The CLASP Study Edwards PASCAL TrAnScatheter Mitral Valve RePair System Study
Phase: NA
Conditions: Mitral Valve Regurgitation
Sponsor: Edwards Lifesciences

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The CLASP Study 
Edwards PASCAL TrAnScatheter Mitral Valve RePair System Study 
 
Clinical Investigation Plan 
 
Study Number: 2016-05 
Version: 
 
Effective Date: August 20, 2018 
 
 
CONFIDENTIAL 
 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 USA 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................................. 5 
1  OVERVIEWS .......................................................................................................................................... 13 
1.1 
Study Assessment Overview ...................................................................................................... 13 
1.2 
Enrollment Overview ................................................................................................................... 14 
2  PRIMARY CONTACTS .......................................................................................................................... 15 
2.1 
Sponsor ....................................................................................................................................... 15 
2.2 
Participating Sites ....................................................................................................................... 15 
2.3 
Core Laboratory .......................................................................................................................... 15 
2.4 
Data Safety Monitoring Board ..................................................................................................... 15 
2.5 
Clinical Events Committee .......................................................................................................... 15 
3  INTRODUCTION .................................................................................................................................... 16 
3.1 
Mitral Regurgitation ..................................................................................................................... 16 
3.2 
Prevalence of Mitral Regurgitation .............................................................................................. 16 
3.3 
Morbidity and Mortality Related to Mitral Regurgitation .............................................................. 16 
3.4 
Current Treatment of Patients with Mitral Regurgitation............................................................. 17 
3.4.1 
Medical Therapy ......................................................................................................... 17 
3.4.2 
Surgical Treatment ..................................................................................................... 17 
3.4.3 
Novel therapies ........................................................................................................... 18 
3.5 
Rationale for Study and Device Use ........................................................................................... 20 
3.6 
Intended Use ............................................................................................................................... 21 
3.7 
Prior Clinical Studies ................................................................................................................... 21 
3.8 
Study Device ............................................................................................................................... 22 
3.8.1 
Device Description ...................................................................................................... 22 
4  DEVICE ACCOUNTABILITY ................................................................................................................. 26 
4.1 
Device Shipments ....................................................................................................................... 26 
4.2 
Device Accountability Records ................................................................................................... 27 
4.3 
Device Storage ........................................................................................................................... 27 
4.4 
Device Return ............................................................................................................................. 27 
4.5 
Patient Implant Card ................................................................................................................... 28 
5  TRAINING .............................................................................................................................................. 28 
5.1 
Investigator Device Training ....................................................................................................... 28 
5.2 
Training of Investigational Center Personnel .............................................................................. 28 
5.3 
Training Documentation .............................................................................................................. 28 
6  RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL INVESTIGATION .. 29 
6.1 
Potential Risks  ........................................................................................................................... 29 
6.2 
Risk Management ....................................................................................................................... 33 
6.3 
Benefits ....................................................................................................................................... 33 
7  CLINICAL INVESTIGATION ................................................................................................................. 34 
7.1 
Study Design ............................................................................................................................... 34 
7.2 
Study Objectives ......................................................................................................................... 34 
7.3 
Study Population ......................................................................................................................... 34 
7.4 
Study Duration ............................................................................................................................ 34 
7.5 
Primary Endpoints....................................................................................................................... 35 
7.6 
Secondary Endpoints and Clinical Outcomes ............................................................................ 35 
7.7 
Patients ....................................................................................................................................... 37 
7.7.1 
Inclusion Criteria ......................................................................................................... 37 

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7.7.2 
Exclusion Criteria ........................................................................................................ 37 
7.8 
Study Procedures ....................................................................................................................... 40 
7.8.1 
Pre-screening ............................................................................................................. 40 
7.8.2 
Study Informed Consent Process ............................................................................... 40 
7.8.3 
Patient Enrollment ...................................................................................................... 41 
7.8.4 
Baseline Evaluation .................................................................................................... 42 
7.8.5 
Stroke Assessment and Quality of Life measurements ............................................. 42 
7.8.6 
Imaging Assessments ................................................................................................ 43 
7.8.7 
Recommended Antiplatelet / Anticoagulation Therapy .............................................. 43 
8  ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES ......................... 49 
8.1 
Reporting Procedure ................................................................................................................... 49 
8.2 
Adverse Event Definitions and Classification ............................................................................. 53 
8.2.1 
Adverse Event ............................................................................................................ 53 
8.2.2 
Adverse Device Effect ................................................................................................ 54 
8.2.3 
Serious Adverse Event ............................................................................................... 54 
8.2.4 
Serious Adverse Device Effect ................................................................................... 54 
8.2.5 
Unanticipated Adverse Device Effect ......................................................................... 54 
8.2.6 
Unanticipated Serious Adverse Device Effect ............................................................ 55 
8.2.7 
Adverse Event Causality Assessment ........................................................................ 55 
8.2.8 
Sponsor Assessment of Adverse Events ................................................................... 57 
8.2.9 
Device Deficiency and Malfunction ............................................................................ 57 
8.3 
Deaths and Explants ................................................................................................................... 58 
8.3.1 
Patient Deaths ............................................................................................................ 58 
8.3.2 
Device Explants .......................................................................................................... 58 
9  STATISTICAL CONSIDERATIONS ...................................................................................................... 59 
9.1 
Study Design and Sample Size .................................................................................................. 59 
9.2 
Analysis Population..................................................................................................................... 61 
9.3 
Statistical Analysis ...................................................................................................................... 61 
9.4 
Missing Data ............................................................................................................................... 62 
10 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ................................................ 62 
10.1  Data Safety Monitoring Board (DSMB) and Clinical Events Committee (CEC) ......................... 62 
10.1.1 
Data Safety Monitoring Board (DSMB) ...................................................................... 62 
10.1.2 
Clinical Events Committee (CEC) .............................................................................. 62 
10.2  Core Laboratory .......................................................................................................................... 63 
10.3  Monitoring ................................................................................................................................... 63 
10.3.1 
Monitoring Methods .................................................................................................... 63 
10.4  Data Management ...................................................................................................................... 64 
10.4.1 
Data Collection Methods ............................................................................................ 64 
10.4.2 
Case Report Forms (CRFs) ........................................................................................ 64 
10.4.3 
Source Documentation Requirements ....................................................................... 65 
10.5  Patient Visits ............................................................................................................................... 65 
10.6  Vulnerable Population ................................................................................................................. 66 
11 DEVIATIONS FROM CLINICAL INVESTIGATION PLAN .................................................................... 66 
11.1  Protocol Deviation ....................................................................................................................... 66 
11.2  Audits / Inspections ..................................................................................................................... 67 
11.3  Communication Procedures ....................................................................................................... 67 
12 STATEMENTS OF COMPLIANCE ........................................................................................................ 67 
12.1  Applicable Regulations and Guidelines ...................................................................................... 67 
12.2  Ethics and Regulatory Bodies ..................................................................................................... 67 
12.3  Insurance .................................................................................................................................... 68 

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12.4  Data Protection and Patient Confidentiality ................................................................................ 68 
12.5  Study Termination ....................................................................................................................... 68 
12.6  Investigator Reimbursement and Contracting ............................................................................ 69 
13 INVESTIGATOR RESPONSIBILITIES .................................................................................................. 69 
13.1.1 
General Duties ............................................................................................................ 69 
13.1.2 
Investigator Records ................................................................................................... 69 
13.1.3 
Investigator Reports ................................................................................................... 70 
13.2  Sponsor Responsibilities ............................................................................................................ 70 
13.2.1 
General Duties ............................................................................................................ 70 
14 STUDY CHANGES ................................................................................................................................ 71 
15 PUBLICATION POLICY ........................................................................................................................ 71 
16 ACRONYMS .......................................................................................................................................... 72 
17 DEFINITIONS ......................................................................................................................................... 75 
18 CHRONIC MR SEVERITY GRADING BY ECHOCARDIOGRAPHY .................................................... 88 
19 BIBLIOGRAPHY .................................................................................................................................... 89 
 
APPENDIX A: INFORMED CONSENT FORM………………………………………………………………….A 
APPENDIX B: ECHOCARDIOGRAPHIC ACQUISITION PROTOCOL……………………………………...B 
 
 
 
