Event from either ISO 14155 or ISO 5840-3: 
(from ISO 14155)  Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
Note 1 This definition includes events related to the investigational medical device 
or the comparator. 
Note 2 This definition includes events related to the procedures involved. 
Note 3 For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
 
(from ISO 5840-3)  Untoward medical occurrence in a study subject, which does not 
necessarily have to have a causal relationship with study treatment. 
 
Bleeding (from BARC) 
Six types are hierarchically defined from type 0 in which there is no bleeding to type 5 with 
fatal bleeding. Type 1 is in which the patient does not seek treatment. Type 2 is in which 
intervention or admission to hospital occurs. Type 3a is overt bleeding plus hemoglobin drop 
of 3 to less than 5 g/dl or transfusion. Type 3b is overt bleeding plus hemoglobin drop of at 
least 5 g/dl, cardiac tamponade, bleeding requiring surgical intervention or intravenous 
vasoactive agents. Type 3c is intracranial hemorrhage or intraocular bleeding compromising 
vision. Type 4 is coronary artery bypass grafting-related bleeding and type 5 is fatal bleeding. 
 
Body Surface Area (from ISO 5840-3) 
Total surface area (m2) of the human body.  NOTE:  This can be calculated (Mosteller’s 
formula) as the square root of product of the weight in kg times the height in cm divided by 
3600. 
 
Cardiac Index (from ISO 5840-3) 
Cardiac output divided by the body surface area in units L/min/m2. 

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Cardiovascular Death (from VARC II) 
Any 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 events 
• 
Sudden or unwitnessed death 
• 
Death of unknown cause 
Non-cardiovascular death is any death in which the primary cause of death is clearly related 
to another condition (e.g., trauma, cancer, suicide). 
 
Causal Relationship (from ISO 5840-3) 
Causal relationship is the relationship of the AE to the study device, the implant procedure or 
the patient’s condition.  It should be established in line with the following categories: 
• 
Device-related:  Any AE involving the function of the device, or the presence of the 
device in the body.  Included in this category are events that are directly attributed to 
the device. 
• 
Procedure-related:  Any AE that results from the implant procedure.  Events in this 
category are directly related to the general procedural sequelae. 
• 
Patient condition-related:  Any AE that results from the worsening of a pre-existing 
condition or cannot be attributed to the device procedure. 
• 
Unknown:  Any AE that cannot be assigned to any of the above three conditions. 
 
Chronic Kidney Disease, Stages (from National Institute for Health & Clinical Excellence.  
Clinical Guideline 73: Chronic Kidney Disease, London 2008) 
• 
Stage 1:  Slightly diminished function; kidney damage with normal or relatively high 
GFR (≥90 mL/min/1.73 m2). Kidney damage is defined as pathological abnormalities 
or markers of damage, including abnormalities in blood or urine test or imaging 
studies. 
• 
Stage 2:  Mild reduction in GFR (60–89 mL/min/1.73 m2) with kidney damage. 
Kidney damage is defined as pathological abnormalities or markers of damage, 
including abnormalities in blood or urine test or imaging studies. 
• 
Stage 3:  Moderate reduction in GFR (30–59 mL/min/1.73 m2). British guidelines 
distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of 
screening and referral. 
• 
Stage 4:  Severe reduction in GFR (15–29 mL/min/1.73 m2) Preparation for renal 
replacement therapy. 

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• 
Stage 5:  Established kidney failure (GFR <15 mL/min/1.73 m2), permanent renal 
replacement therapy, or end stage renal disease. 
 
Cycle (from ISO 5840-3) 
One complete sequence in the action of a heart valve substitute under pulsatile flow 
conditions. 
 
Contract Research Organization (from ISO 14155) 
Person or organization contracted by the sponsor to perform one or more of the sponsor’s 
clinical investigation-related duties and functions. 
 
Data Monitoring Committee/Data and Safety Monitoring Board (from ISO 14155) 
Independent committee that may be established by the sponsor to assess, at intervals, the 
progress of the clinical investigation, the safety data or the critical performance endpoints 
and to recommend the sponsor whether to continue, suspend, modify, or stop the clinical 
investigation. 
 