 
The following terms will be used synonymously:  
Sponsor 
Edwards 
Edwards 
Edwards Lifesciences LLC 
Clinical investigation 
(clinical) study, (clinical) trial 
Clinical investigation device 
study device, Edwards PASCAL system 
Clinical investigation Plan (CIP) 
(clinical) protocol, (study) plan, (study) protocol 
Competent authority 
regulatory authority, Ministry of Health, MoH 
CRF 
eCRF 
EC 
Ethics committee, Investigational Review Board, Regional Ethics 
Board  
 
 
 
 

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PROTOCOL SYNOPSIS  
Study Number: 
2016-05 
Version: 
; August 20, 2018 
Title: 
The CLASP (Edwards PASCAL TrAnScatheter Mitral Valve RePair 
System) Study 
Study Sponsor:  
Edwards Lifesciences LLC 
One Edwards Way, Irvine, CA 92614 USA 
Principal 
Investigators: 
Investigators from Australia, Canada, Germany, Greece, Switzerland, 
Italy, US and other countries identified at a later date if applicable. 
Study Objective: 
The purpose of this study is to assess the safety, performance and 
clinical outcomes of the Edwards PASCAL Transcatheter Mitral Valve 
Repair (TMVr) System. 
Study Device: 
Edwards PASCAL Transcatheter Mitral Valve Repair System  
 
 
 
 
 
 
 
 
Intended Use: 
The Edwards PASCAL System is intended for the percutaneous 
reconstruction of an insufficient mitral valve in patients with clinically 
significant, symptomatic mitral regurgitation and:  
 New York Heart Association (NYHA) Functional Class II, III and 
ambulatory IV heart failure 
 The primary regurgitant jet is non-commissural.  If a secondary jet 
exists, it must be considered clinically insignificant 
Study Design: 
This is a multi-center (up to 20 sites initially), multi-national, 
prospective, single arm study. The analysis population will consist of 60 
patients. No site will be allowed to enroll more than 20% of the analysis 
population in the primary cohort. All enrolled study patients will be 
assessed for clinical follow-up at the following intervals:  30 days, 6 
months, 1 year and annually for 5 years post implant procedure. In 
addition, the study allows for 0 to 3 roll-in patients per site, for a total 
maximum of 60 roll-in patients. The overall study therefore allows for up 
to 120 patients: 60 in the analysis population, and up to 60 additional 
roll-in patients. 

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Following completion of the primary cohort of 60 patients in the analysis 
population (up to 45 of which may be US patients), an additional 50 
patients will be enrolled in the U.S. at up to 15 clinical sites. 
 
 
 
 
 
 
 
Study Population: 
Adult patients with clinically significant, symptomatic, mitral 
regurgitation despite optimal medical therapy and/or who are being 
considered by the heart team for standard mitral valve repair or 
replacement. 

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Inclusion Criteria:  1. 
Signed and dated ethics committee/institutional review board 
approved study consent form prior to study related procedures  
2. 
Eighteen (18) years of age or older 
3. 
New York Heart Association (NYHA) Functional Class II, III and 
ambulatory IV heart failure despite optimal medical therapy 
4. 
Candidate for surgical mitral valve repair or replacement as 
determined by a Heart Team evaluation 
5. 
For patients whose primary mechanism of mitral regurgitation is 
functional (secondary; FMR) in nature:  Elevated BNP > 150 pg/ml 
or corrected NT-proBNP of 600 pg/ml measured within 90 days 
prior to enrollment or heart failure hospitalization within 12 months 
prior to enrollment.  These criteria do not apply to patients whose 
primary mechanism of mitral regurgitation is degenerative (DMR) in 
nature.  
6. 
Clinically significant mitral regurgitation (3+ to 4+, as defined in 
section 18.0) confirmed by transesophageal echocardiography 
(TEE) within 90 days prior to intervention, or transthoracic 
echocardiography (TTE) within 60 days prior to intervention 
7. 
Left ventricular ejection fraction (LVEF) ≥ 20% determined by TTE 
within 60 days prior to intervention 
8. 
The primary regurgitant jet is non-commissural.  If a secondary jet 
exists, it must be considered clinically insignificant 
9. 
Patient agrees to return for all required post-procedure follow-up 
visits 
10. For patients whose primary mechanism of mitral regurgitation is 
functional (secondary; FMR) in nature:  Six-minute walk test 
(6MWT) ≥ 150 m and ≤ 400 m within 60 days prior to intervention.  
These criteria do not apply to patients whose primary mechanism 
of mitral regurgitation is degenerative (DMR) in nature.  
 

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Exclusion Criteria  
1. Patient in whom a TEE is contraindicated or screening TEE is 
unsuccessful 
2. Leaflet anatomy which may preclude PASCAL device implantation, 
proper device positioning on the leaflets, or sufficient reduction in 
mitral regurgitation that may include: 
 
Evidence of moderate to severe calcification in the grasping 
area. 
 
Evidence of severe calcification in the annulus or subvalvular 
apparatus 
 
Evidence of severe Barlow’s disease 
 
Presence of significant cleft or perforation in the grasping area 
 
Flail width > 15mm and/or flail gap > 10mm 
 
Leaflet mobility length < 8mm 
 
Coaptation gap > 5mm 
 
Transseptal puncture height < 3.5cm 
 
LA diameter ≤ 35mm 
 
Presence of two or more significant jets  
 
Presence of one significant jet in the commissural area 
3. Mitral valve area (MVA) < 4.0 cm² as measured by planimetry  
(If MVA by planimetry is not measurable, PHT measurement is 
acceptable) 
4. Echocardiographic evidence of intracardiac mass, thrombus, or 
vegetation 
5. Clinical evidence of right sided congestive heart failure and/or 
echocardiographic evidence of severe right ventricular dysfunction 
6. LVEDD > 8.0 cm determined by TTE within 60 days prior to 
intervention 
7. End-stage Heart Failure with inotrope support and/or consideration 
for LVAD or heart transplant 
8. Untreated significant coronary artery disease / stenosis, unstable 
angina, evidence of acute coronary syndrome, myocardial 
infarction, transient ischemic attack or stroke within 30 days prior 
to intervention 

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9. Clinically significant uncorrected valvular disease or left ventricular 
outflow obstruction, obstructive cardiomyopathy, poorly controlled 
rapid atrial fibrillation or flutter, poorly controlled symptomatic 
brady- or tachy-arrhythmias 
10. Any percutaneous cardiovascular intervention, carotid surgery, 
cardiovascular surgery or atrial fibrillation ablation within 90 days 
prior to intervention 
11. Implant of any rhythm management device (i.e., pacemaker, 
cardiac resynchronization therapy [CRT] with or without 
cardioverter-defibrillator [CRT-D]) within 90 days prior to 
intervention, or revision of any implanted rhythm management 
device within 90 days prior to intervention 
12. Need for emergent or urgent surgery for any reason or any 
planned cardiac surgery within the next 12 months 
13. Any prior mitral valve surgery or transcatheter mitral valve 
procedure 
14. Contraindication to transseptal catheterization 
15. Active endocarditis or active infections requiring current antibiotic 
therapy or last antibiotic treatment was administered within 14 
days prior to intervention 
16. Active rheumatic heart disease or rheumatic etiology for MR 
17. Infiltrative cardiomyopathies (e.g., amyloidosis, hemochromatosis, 
sarcoidosis), hypertrophic cardiomyopathy, restrictive 
cardiomyopathy, constrictive pericarditis, or any other structural 
heart disease causing heart failure other than dilated 
cardiomyopathy of either ischemic or non-ischemic etiology 
18. Tricuspid valve disease requiring surgery or severe tricuspid 
regurgitation 
19. Severe aortic stenosis (aortic valve area <1.0 cm²) or severe aortic 
regurgitation 
20. Absence of CRT with Class I indication criteria for biventricular 
pacing  
21. Uncontrolled hypertension (i.e., BP >180 mmHg systolic and/or 
>105 mmHg diastolic) or hypotension (i.e., BP <90 mmHg systolic)  

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22. Pulmonary artery systolic hypertension >70mmHg  
23. Severe symptomatic carotid stenosis (>50% by ultrasound) or 
asymptomatic carotid stenosis (>70% by ultrasound)  
24. Severe Kidney Renal Disease with creatinine >2.5mg/dL and/or 
eGFR <30 mL/min/1.73 m2 
25. Presence of an occluded or thrombosed IVC filter that would 
interfere with the delivery catheter, or ipsilateral deep vein 
thrombosis is present 
26. Known hypersensitivity to nitinol or contraindication to procedural 
medications which cannot be adequately managed medically 
27. History of bleeding diathesis or coagulopathy or patient who 
refuses blood transfusions 
28. Pregnant or planning pregnancy within next 12 months. Note: 
Female patients of childbearing potential need to have a negative 
pregnancy test performed within 14 days prior to intervention and 
be adherent to an accepted method of contraception 
29. Severe COPD evidenced by oral steroid therapy or oxygen therapy 
30.  Concurrent medical condition with a life expectancy of less than 
12 months in the judgment of the Investigator  
31. Patient is currently participating or has participated in another 
investigational drug or device clinical study where the primary 
study endpoint was not reached at time of enrollment 
32. Patient is under guardianship 
Primary 
Endpoints 
Safety: 
Composite of major adverse events (MAE) defined as cardiovascular 
mortality, stroke, myocardial infarction, new need for renal replacement 
therapy, severe bleeding and re-intervention for study device related 
complications at 30 days. 
Performance: 
 
Device success: device is deployed as intended and the 
delivery system is successfully retrieved as intended at the time 
of the patient’s exit from the cardiac catheterization laboratory. 
Per device analysis. 

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 
Procedural success: device success with evidence of MR 
reduction ≤ MR2+ at discharge and without the need for a 
surgical or percutaneous intervention prior to hospital discharge. 
Per patient analysis. 
 
Clinical success: procedural success with evidence of MR 
reduction ≤ MR2+ and without MAEs at 30 days. Per patient 
analysis.  
Secondary 
Endpoints and 
Clinical 
Outcomes: 
 
Mitral regurgitation reduction at  30 days, 6 months, 1 year and 
annually thereafter over baseline 
 
All-cause mortality at 30 days, 6 months, 1 year, and annually 
thereafter 
 
Recurrent heart failure hospitalization at 30 days, 6 months, 1 year, 
and annually thereafter 
 
Re-intervention rates for mitral regurgitation at 30 days, 6 months, 1 
year and annually thereafter  
 
Composite of major adverse events (MAE) defined as 
cardiovascular mortality, stroke, myocardial infarction, new need for 
renal replacement therapy, severe bleeding and re-intervention for 
study device related complications at  6 months, 1 year and 
annually thereafter  
 
Change in Left Ventricular End Diastolic Volume (LVEDV) at 6 
months and 1 year and annually thereafter over baseline  
 
Change in Left Ventricular End Systolic Volume (LVESV) at 6 
months and 1 year and annually thereafter over baseline  
 
Change in Pulmonary Artery Systolic Pressure at 6 months and 1 
year and annually thereafter over baseline 
 
Change in 6MWT distance at 6 months and 1 year over baseline 
 
Change in Quality of Life (QoL) score, as measured by Kansas City 
Cardiomyopathy Questionnaire (KCCQ), and EQ5D at 30 days, 6 
months and 1 year and annually thereafter over baseline  
 
Change in NYHA Functional Classification at 6 months and 1 year 
and annually thereafter over baseline 
 
Change in BNP/NT-pro-BNP level at 6 months and 1 year and 
annually thereafter over baseline 
 
Change in tricuspid regurgitation at 6 months and 1 year and 
annually thereafter over baseline 

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 
Change in effective regurgitant orifice area (EROA) at 30 days, 6 
months, 1 year and annually thereafter over baseline 
 
Change in mitral regurgitant volume at 30 days, 6 months and 1 
year and yearly thereafter over baseline 
Study 
Committees: 
Independent Data Safety Monitoring Board (DSMB) / independent 
Clinical Events Committee (CEC)  
 
The DSMB will consist of a minimum of three physician 
members and will be selected for their expertise in specific 
medical disciplines, including CT surgery, Interventional 
Cardiology, and Heart Failure. The DSMB will also include an 
experienced biostatistician with experience in clinical research. 
 
 
The CEC is a defined group of physicians in clinical practice, 
inclusive of the CEC Chair, and will be further defined in the 
CEC Charter. 
Echocardiography 
Core Laboratory: 
 
 
 
 
 
 

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3 
INTRODUCTION 
3.1 Mitral Regurgitation  
Mitral regurgitation (MR), also known as mitral insufficiency, is the condition in which 
incompetency of the mitral valve causes abnormal backflow of blood from the left ventricle to the 
left atrium during the systolic phase of the cardiac cycle.   
MR can have many underlying etiologies, but the majority of these can be divided into two major 
categories: degenerative and functional.  Degenerative mitral valve regurgitation (DMR), also 
known as primary MR, refers to regurgitation resulting from structural abnormality of the mitral 
valve leaflets and/or valve apparatus.  The most common causes of DMR is mitral valve 
prolapse, rheumatic disease, and endocarditis. In contrast, functional mitral regurgitation (FMR), 
also known as secondary MR, occurs when the valve and/or valve apparatus are structurally 
normal, but dysfunction, distortion, or dilation of the left atrial or ventricular chambers results in 
tethering of leaflets and/or mitral annular dilation that prevent leaflet coaptation. FMR can occur 
in the setting of underlying ischemic heart disease or heart failure with dilated cardiomyopathy. 
3.2 Prevalence of Mitral Regurgitation  
Mitral regurgitation is the most common valvular heart disease after aortic stenosis.  
Approximately 2% of the population is affected, with 250,000 new diagnoses annually.  The 
prevalence and severity of MR increases with age, with significant MR affecting nearly 10% of 
the U.S. population aged >75 years and associated with increased morbidity and mortality in the 
setting of left ventricular dysfunction and heart failure symptoms1, 2.  
Amongst those with severe MR, the predominant mechanism of MR has been shown to be up to 
74% functional and 21% degenerative3. In patients with severe heart failure, the onset of FMR 
increases the hemodynamic stress on the failing left ventricle resulting in a cycle of progressive 
dilation and dysfunction and volume overload.  Between 54 and 60% of patients with dilated 
cardiomyopathy have been reported to have FMR4.   
3.3 Morbidity and Mortality Related to Mitral Regurgitation  
Chronic MR imposes volume overload on the left ventricle (LV) which results in LV remodeling 
and cyclical worsening of MR. This may lead to worsening of left ventricular failure, pulmonary 
hypertension, atrial fibrillation and increased mortality.1 Although MR may be tolerated for a long 
time in some patients, in others, progression of heart failure with LV muscle dysfunction may be 
more rapid5. The natural course of severe MR depends on many factors including, but not 

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limited to, the type of MR, presence of symptoms, LV function and presence of atrial fibrillation 
or pulmonary hypertension6. 
Symptomatic patients with severe MR have an annual death rate of 5%7. The risk of death in 
subjects aged ≥70 years old with moderate/severe MR has been shown to be more than four-
fold higher than that of age and sex matched subjects with absent/mild MR8.   
Nearly 50% of patients with ischemic FMR develop heart failure or cardiac death within 5 years 
(three times more likely than post-MI patients without MR) 9.   
In patients with ischemic and non-ischemic cardiomyopathies and heart failure, MR 
independently predicts increased mortality, and mortality is directly associated with the degree 
of regurgitation7. 
FMR has a 50% composite rate of mortality and heart failure (HF) hospitalization at 3 years, 
compared with 30% in HF patients without FMR10.  
3.4 Current Treatment of Patients with Mitral Regurgitation  
3.4.1 Medical Therapy  
For chronic DMR patients without heart failure, medical treatment is limited to diuretics and 
nitrates to reduce afterload.  Medical therapy for FMR patients with heart failure is focused on 
symptom relief from left-ventricular dysfunction.  This includes diuretics, angiotensin converting 
enzyme (ACE) inhibitors, angiotensin-receptor antagonists, beta blockers, and aldosterone 
antagonists.  Although these drugs have been shown to improve the symptoms of heart failure 
and some have been shown to improve survival, there are no data that show that current 
medical therapies will reduce the severity or consequences of functional MR or reverse the 
progression of the underlying pathology.11-13 
3.4.2 Surgical Treatment 
For DMR, surgical mitral valve repair or replacement is indicated in patients with symptoms and 
LVEF>30%, or in asymptomatic patients with LVEF between 30 and 60% or LVESD ≥40mm.  
Surgical repair of abnormal structural valve apparatus includes prolapsed leaflet resection, 
chordae reconstruction, leaflet augmentation, and cleft closure.  Surgical options for treatment 
of symptomatic severe FMR include partial or complete annuloplasty and/or edge-to-edge 
leaflet repair. Surgery for FMR is generally only recommended when patients become 
unresponsive to optimal medical therapy and have adequate LV function (>30% LVEF), as the 
clinical benefit of surgical treatment for FMR is controversial15 