Device Deficiency (from ISO 14155) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance.  NOTE:  Device deficiencies include malfunctions, use errors, and 
inadequate labeling. 
 
Device Embolization (from ISO 5840-3) 
Dislodgment from the intended and documented original position to an unintended and non-
therapeutic location. 
 
Device Failure (from ISO 14155 and ISO 5840-3) 
Inability of a device to perform its intended function sufficient to cause a hazard. 
 
Device Migration (from ISO 5840-3) 
Detectable movement or displacement of the device from its original position within the 
implant site, without embolization. 
 
Ethics Committee (from ISO 14155) 
Independent body whose responsibility it is to review clinical investigations in order to 
protect the rights, safety, and well-being of human subjects participating in a clinical 
investigation.  NOTE:  “Ethics Committee” is synonymous with “research ethics committee”, 
“independent ethics committee” or “institutional review board”.  The regulatory 
requirements pertaining to ethics committees or similar institutions vary by country or 
region. 
 
Follow-up (from ISO 5840-3) 
Continued assessment of patients who have received the heart valve substitute. 

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Heart Valve Substitute (from ISO 5840-3) 
Device used to replace the function of a natural valve of the heart. 
 
Implant Site (from ISO 5840-3) 
Intended site of transcatheter heart valve substitute deployment. 
 
Informed Consent Process (from ISO 14155) 
Process by which an individual is provided information and is asked to voluntarily participate 
in a clinical investigation.  NOTE:  Informed consent is documented by means of a written, 
signed and dated informed consent form. 
 
Intended Use (from ISO 5840-3) 
Use of a product, process or service in accordance with the specifications, instructions and 
information provided by the manufacturer. 
 
Investigation Site/Investigational Site (from ISO 14155) 
Institution or site where the clinical investigation is carried out.  NOTE:  “Investigation site” 
is synonymous with “investigation centre”. 
 
Investigational Device/Investigational Medical Device (from ISO 14155) 
Medical device being assessed for safety or performance in a clinical investigation. 
 
Investigator (from ISO 14155) 
Individual member of the investigation site team designated and supervised the principal 
investigator at an investigation site to perform critical clinical-investigation-related 
procedures or to make important clinical-investigation-related decisions.  NOTE:  An 
individual member of the investigation site team can also be called “sub-investigator” or “co-
investigator”. 
 
Legally Authorized Representative (from ISO 14155) 
Individual or judicial or other body authorized under applicable law to consent, on behalf of 
a prospective subject, to the subject’s participation in the clinical investigation. 
 
Malfunction (from ISO 14155) 
Failure of an investigational medical device to perform in accordance with its intended 
purpose when used in accordance with the instructions for use or clinical study protocol. 
 
Myocardial Infarction, Peri-procedural (from VARC II) 
Peri-procedural is ≤72 hours 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 

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contiguous leads, imaging evidence of new loss of viable myocardium or new wall 
motion abnormality) AND 
• 
Elevated cardiac biomarkers (preferable CK-MB) within 72 hours after the index 
procedure, consisting of at least one sample post-procedure with a peak value 
exceeding 15 x as the upper reference limit for troponin or 5 x 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. 
 
Myocardial Infarction, Spontaneous (from VARC II) 
Spontaneous is prior to or >72 hours 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 the 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 a new loss of viable myocardium or new wall motion 
abnormality 
o Sudden, unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by 
presumable new ST 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. 
o Pathological findings of an acute myocardial infarction. 
 
Non-Structural Valve Dysfunction (from ISO 5840-3) 
Abnormality extrinsic to the transcatheter heart valve substitute that results in valve 
dysfunction (stenosis, regurgitation, or both). 
 
Principal Investigator (from ISO 14155) 
Qualified person responsible for conducting the clinical investigation at an investigation site.  
NOTE:  If a clinical investigation is conducted by a team of individuals at an investigation site, 
the principal investigator is responsible for leading the team. 
 