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Surgical mitral valve repair is preferred over replacement if a successful and durable repair can 
be achieved.  Mitral valve replacement surgery is associated with a high incidence of 
complications including valve failure and bleeding due to the need for anticoagulants14. 
Although surgical repair and replacement options have been shown to be the standard 
treatment for MR in the surgically eligible population, it has been estimated that nearly 50% of 
patients with severe MR are not referred for surgery because they are prohibitively high risk due 
to advanced age, impaired left ventricular function or the presence of comorbidities15.  In 
practice, isolated surgery for FMR is performed in less than 15% of eligible patients16. 
3.4.3 Novel therapies   
3.4.3.1 
Cardiac resynchronization  
Cardiac resynchronization therapy (CRT) may provide benefit for patients with chronic severe 
FMR in the presence of conduction abnormalities that may cause cardiac wall motion that 
exacerbates the MR.  While this therapy has been shown to improve quality of life and exercise 
tolerance, it is applicable only to those with conduction abnormalities. 
3.4.3.2 
Percutaneous valve replacement 
Several percutaneous mitral valve replacement technologies, either via trans-apical, trans-atrial, 
or trans-septal approaches, are in early stages of pre-clinical and clinical evaluation17-20 
indicating a trend in catheter based therapies to treat the high surgical risk MR patient 
population.  None are yet commercially available.   
3.4.3.3 
Percutaneous valve repair  
Percutaneous mitral valve repair therapies have raised interest due to the minimally invasive 
nature of the procedures.  Various technologies have emerged and can be grouped by the 
treatment area: leaflet repair, direct annuloplasty or indirect annuloplasty via the coronary sinus, 
and chamber (LV) remodeling17, 18. 
The MitraClip System (Abbot Vascular, Menlo Park, CA) is a catheter-based technology that 
delivers a clip to grasp and COAPT the native mitral valve leaflets, based on the edge-to-edge 
surgical repair technique which approximates the mitral posterior and anterior leaflets to create 
a double orifice. MitraClip received CE mark 2008 (indicated for MR) and FDA approval in 2013 
(indicated for severe symptomatic DMR in high-surgical risk population only).  To date, the 
MitraClip has been implanted in more than 40,000 patients.  

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The MitraClip has demonstrated rates of procedural success greater than 90%, a good safety 
profile, left ventricular reverse remodeling, and improved clinical outcomes in a randomized 
study and large multi-center registries21-25. The U.S. EVEREST II randomized controlled trial 
compared the MitraClip to conventional surgical treatment of MR in 258 patients in an operable 
population with mostly DMR.  The study concluded that MitraClip was superior to surgery for 
safety  but less effective in the reduction of MR. 23 Five-year results have recently been 
published and have shown that between 1- and 5-year follow-up, showing comparable and low 
rates of surgery for mitral valve dysfunction between the groups, strengthening the evidence for 
durability of MR reduction.  At 1- and 5-year follow up, the mortality rates were similar between 
both groups (at 1-year 6% vs. 6% for MitraClip and Surgery, respectively; p=1.0 and at 5-years 
20.8% vs. 26.8% for MitraClip and Surgery, respectively; p=0.36), but residual moderate or 
severe MR was higher in the MitraClip group (12.3% vs. 1.8%; p=0.02)26.   
Glower et al27 reported results from the prospective multi-center EVEREST II high-risk registry 
(n=78) and the REALISM continued access high risk arm (n=273). Twelve-month data showed 
that MitraClip treatment significantly reduced MR, improved clinical symptoms and decreased 
left ventricular dimensions in this high-risk cohort.   
The ACCESS-EU was a prospective, multi-center, nonrandomized post-approval study 
conducted in 567 patients in Europe. In this patient population, the procedure was effective with 
low hospital mortality and low adverse event rates24.   
In these studies, it was observed that 30-day safety performance outcomes after MitraClip 
implantation are similar to those at one year.  Only complications related to the underlying 
disease such as mortality and re-hospitalizations continually increase.  Glower at al discussed 
“In these high-risk patients, the results of MV (mitral valve) device placement appear to be very 
stable from 30 days to 12 months”. Additionally, Feldman et al26 discussed: “The landmark 
analysis of this device demonstrated that the clinical failures primarily occurred within the first 6 
months, most of which were caused by inadequate MR reduction during the index procedure or 
early SLDA (single-leaflet device attachment).” 
Other recent commercially available (in select regions) Mitral Valve repair devices include 
percutaneous direct annuloplasty using Cardioband (Valtech Cardio, Israel, recently acquired by 
Edwards, Irvine, CA, USA; CE mark 2015), direct annuloplasty using Mitralign (Mitralign Inc., 
Tewksbury, MA; CE mark 2016), indirect annuloplasty using Carillon (Cardiac Dimensions, 
Kirkland, WA; CE mark 2009), and percutaneous chordal repair using NeoChord (NeoChord, 
Minneapolis, Minnesota; CE mark 2013).  

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3.5  Rationale for Study and Device Use   
Percutaneous approaches to treating MR are appealing for their potential to provide sufficient 
reduction in MR without the risks typically associated with open heart surgery.  Additionally, as 
previously stated, nearly 50% of patients with severe MR are not referred or denied to surgery 
due to prohibitive risks, and the uncertainty of benefit form surgical repair or replacement.  
Percutaneous therapy provides an alternative treatment option for these high risk surgical 
candidates and in those whom medical therapy is suboptimal.  
Edwards has developed a catheter-based technique for the delivery of a permanent implant to 
the mitral valve via a trans-septal access to grasp and approximate the anterior and posterior 
leaflets, creating a double orifice and thereby reducing MR, much like surgical repair and the 
MitraClip System procedure.   The MitraClip procedure has already been shown to be a viable 
alternative for high risk MR patients.  However, MitraClip treatment is limited to specific 
anatomies, and often requires multiple devices (at least 40% of cases require ≥2 devices21, 24, 25) 
to treat large regurgitant jets, which adds to clinical risk and increases procedural time.  
Additionally, MitraClip often leaves significant residual MR as previously discussed.  The 
Edwards PASCAL Transcatheter Mitral Valve Repair (TMVr) System is designed to address 
some of these limitations, including: a larger implant with wider paddles and independent Clasp 
control to address complex anatomies and regurgitant jets and to potentially reduce the number 
of implants required for adequate MR reduction; a Spacer in the center of the implant to act as a 
filler in the regurgitant orifice for reduction of MR; working length that allows maneuverability 
even with higher septal puncture heights; ergonomic controls similar to other Edwards 
transcatheter product lines which are already familiar to many interventional cardiologists.  
 
 

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3.6  Intended Use 
The Edwards PASCAL System is intended for the percutaneous reconstruction of an insufficient 
mitral valve in patients with clinically significant, symptomatic mitral regurgitation and:  
 
New York Heart Association (NYHA) Functional Class II, III and ambulatory IV heart 
failure 
 
The primary regurgitant jet is non-commissural.  If a secondary jet exists, it must be 
considered clinically insignificant  
A Clinical Investigator’s Brochure (CIB) has been prepared for the Edwards PASCAL System.  
This brochure provides the prior testing conducted on the system components. 
3.7  Prior Clinical Studies 
 
 
  
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
Steerable Catheter (Figure 4) 
 
 
 
 
Implant Catheter (Figure 4) 
 
 
 
 
  
 
Loader  
 
 
 

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4.2 Device Accountability Records  
All device shipments will have inventory and shipment records will be maintained by both the 
Study Sponsor and the study center. Devices may be hand carried to participating study centers 
by the Study Sponsor personnel and will be accompanied by delivery of investigational device 
documentation (packing lists, transfer of investigational product form, etc.). The Investigator (s) 
or designee will take inventory of the product and complete the delivery documentation with 
receipt date, condition of the device and signature. The Investigator will maintain a Device 
Accountability Log (as provided by the Sponsor) of all investigational devices documenting their 
receipt, disposition and return during this clinical study. The log will be kept with the documents 
for the clinical study and will be available for review during Study Sponsor monitoring visits. 
Upon Sponsor request or when enrollment has ended, Edwards PASCAL System components 
must be returned to Edwards Lifesciences and the date of return must be recorded on the log. 
4.3 Device Storage 
The device inventory will be stored in a locked, controlled, cool and dry area as described in the 
Instructions for Use (IFU) and/or presented on the device labeling.  This secured area will be 
only accessible to the Investigators or approved designee.  Only Investigators trained and 
identified in the Investigator’s Agreement and the Delegation of Authority form may use the 
investigational devices. 
4.4 Device Return  
The Investigator will be notified in writing upon termination of the clinical study. All unused 
devices in original package and/or those in opened packages as well as those removed from 
the original package will be returned to Edwards Lifesciences upon receipt of this notice.  The 
Investigator will receive instructions from the Study Sponsor on the return process. The 
Investigator’s copy of the Device Accountability log must document any unused devices that 
have been returned.  
 
Used devices may be handled and disposed of in the same manner as hospital waste and bio-
hazardous materials in accordance with local regulations. There are no special risks related to 
the disposal of these devices. All returns and dispositions of devices will be captured on the 
Device Accountability Log Procedure needed. 

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4.5 Patient Implant Card  
The patient implant card will be supplied with the device.  
5 
TRAINING 
5.1 Investigator Device Training 
 
 
 
   
 
 
 
5.2 Training of Investigational Center Personnel 
 
 
 
 
 
 
 
5.3 Training Documentation 
 
 
 
 
 

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6 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL 
INVESTIGATION 
A risk analysis has been conducted, in accordance with ISO 14971: “Application of risk 
management to medical devices”. The risks associated with this investigational device have 
been identified by performing Failure Mode and Effect Analysis (FMEA)/Risk Analysis. Risks 
have been proven minimized through appropriate design control, confirmed by bench testing, 
pre-clinical animal testing and clinical surveillance presented in the CIB. 
During the conduct of the clinical study, the existing risk control measures shall be reviewed to 
identify if other hazards have been introduced. If any new hazards were introduced by any risk 
control measures, the associated risk(s) shall be re-assessed and addressed.  
6.1 Potential Risks  
Complications associated with standard cardiac catheterization, the use of anesthesia and use 
of the PASCAL system could lead to reoperation, explant, permanent disability, or death.  
 
The following anticipated adverse events have been identified as possible complications of the 
PASCAL system and/or implant procedure: 
 
 
Abnormal lab values; 
 
access site AV fistula or pseudoaneurysm; 
 
allergic reaction to anesthetic, contrast, heparin, Nitinol; 
 
anemia, may require transfusion 
 
angina or chest pain 
 
arrhythmias; 
 
atrial fibrillation; 
 
atrial septal defect requiring intervention; 
 
arterio-venous fistula; 
 
bleeding; 
 
cardiac arrest; 
 
cardiac failure/low cardiac output; 
 
cardiac injury including perforation, obstruction, or dissection that may require 
intervention; 
 
cardiogenic shock; 

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 
chordal entanglement or rupture; 
 
coagulopathy, coagulation defect or disorder,  bleeding diathesis; 
 
conversion to open valve surgery 
 
conduction system injury which may require permanent pacemaker implantation 
 
death; 
 
deterioration of native valve (leaflet tear/tearing, leaflet retraction, leaflet thickening, or 
other); 
 
device deterioration (wear, tear, fracture, calcification, or other); 
 
device migration (including single leaflet device attachment (SLDA), malposition or 
embolization requiring intervention; 
 
device thrombosis requiring intervention; 
 
emergency cardiac surgery; 
 
deep venous thrombosis; 
 
reaction to anti-platelet, anticoagulation agents or contrast media 
 
dyspnea; 
 
edema 
 
electrolyte imbalance; 
 
emboli/embolization including air, particulate, calcific material, or thrombus; 
 
endocarditis; 
 
esophageal irritation; 
 
esophageal perforation or stenosis; 
 
exercise intolerance or weakness;  
 
fever; 
 
failure to deliver PASCAL to the intended site; 
 
failure to retrieve any PASCAL system components; 
 
gastrointestinal bleeding or infarct; 
 
heart failure;  
 
heart murmur; 
 
hematoma; 
 
hemodynamic compromise; 
 
hemolysis; 
 
hemorrhage requiring transfusion or intervention; 
 
hypertension 

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 
hypotension; 
 
Implantation of additional transcatheter mitral repair device 
 
infection; 
 
Inflammation 
 
Leaflet damage; 
 
mesenteric ischemia  
 
mitral valve stenosis 
 
mitral valve injury; 
 
multi-system organ failure; 
 
myocardial infarction; 
 
nausea or vomiting; 
 
nerve injury 
 
neurological symptoms, including dyskinesia, without diagnosis of TIA or stroke 
 
non-emergent reoperation; 
 
nonstructural implant dysfunction; 
 
obstruction of valvular structures, e.g. LVOT obstruction; 
 
pain or changes at the access site; 
 
papillary muscle damage;  
 
paralysis; 
 
PASCAL system component(s) embolization 
 
pericardial effusion, cardiac tamponade; 
 
peripheral ischemia; 
 
permanent disability; 
 
pleural effusion; 
 
prolonged ventilation; 
 
pulmonary edema;  
 
pulmonary embolism; 
 
renal failure; 
 
renal insufficiency; 
 
respiratory compromise, respiratory failure, atelectasis, pneumonia 
 
reoperation; 
 
restenosis; 

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 
retroperitoneal bleed; 
 
septicemia, sepsis 
 
shock, e.g. anaphylactic or cardiogenic 
 
skin burn,  injury or tissue changes due to exposure to ionizing radiation  
 
syncope; 
 
systemic peripheral ischemia; 
 
thromboembolic events, stroke, transient ischemic attack, clusters, or other neurological 
changes; 
 
thromboembolism (permanent or transient pulmonary and/or neurological events) 
 
transvalvular flow disturbances;  
 
urinary tract infection and/or bleeding 
 
vascular injury or trauma, dissection or occlusion, that may require intervention 
 
valvular regurgitation;  
 
vessel spasm 
 
ventricular wall, atrial wall or septal damage, abrasion, or perforation;  
 
wound dehiscence, delayed or incomplete healing; 
 
worsening of heart failure; 
 
worsening mitral regurgitation / valvular insufficiency 
 
There may be other risks that are unknown at this time. All safety events will be collected and 
reviewed periodically throughout the entire study periodically. The Investigators will be notified 
of any additional risks identified that could affect the health, safety or welfare of the study 
patients. 

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6.2 Risk Management 
All efforts will be made to minimize the identified risks.  Careful patient selection will be 
performed by the Heart Team11 in collaboration with the Sponsor. 
 
The Investigators selected at each site will include an Interventional Cardiologist or Surgeon 
who is an expert in mitral valve disease and experienced in performing transcatheter mitral 
valve repair and/or replacement, and skilled in percutaneous coronary interventions and 
structural heart interventions to assess patient risk and anatomical suitability.  Each implanting 
physician will be thoroughly trained on the investigational device before first implantation in a 
patient.  There will be strong collaboration between interventional cardiology or cardiac surgery 
and a designated team of nurses, technicians and colleagues from supporting medical 
disciplines (e.g., anesthesiologist, echocardiographer, and radiologist).  
 
The procedure will be performed in an operating room, catheterization lab or hybrid operating 
room with fluoroscopic and echocardiographic imaging capabilities.    
All adverse events will be thoroughly monitored and reviewed by the Study Sponsor and DSMB.  
Stopping rules will be applied for patient safety throughout enrollment. 
6.3 Benefits 
 
 
 
  
 
 
 
 
 
 

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7 
CLINICAL INVESTIGATION 
7.1 Study Design  
This is a multi-center (up to 20 sites initially), multi-national, prospective, single arm study. The 
analysis population will consist of 60 patients. No site will be allowed to enroll more than 20% of 
the analysis population in the primary cohort.  All enrolled study patients will be assessed for 
clinical follow-up at the following intervals:  30 days, 6 months, 1 year and annually for 5 years 
post implant procedure. In addition, the study allows for 0 to 3 roll-in patients per site where 
allowed, for a total maximum of 60 roll-in patients. The overall study therefore allows for up to 
120 patients: 60 in the analysis population, and up to 60 additional roll-in patients. 
 