Protocol Deviation 
Instance of failure to follow, intentionally or unintentionally, the requirements of the clinical 
study protocol. 
 
Regurgitant Fraction (from ISO 5840-3) 
Regurgitant volume expressed as a percentage of the forward flow volume. 

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Repositioning (from ISO 5840-3) 
Change in implant position of a partially or fully deployed transcatheter heart valve 
substitute via a transcatheter technique, possibly requiring full or partial recapturing of the 
device. 
 
Retrieval (from ISO 5840-3) 
Removal of a partially or fully deployed transcatheter heart valve substitute via a 
transcatheter technique. 
 
Serious Adverse Device Effect (SADE) (from ISO 14155) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. 
 
Serious Adverse Event (from ISO 14155) 
Adverse event that 
a) Led to death, 
b) Led to serious deterioration in the health of the subject, that either resulted in 
1) A life-threatening illness or injury, or 
2) A permanent impairment of a body structure or a body function, or 
3) In-patient or prolonged hospitalization, or 
4) Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE:  Planned hospitalization for a pre-existing condition, or a procedure required by the 
study protocol, without serious deterioration in health, is not considered a serious adverse 
event. 
 
Severity (from ISO 5840-3) 
Measure of the possible consequences of a hazard. 
 
Source Data (from ISO 14155) 
All information in original records, certified copies of original records of clinical findings, 
observations, or other activities in a clinical investigation, necessary for the reconstruction 
and evaluation of the clinical investigation. 
 
Source Document (from ISO 14155) 
Printed, optical, or electronic document containing source data. 
 
Stroke and TIA (from VARC II) 
Diagnostic criteria: 

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• 
Acute episode of a focal or global neurological deficit with at least one of the following:  
change in the level of consciousness, hemiplegia, hemiparesis, numbness, or sensory 
loss affecting one side of the body, dysphasia or aphasia, hemianopia, amaurosis 
fugax, or other neurological signs or symptoms consistent with stroke. 
• 
Stroke:  Duration of a focal or global neurological deficit ≥24 hours; OR <24 hours 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 <24 hours, 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, hypoglycemia, peripheral lesion, pharmacological 
influences), to be determined by or in conjunction with the designated neurologist. 
• 
Confirmation of the diagnosis by 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. 
• 
Disabling Stroke:  A modified Rankin Scale (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. 
 
Stroke Classification 
A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or hemorrhagic. 
• 
Ischemic:  An acute episode of focal cerebral, spinal, or retinal dysfunction caused by 
infarction of the central nervous system tissue. 
• 
Hemorrhagic:  An acute episode of focal or global cerebral or spinal dysfunction 
caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
 
Structural Valve Dysfunction (from ISO 5840-3) 
Structural abnormality intrinsic to the transcatheter heart valve substitute that results in 
valve dysfunction (stenosis and/or transvalvular and/or paravalvular regurgitation) 
 
Subject (from ISO 14155) 
Individual who participates in a clinical investigation. 
 
Usability (from ISO 5840-3) 
Characteristic of the user interface that established effectiveness, efficiency, ease of user 
learning and user satisfaction. 
 
Unanticipated Serious Adverse Device Effect (USADE) (from ISO 14155) 
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. 

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Use Error (ISO 14155) 
Act or omission of an act that results in a different medical device response than intended by 
the manufacturer or expected by the user. 
 
 
 

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23  Appendix B, Statistical Methodologies 
23.1 Scope of Analysis 
This addendum integrates the analysis plan described in protocol Section 8. The analysis 
presented in this Addendum, will be applied to data from all patients enrolled in the study 
and suitable to be implanted with the Tendyne 1.0 valve and Tendyne LP value in Europe and 
worldwide.  
23.2 Purpose 
The data gathered in this study will be used to support conformity requirements for CE Mark 
of the Tendyne Mitral Valve using an appropriately powered sample size as described in 
Section 1 to enable assessment of the 30-day safety and performance endpoints of the 
Tendyne Mitral Valve System in the intended populations. 
This study will be continued after the CE Mark to include a maximum of 350 patients enrolled 
at a maximum of 40 clinical sites with the purpose to collect broader safety and performance 
data as part of the Tendyne post-market follow-up program. In addition, all patients shall 
continue to be followed through 5 years in the post-market setting, to capture long-term data 
on less common or unanticipated adverse events, on adverse events which are time-related 
(e.g., structural deterioration, adverse effects on native valve anatomy) and on long-term 
performance. 
As enrollment will continue in the post-market phase, subgroup analyses are planned in a 
broader patient group, up to 350 patients, to evaluate the safety and performance profile of 
the Tendyne Mitral Valve in primary and secondary MR, and to analyze and compare data for 
different valve sizes. 
All statistical analyses will be performed using Statistical Analysis System (SAS) for Windows 
(version 9.4, SAS Institute Inc. Cary, NC) or other widely accepted statistical or graphical 
software.   
23.3  Hypotheses (HO, HA) for 30-day mortality 
Safety will be evaluated by examining the 30-day mortality in comparison to other MV 
replacement devices using the following hypothesis: 
Ho: P ≥ 20% 
Ha: P < 20%, 
Where P is the proportion of subjects that died within the first 30 days, and the performance 
goal of 20% is based upon an assumption of true mortality of 8% with a non-inferiority 
margin of 12%. 
 

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23.4 Calculation of Sample Size for Mortality  
The estimated mortality of mitral valve replacement at 30 days is expected to be around 7-
9% based upon in-hospital mortality rates from current literature with larger sample size for 
MV replacement devices. We will assume the true mortality at 30 days is in the middle at 
approximately 8%.   
 
Table 5 Estimated Mortality 
 
In-hospital mortality 
 
Reference 
Mitral Valve Replacement 
Mitral Valve Repair 
Thourani et al., 
Circulation. 2003;  
108:298-304 
6.90% 
4.30% 
Vassileva et al., 
Circulation. 2013;  
127: 1870-1876. 
8.90% 
3.90% 
 
Allowing a 12% Non-Inferiority margin and a one-sided alpha of 0.05, a sample size of 57 
subjects will have at least 80% power to test against the mortality performance goal of 20%.  
Calculations performed using PASS 14 (Kaysville, UT, USA).  Allowing up to 15% attrition, up 
to 68 subjects, will be needed for the evaluation of this objective performance criterion. 
23.5  Criteria for Termination  
If the upper 95% exact binomial confidence bound is less than the mortality performance 
goal of 20%, then the trial will be considered a success and the Tendyne Mitral Valve System 
is deemed safe.  Enrollment will continue beyond this endpoint for additional data. 
Additionally, the independent Data Safety Monitoring Board (DSMB) will be monitoring the 
conduct of the trial. The protocol Section 21.1 states that the entire study or any individual 
site may be suspended or terminated prematurely by the sponsor based on recommendation 
from the DSMB or if otherwise deemed necessary. Possible reasons for early study 
termination include the discovery of an unexpected, significant, or unacceptable risk to the 
subjects enrolled in the study. For details, refer to protocol Section 19.6.  
The role of the DSMB is described in the protocol Section 19.6. The DSMB is responsible for 
the study review and to recommend any modification or study termination for any perceived 
safety concern based on clinical judgement, including but not limited to: a higher than 
anticipated rate for any component of the primary safety endpoint; device failures resulting 
in adverse events; or unexpected SAEs. Possible reasons for early study termination include 
the discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study.  
At the conclusion of each DSMB meeting, a recommendation will be made to the sponsor on 
whether to continue, suspend, modify or stop the study. 