Following completion of the primary cohort of 60 patients in the analysis population (up to 45 of 
which may be US patients), an additional 50 patients  will be enrolled in the U.S. at up to 15 
clinical sites.   
7.2 Study Objectives  
The objectives of this clinical study are to: 
 
Evaluate the safety and performance of the Edwards PASCAL System 
 
Provide guidance for future clinical study designs utilizing the Edwards PASCAL System 
 
Provide guidance for future Edwards PASCAL System development efforts 
7.3 Study Population  
Adult patients with clinically significant, symptomatic, mitral regurgitation despite optimal 
medical therapy and/or are being considered by the heart team for standard mitral valve repair 
or replacement. 
7.4 Study Duration  
 
 
 
 
 
 

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7.5 Primary Endpoints  
Safety: 
Composite of major adverse events (MAE) defined as cardiovascular mortality, stroke, 
myocardial infarction, new need for renal replacement therapy, severe bleeding and re-
intervention for study device related complications at 30 days. 
Performance: 
 
Device success: device is deployed as intended and the delivery system is successfully 
retrieved as intended at the time of the patient’s exit from the cardiac catheterization 
laboratory. Per device analysis. 
 
Procedural success: device success with evidence of MR reduction ≤ MR2+ at discharge 
and without the need for a surgical or percutaneous intervention prior to hospital 
discharge. Per patient analysis. 
 
Clinical success: procedural success with evidence of MR reduction ≤ MR2+ and without 
MAEs at 30 days. Per patient analysis. 
7.6 Secondary Endpoints and Clinical Outcomes  
 
Mitral regurgitation reduction at 30 days, 6 months, 1 year and annually thereafter over 
baseline 
 
All-cause mortality at 30 days, 6 months, 1 year, and annually thereafter 
 
Recurrent heart failure hospitalization at 30 days, 6 months, 1 year, and annually thereafter 
 
Re-intervention rates for mitral regurgitation at 30 days, 6 months, 1 year and annually 
thereafter  
 
Composite of major adverse events (MAE) defined as cardiovascular mortality, stroke, 
myocardial infarction, new need for renal replacement therapy, severe bleeding and re-
intervention for study device related complications at  6 months, 1 year and annually 
thereafter  
 
Change in Left Ventricular End Diastolic Volume (LVEDV) at 6 months and 1 year and 
annually thereafter over baseline  
 
Change in Left Ventricular End Systolic Volume (LVESV) at 6 months and 1 year and 
annually thereafter over baseline  
 
Change in Pulmonary Artery Systolic Pressure at 6 months and 1 year and annually 
thereafter over baseline 
 
Change in 6MWT distance at 6 months and 1 year over baseline 

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 
Change in Quality of Life (QoL) score, as measured by Kansas City Cardiomyopathy 
Questionnaire (KCCQ), and EQ5D at 30 days, 6 months and 1 year and annually thereafter 
over baseline  
 
Change in NYHA Functional Classification at 6 months and 1 year and annually thereafter 
over baseline 
 
Change in BNP/NT-pro-BNP level at 6 months and 1 year and annually thereafter over 
baseline 
 
Change in tricuspid regurgitation at 6 months and 1 year and annually thereafter over 
baseline 
 
Change in effective regurgitant orifice area (EROA) at 30 days, 6 months, 1 year and 
annually thereafter over baseline 
 
Change in mitral regurgitant volume at 30 days, 6 months and 1 year and yearly thereafter 
over baseline 

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7.7 Patients  
7.7.1 Inclusion Criteria  
The Investigator has the responsibility of screening potential patients to determine if the patients 
meet all the inclusion criteria.  The following are requirements for entry into the study:  
1. 
Signed and dated ethics committee/institutional review board approved study consent 
form prior to study related procedures  
2. 
Eighteen (18) years of age or older 
3. 
New York Heart Association (NYHA) Functional Class II, III and ambulatory IV heart 
failure despite optimal medical therapy 
4. 
Candidate for surgical mitral valve repair or replacement as determined by a Heart Team 
evaluation  
5. 
For patients whose primary mechanism of mitral regurgitation is functional (secondary; 
FMR) in nature:  Elevated BNP > 150 pg/ml or corrected NT-proBNP of 600 pg/ml 
measured within 90 days prior to enrollment or heart failure hospitalization within 12 
months prior to enrollment.  These criteria do not apply to patients whose primary 
mechanism of mitral regurgitation is degenerative (DMR) in nature.  
6. 
Clinically significant mitral regurgitation (3+ to 4+, as defined in Section 18.0) confirmed by 
transesophageal echocardiography (TEE) within 90 days prior to intervention, or 
transthoracic echocardiography (TTE) within 60 days prior to intervention  
7. 
Left ventricular ejection fraction (LVEF) ≥ 20% determined by TTE within 60 days prior to 
intervention 
8. 
The primary regurgitant jet is non-commissural.  If a secondary jet exists, it must be 
considered clinically insignificant 
9. 
Patient agrees to return for all required post-procedure follow-up visits 
10. 
For patients whose primary mechanism of mitral regurgitation is functional (secondary; 
FMR) in nature:  Six-minute walk test (6MWT) ≥ 150 m and ≤ 400 m within 60 days prior 
to intervention. These criteria do not apply to patients whose primary mechanism of mitral 
regurgitation is degenerative (DMR) in nature. 
 
7.7.2 Exclusion Criteria  
The Investigator at the study site must exclude patients if any of the exclusion criteria are 
present. The following are the criteria for exclusion from participating in the clinical study: 
1. 
Patient in whom a TEE is contraindicated or screening TEE is unsuccessful 

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2. 
Leaflet anatomy which may preclude PASCAL device implantation, proper device 
positioning on the leaflets, or sufficient reduction in mitral regurgitation that may include: 
• 
Evidence of moderate to severe calcification in the grasping area. 
• 
Evidence of severe calcification in the annulus or subvalvular apparatus 
• 
Evidence of severe Barlow disease 
• 
Presence of significant cleft or perforation in the grasping area 
• 
Flail width  15mm and/or flail gap  10mm 
• 
Leaflet mobility length < 8mm 
• 
Coaptation gap > 5mm 
• 
Transseptal puncture height < 3.5cm 
• 
LA diameter ≤ 35mm 
• 
Presence of two or more significant jets  
• 
Presence of one significant jet in the commissural area 
3. 
Mitral valve area (MVA) < 4.0 cm² as measured by planimetry (If MVA by planimetry is not 
measurable, PHT measurement is acceptable) 
4. 
Echocardiographic evidence of intracardiac mass, thrombus, or vegetation 
5. 
Clinical evidence of right sided congestive heart failure and/or echocardiographic 
evidence of severe right ventricular dysfunction 
6. 
LVEDD > 8.0 cm determined by TTE within 60 days prior to intervention 
7. 
End-stage Heart Failure with inotrope support and/or consideration for LVAD or heart 
transplant 
8. 
Untreated significant coronary artery disease / stenosis, unstable angina, evidence of 
acute coronary syndrome, myocardial infarction, transient ischemic attack or stroke within 
30 days prior to intervention 
9. 
Clinically significant uncorrected valvular disease or left ventricular outflow obstruction, 
obstructive cardiomyopathy, poorly controlled rapid atrial fibrillation or flutter, poorly 
controlled symptomatic brady- or tachy-arrhythmias 
10. 
Any percutaneous cardiovascular intervention, carotid surgery, cardiovascular surgery or 
atrial fibrillation ablation within 90 days prior to intervention 
11. 
Implant of any rhythm management device (i.e., pacemaker, cardiac resynchronization 
therapy [CRT] with or without cardioverter-defibrillator [CRT-D]) within 90 days prior to 
intervention, or revision of any implanted rhythm management device within 90 days prior 
to intervention 

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12. 
Need for emergent or urgent surgery for any reason or any planned cardiac surgery within 
the next 12 months 
13. 
Any prior mitral valve surgery or transcatheter mitral valve procedure 
14. 
Contraindication to transseptal catheterization 
15. 
Active endocarditis or active infections requiring current antibiotic therapy or last antibiotic 
treatment was administered within 14 days prior to intervention 
16. 
Active rheumatic heart disease or rheumatic etiology for MR 
17. 
Infiltrative cardiomyopathies (e.g., amyloidosis, hemochromatosis, sarcoidosis), 
hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or any 
other structural heart disease causing heart failure other than dilated cardiomyopathy of 
either ischemic or non-ischemic etiology 
18. 
Tricuspid valve disease requiring surgery or severe tricuspid regurgitation 
19. 
Severe aortic stenosis (aortic valve area <1.0 cm²) or severe aortic regurgitation 
20. 
Absence of CRT with Class I indication criteria for biventricular pacing  
21. 
Uncontrolled hypertension (i.e., BP >180 mmHg systolic and/or >105 mmHg diastolic) or 
hypotension (i.e., BP <90 mmHg systolic)  
22. 
Pulmonary artery systolic hypertension >70mmHg  
23. 
Severe symptomatic carotid stenosis (>50% by ultrasound) or asymptomatic carotid 
stenosis (>70% by ultrasound)  
24. 
Severe Kidney Renal Disease with creatinine >2.5mg/dL and/or  
eGFR <30 mL/min/1.73 m2 
25. 
Presence of an occluded or thrombosed IVC filter that would interfere with the delivery 
catheter, or ipsilateral deep vein thrombosis is present 
26. 
Known hypersensitivity to nitinol or contraindication to procedural medications which 
cannot be adequately managed medically 
27. 
History of bleeding diathesis or coagulopathy or patient who refuses blood transfusions 
28. 
Pregnant or planning pregnancy within next 12 months. Note: Female patients of 
childbearing potential need to have a negative pregnancy test performed within 14 days 
prior to intervention and be adherent to an accepted method of contraception 
29. 
Severe COPD evidenced by oral steroid therapy or oxygen therapy 
30. 
 Concurrent medical condition with a life expectancy of less than 12 months in the 
judgment of the Investigator  

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31. 
Patient is currently participating or has participated in another investigational drug or 
device clinical study where the primary study endpoint was not reached at time of 
enrollment 
32. 
Patient is under guardianship 
 
7.8 Study Procedures  
7.8.1 Pre-screening  
Adult patients with clinically significant, symptomatic, mitral regurgitation despite optimal 
medical therapy and/or are being considered by the heart team for standard mitral valve repair 
or replacement.  
Prior to performing any study specific activities/evaluations, except the standard assessments 
for this population, the patient must be thoroughly informed about all aspects of the study and 
the patient must have provided written informed consent. 
If local IRB approval is obtained, a screening consent form may be implemented to enable the 
collection of standard assessments for this population (e.g., TEE and TTE.).  Data collected 
from screening assessments may be used to simultaneously assess the patient’s anatomic 
eligibility for this Study using the PASCAL repair device or other Edwards Clinical Studies using 
a transcatheter mitral repair or replacement study device.  If local IRBs do not allow the use of a 
screening consent form, all screening assessments will be described under the applicable 
standard study Informed Consent Form.   
7.8.2 Study Informed Consent Process 
The patient must sign the Study Informed Consent Form that is currently approved by the 
institution’s overseeing IRB/EC prior to participation. Failure to provide Study informed consent 
renders the patient ineligible for the study. Study Informed consent must be obtained prior to 
any study related procedures.   
It has to be emphasized that a patient's participation in the trial is voluntary and that the patient 
may refuse to participate or withdraw from the trial, at any time, without penalty or loss of 
benefits to which the patient is otherwise entitled. 
Signed Screening Consent Form (where applicable) and Study Informed Consent Form must be 
retained by the Investigational Center for verification during on-site monitoring visits. The 

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Investigator will retain the original consent forms, a copy will be filed in the sites specific study 
files, and a copy of the Screening Consent Form (where applicable) and Study Informed 
Consent Form will be provided to the patient. 
The consent forms will be written in the native language/languages of the patient and 
administered only by the Investigator or authorized designee.  The Principal Investigator or 
delegated person administering the consent must sign and date the Study Informed Consent 
Form to indicate that the purpose, risks and benefits of the study were explained to the patient 
and that their signature was witnessed. 
The Investigator will retain the original consent form(s), a copy will be filed in the patient’s 
medical record, and a copy of the Screening Consent Form (where applicable) and Study 
Informed Consent Form will be provided to the patient. 
As the Study Sponsor, Edwards Lifesciences must approve any modifications to the Screening 
Consent (where applicable) and Study Informed Consent Form prior to submission to the ethics 
committee (EC)/institutional review board (IRB), and/or Competent Authority (as required).     
7.8.3 Patient Enrollment  
The enrollment overview is shown in Figure 1 in Section 1.2. A patient will be considered a 
“patient” and “provisionally enrolled” when they have signed the informed consent form.   
Provisionally enrolled patients will be reviewed by the Heart Team to assure that all inclusion 
criteria and none of the exclusion criteria are met at which point the patient will be considered 
“eligible”.  If a patient has signed the informed consent but are deemed not eligible, the patient 
is considered a “screen failure” and exit the study.        
Eligible patients will be screened for imaging and anatomical suitability and if pre-procedural lab 
criteria are met.  Once these criteria are met, the patient is considered “enrolled”.     
A Screening/Enrollment Log provided by the Sponsor, will be maintained at the study site.  All 
patients assessed for study participation will be entered on the screening log. “Screen failures” 
will be recorded on the log with a failure reason.   
The screening of patients qualifying for this study should be carried out in a sequential, 
prospective manner, such that all patients are offered the possibility of participating in the study 
and are therefore, evaluated according to the selection criteria defined in this protocol.   
All patients that have signed the informed consent form, been assessed for study participation 
and deemed eligible for study participation by meeting the study criteria, will be assigned a 

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http://www.strokecenter.org/wp-content/uploads/2011/08/modified rankin.pdf  
 
 EuroQol (EQ – 5D)  
http://www.aaos.org/uploadedFiles/EQ5D3L.pdf 
 
 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
http://cvoutcomes.org/pages/3214 
 
7.8.6 Imaging Assessments  
Imaging assessments (TTE, TEE) shall be done according to the current version of the core lab 
echocardiographic acquisition protocol Appendix B.  Severity of baseline MR shall be defined as 
described in Section 18.0 and confirmed by the echo core lab prior to enrollment. 
7.8.7 Recommended Antiplatelet / Anticoagulation Therapy  
Recommendations for antiplatelet/anticoagulation therapy are detailed in the following sections.  
Alternative anticoagulation/antiplatelet regimens may be considered according to the needs of 
individual patients or a hospital’s standard practice; these will not constitute a protocol deviation. 
7.8.7.1 Pre Procedure Therapy 
All patients are recommended to receive aspirin (at least 75-100 mg daily) prior to implant 
procedure.  Patients on warfarin should be asked to discontinue use prior to implant procedure.   
7.8.7.2 Procedural Therapy 
Heparin will be administered at procedure start.  During the procedure, activated clotting time 
(ACT) will be monitored.  It is recommended that Heparin will be administered during the 
procedure as needed to maintain the patient’s ACT at ≥ 250 seconds. The sheaths may be 
removed when ACT level is appropriate (e.g., reaches < 150 seconds) after implantation of the 
study devices. 
7.8.7.3 Post Procedure Therapy 
 
Patients without other indication for therapeutic anticoagulation should receive antiplatelet 
therapy with aspirin (acetylsalicyclic acid; ASA) (100 mg daily) for at least 6 months.  
Additionally patients should receive a combination of Clopidogrel (75mg daily) and ASA 
(100mg daily) for the first month post-intervention. 
 
In patients with other indications for therapeutic anticoagulation treatment (e.g. atrial 
fibrillation), triple therapy is not recommended for the first month post-intervention.  

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documented unsuccessful attempts to schedule follow up visits sequentially (e.g., 1 year 
and 2 year follow-up), the patient will be considered “lost to follow-up.” 
 
In all cases of withdrawal (as described above), withdrawn patients will not undergo further 
study follow-up procedures after the time of study exit. A study patient that has been withdrawn 
from the study will not be replaced. 
7.8.7.11   Patient Study Completion  
Study patients complete and exit the study when no additional follow-up visits, procedures, or 
data collection are required. Patients may then continue to be followed by their primary health 
care provider as required.   
A patient will also be exited from the study in the following instances:  
 
Patient signs informed consent form, is deemed eligible and considered provisionally 
enrolled but does not undergo the study procedure 
 
Patient undergoes study procedure and does not receive investigational device (will exit 
study at the 30 day follow up visit)  
 
Patient undergoes study device explant or removal (will exit study 30 days post-explant 
or removal) 
 
Patient withdraws participation from the study or is withdrawn from the study 
 
Patient is lost-to-follow-up  
 
Patient expiration 
 
 

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8 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 
8.1 Reporting Procedure 
Adverse events will be captured from the time of enrollment (after patient eligibility is confirmed, 
per section 7.8.3) until the study patient’s participation has ended (i.e. completion of study or 
withdrawal of consent).  
 
The Investigator will report all adverse events to the Sponsor as soon as possible, but no later 
than 10 working days after the Investigator first learns of the event (but no later than 3 calendar 
days after awareness for patients at EU sites) 
 
Each adverse event must be reported on a separate AE CRF. In the event that the EDC system 
is not in service or is otherwise not accessible, the Sponsor must be notified by email 
 The AE CRF should be completed as 
soon as possible thereafter.  
 