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23.6  Analysis Populations  
All subjects with a procedure attempt where the Tendyne Mitral Valve System is introduced 
into the body will be included in the analysis (Intent to Treat). The portion of subjects that 
have died within 30 days of the procedure attempt will be summarized. An analysis will also 
be conducted in the implanted patient population (IPP), which includes subjects leaving the 
operating room with study device implanted. The one-sided 95% exact binomial upper 
confidence bound will be calculated for this 30-day mortality rate.  If this value is less than 
the performance goal of 20%, then we will conclude that the Tendyne Mitral Valve System is 
safe. 
For adverse event reporting, which includes the primary and secondary safety endpoints, the 
primary analysis will be based on subject counts, not event counts.  A subject with more than 
one event will be counted only once toward the event rate based on the total number of 
subjects with adverse events.  An event rate based on event counts will also be presented.   
All CEC adjudicated device, system, and/or procedure related serious AEs will be summarized 
including 95% exact Clopper Pearson confidence interval as the primary endpoint. Unless 
specified otherwise, statistical significance will be declared if the two-sided p-value is < 0.05. 
23.7 Calculation of Sample Size for Safety 
In addition to gathering of long-term performance of the Tendyne Mitral Valve System, 
another goal of this trial is to gather more information on rare adverse events.  While no pass 
or fail endpoint is specified, a certain level of precision can be achieved around rare AEs.  For 
example, for events that occur in 1% of the population, a sample size of 200 subjects will 
provide a 95% confidence interval width of 3.4% around that estimate.  The following table 
calculates the expected confidence interval width for AEs with a 1% incidence rate. 
Table 6 Sample Size, 95% Confidence Interval 
 
Sample Size  
95% Confidence Interval Width 
with 1% Event Rate 
150 
4.1% 
175 
3.7% 
200 
3.4% 
225 
3.2% 
250 
3.0% 
275 
2.8% 
300 
2.7% 
325 
2.6% 
350 
2.5% 
375 
2.4% 
400 
2.3% 

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A sample size of up to 350 subjects may be enrolled to achieve an estimated confidence 
interval width of 2.5% for events occurring in 1% of the population.  The goal is to achieve at 
least a 4% CI width for events occurring in 1% of the populations, and at least 150 subjects 
will be enrolled. 
23.8  Planned Subgroup Analyses 
Sub-group analyses on performance, effectiveness, and safety endpoints are planned. These 
analyses 
will 
include 
certain 
baseline 
demographics, 
disease 
characteristics, 
echocardiography parameters, and procedural characteristics selected by investigators and 
sponsor aimed at a comprehensive understanding of device performance and safety profile. 
23.9  Comparison of Tendyne 1.0 Valve and Tendyne Low Profile (LP) 
Comparisons will be made between the Tendyne 1.0 valve and the low profile valve patient 
populations including age, gender, key medical histories, STS scores, and primary safety 
endpoint at minimum.  It is anticipated that fewer subjects will use the LP valve as the 
screening first assesses fit of the original device so there is not a minimum specified number 
for either device. Kaplan-Meier and Cox proportional hazard models may be used to assess 
impact of model type or other clinically meaningful predictors for analyses of the endpoints 
as applicable. 
23.10  Handling Missing Data 
Primary analyses will consist of all available data evaluated under ITT principles, referred to 
in International Conference on Harmonization module E9 (Statistical Principles for Clinical 
Trials) as the full analysis set. Consequently, data will only be absent from analyses of study 
outcomes in the event that they were not available for collection. 
Tendyne will minimize the incidence of missing data through appropriate management of the 
clinical investigation, proper screening of study participants as well as thorough training of 
investigators, monitors and study coordinators. Every effort must be taken by the 
Investigators and designated site personnel to ensure that all data required on every CRF is 
obtained and recorded. Queries will be sent to investigators, whenever inconsistent or 
missing data occurs, by the study monitor, data management personnel or other Sponsor 
designated personnel. Missing data is documented as “ND” (“Not Determined”) on the CRF. 
In general, missing values in any of the endpoints will not be imputed when summarizing 
these endpoints using descriptive statistics. Patients lost to follow-up will not be excluded 
from further analysis. 
 
 

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24 Appendix C 
References 
 
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2 McCarthy KP, Ring L, Rana BS. Anatomy of the mitral valve: understanding the mitral valve 
complex in mitral regurgitation. Eur J Echocardiogr. 2010;11(10):i3–9. 
doi:10.1093/ejechocard/jeq153. 
3 Chandrashekhar Y, Westaby S, Narula J. Mitral stenosis. Lancet. 2009;374(9697):1271–83. 
doi:10.1016/S0140-6736(09)60994-6. 
4 Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular heart 
disease: The Task Force on the Management of Valvular Heart Disease of the European 
Society of Cardiology. Eur Heart J. 2007;28(2):230–68. doi:10.1093/eurheartj/ehl428. 
5 Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of 
valvular heart diseases: a population-based study. Lancet. 2006;368(9540):1005–11. 
doi:10.1016/S0140-6736(06)69208-8. 
6 Iung B, Baron G, Tornos P, Gohlke-Bärwolf C, Butchart EG, Vahanian A. Valvular heart 
disease in the community: a European experience. Curr Probl Cardiol. 2007;32(11):609–61. 
doi:10.1016/j.cpcardiol.2007.07.002. 
7 Iung B. A prospective survey of patients with valvular heart disease in Europe: The Euro 
Heart Survey on Valvular Heart Disease. Eur Heart J. 2003;24(13):1231–1243. 
doi:10.1016/S0195-668X(03)00201-X. 
8 Iung B, Baron G, Tornos P, Gohlke-Bärwolf C, Butchart EG, Vahanian A. Valvular heart 
disease in the community: a European experience. Curr Probl Cardiol. 2007;32(11):609–61. 
doi:10.1016/j.cpcardiol.2007.07.002. 
9 Carpentier A. Cardiac valve surgery--the “French correction”. J Thorac Cardiovasc Surg. 
1983;86(3):323–37. 
10 Trichon BH, O’Connor CM. Secondary mitral and tricuspid regurgitation accompanying 
left ventricular systolic dysfunction: Is it important, and how is it treated? Am Heart J. 
2002;144(3):373–376. doi:10.1067/mhj.2002.123576. 
11 Avierinos J-F. Natural History of Asymptomatic Mitral Valve Prolapse in the Community. 
Circulation. 2002;106(11):1355–1361. doi:10.1161/01.CIR.0000028933.34260.09. 
12 Bursi F, Enriquez-Sarano M, Nkomo VT, et al. Heart failure and death after myocardial 
infarction in the community: the emerging role of mitral regurgitation. Circulation. 
2005;111(3):295–301. doi:10.1161/01.CIR.0000151097.30779.04. 
13 Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik a. J. Ischemic Mitral 
Regurgitation : Long-Term Outcome and Prognostic Implications With Quantitative Doppler 
Assessment. Circulation. 2001;103(13):1759–1764. doi:10.1161/01.CIR.103.13.1759. 
14 Pellizzon GG, Grines CL, Cox D a, et al. Importance of mitral regurgitation inpatients 
undergoing percutaneous coronary intervention for acute myocardial infarction: the 
Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications 
(CADILLAC) trial. J Am Coll Cardiol. 2004;43(8):1368–74. doi:10.1016/j.jacc.2003.11.046. 
 

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15 De Servi S, Vaccari L, Assandri J, et al. Clinical significance of mitral regurgitation in 
patients with recent myocardial infarction. Eur Heart J. 1988;9 Suppl F:5–9. 
16 Vassileva CM, Enriquez-Sarano M. No man’s land: ischemic mitral regurgitation 
afterprimary percutaneous coronary intervention. J Thorac Cardiovasc Surg. 
2013;146(1):2–3. doi:10.1016/j.jtcvs.2013.04.004. 
17 Bonow RO, Carabello B a, Kanu C, et al. ACC/AHA 2006 guidelines for the management of 
patients with valvular heart disease: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 
Guidelines for the Manage.; 2006:e84–231. doi:10.1161/CIRCULATIONAHA.106.176857. 
18 Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart 
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