At the time of initial notification, the following minimal information must be provided:  
 
Study site number 
 
Patient ID number 
 
Date of event 
 
Site’s awareness date 
 
AE description 
 
Causal relationship to device and implant procedure, if known 
 
The site will provide the Sponsor or designee copies of relevant supporting source 
documentation (e.g. admission H&P, implant procedure report, discharge summary, 
echocardiogram and laboratory results) for all adverse events requiring CEC adjudication (at a 
minimum, safety endpoints) and those events determined by the Sponsor to require additional 
investigation.  
 
Study patients will be carefully monitored during the clinical study for any possible adverse 
event. All adverse events will be fully investigated by the Investigator. Appropriate treatment for 
the patient will be initiated while the study follow up continues. Adverse events must be followed 

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until resolution, the patient is lost to follow-up, the patient has withdrawn consent, or the adverse 
event is otherwise explained. 
 
The Investigator will attempt to assess the involvement of the investigational device and / or 
study procedure in the adverse event. All observations and clinical findings, including the nature 
or the severity, will be documented on the appropriate case report form.  
 
The Investigator will report all adverse events to their local Institutional Review Board/Ethical 
Committee and / or National Regulatory Agency in accordance with the applicable 
requirements. 

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8.1.1 Findings that do not require reporting to the sponsor: 
 
For purposes of this study, the following findings are not considered adverse events requiring 
reporting to the Sponsor. These findings are normally expected to occur in association with 
treatment of mitral regurgitation or interventional structural heart procedures, or are associated 
with customary, standard care of patients undergoing transcatheter cardiovascular intervention: 
 
Post-operative pain (within 48 hour of procedure) not requiring treatment or treated with 
non-opioids 
 
Post-anesthesia emesis, nausea, or headache (within 24 hours of procedure). 
 
Abnormal or out of range lab values (e.g. electrolyte imbalance) that are not clinically 
significant and do not require correction or treatment.  
Note: Abnormal lab values that roll up to a diagnosis should not be reported as separate 
AEs (e.g. elevated BNP in patient with heart failure; increased K+ in patient with renal 
insufficiency; elevated WBC in patient with infection 
 
Pre-planned future surgical procedures not associated with the study procedure or 
device. 
 
Low grade temperature increase (≤ 101°F or 38.5°C) without signs or symptoms of 
infection.  
 
Minor, localized tenderness, swelling, induration, oozing, etc. at access site(s). 
 
Sinus bradycardia or tachycardia that does not require treatment or intervention 
 
Systolic or diastolic blood pressure changes that do not require treatment or intervention. 
 
Expected, non-clinically significant events such as non-clinically significant lab variances 
that do not require treatment. 
This listing of findings is intended to provide guidance to the investigational sites for the purpose 
of adverse event reporting. The Investigator should utilize his/her own clinical judgment in 
evaluating adverse experiences, and may decide that the above findings should be reported as 
adverse events. 
 
 
8.1.2 Pre-existing condition 
 

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Pre-existing medical conditions or symptoms reported prior to subject enrollment will not be 
recorded as an AE. In the event there is a worsening in the pre-existing medical condition or 
symptoms due to the device, implant procedure, or study related procedures, then an AE must 
be recorded. 
 
 

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8.2 Adverse Event Definitions and Classification 
 
Figure 10: Adverse Event Classification
 
8.2.1 Adverse Event  
An adverse event (AE) is defined in ISO 14155:2011 as any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory finding) 
in patients, users or other persons, whether or not related to the investigational medical device. 
 Note:  anticipated adverse events are adverse events that have been identified as possible 
adverse events related to the investigational medical device or the study procedure.  The 
anticipated events of this clinical study are summarized in Section 6.1. 

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8.2.2 Adverse Device Effect  
An adverse device effect (ADE) is defined in ISO 14155:2011 as any adverse event related to 
the use of an investigational medical device. This definition includes: 
 
Adverse event resulting from insufficient or inadequate IFU, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device. 
 
Any event resulting from use error or from intentional misuse of the investigational 
medical device. 
8.2.3 Serious Adverse Event  
A serious adverse event (SAE) is defined in ISO 14155:2011 as an adverse event that: 
 
led to death 
 
led to serious deterioration in the health of the patient that either resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization, or 
o Medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
 
Led to fetal distress, fetal death or a congenital abnormality or birth defect (not 
anticipated in this study as pregnant women are excluded from the study). 
8.2.4 Serious Adverse Device Effect 
A serious adverse device effect (SADE) is defined in ISO 14155:2011 as an adverse device 
effect that resulted in any of the consequences characteristics of a serious adverse event or that 
might have led to any of these consequences if suitable action had not been taken or 
intervention had not been made or if circumstances had been less opportune. 
 
8.2.5 Unanticipated Adverse Device Effect 
Unanticipated adverse device effect (UADE) means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. (21 CFR part 812.3 (s)). 

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8.2.6 Unanticipated Serious Adverse Device Effect  
Unanticipated adverse device effect (USADE) is defined in ISO 14155:2011 as any serious 
adverse device effect which by its nature, incidence, severity or outcome has not been identified 
in the risk analysis section of the study protocol. 
 
8.2.7 Adverse Event Causality Assessment 
For each AE, the Investigator will determine whether the event is related to the device and/or 
the implant procedure, and whether the event meets the definition of a SAE as outlined in 
section 8.2.3 
 
For the purpose of this study, each AE will be classified according to five different levels of 
causality per MEDEV 2.7/3 rev. 3 May 2015 as follows:  
 
Not related: relationship to the device or procedures can be excluded when:  
 
the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures;  
 
the event has no temporal relationship with the use of the investigational device or the 
procedures;  
 
the serious event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible;  
 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event;  
 
the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
 
the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
 
the event does not depend on a false result given by the investigational device used for 
diagnosis, when applicable; 
 
harms to the subject are not clearly due to use error; 
 
In order to establish the non-relatedness, not all the criteria listed above might be met at 
the same time, depending on the type of device/procedures and the serious event.  

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Unlikely: the relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be obtained.  
Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be 
classified as possible. 
Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explained by another cause, but additional information may be 
obtained. 
Related: the serious event is associated with the investigational device or with procedures 
beyond reasonable doubt when:  
 
the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures;  
 
the event has a temporal relationship with investigational device use/application or 
procedures;  
 
the event involves a body-site or organ that  
o the investigational device or procedures are applied to;  
o the investigational device or procedures have an effect on;  
 
the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known);  
 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible);  
 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out;  
 
harm to the subject is due to error in use;  
 
the event depends on a false result given by the investigational device used for 
diagnosis, when applicable;  
 
In order to establish the relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event.  

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The sponsor and the investigators will distinguish between the serious adverse events related to 
the investigational device and those related to the procedures (any procedure specific to the 
clinical investigation). An adverse event can be related both to procedures and the 
investigational device. Complications of procedures are considered not related if the said 
procedures would have been applied to the patients also in the absence of investigational 
device use/application.  
 
In some particular cases the event may not be able to be not adequately assessed because 
information is insufficient or contradictory and/or the data cannot be verified or supplemented. 
The sponsor and the Investigators will make the maximum effort to define and categorize the 
event and avoid these situations.  
 
8.2.8 Sponsor Assessment of Adverse Events 
All AEs will be reviewed by the Sponsor’s Clinical Safety department. Each AE will be assessed 
as to its relationship to the study device and/or implant procedure, whether it was anticipated or 
not anticipated, (based on the list of potential risks provided in section 6), and whether it 
qualifies as an SAE. 
 
8.2.9 Device Deficiency and Malfunction  
Device deficiency is defined in ISO 14155:2011 as an inadequacy of a medical device with 
respects to its identity, quality, durability, reliability, safety or performance. Device deficiencies 
include malfunctions, use errors and inadequate labeling.  
 
Device malfunction is defined in ISO 14155:2011 as a failure of an investigational medical 
device to perform in accordance with its intended purpose when used in accordance with the 
IFU. All reported device observations, malfunctions or deficiencies for the Edwards PASCAL 
System are required to be documented on the appropriate eCRF.  In the event of a suspected 
observation or device problem, the device shall be returned to the Sponosr to the extent 
possible for analysis.  Instructions for returning the investigational device will be provided by the 
Sponsor. 

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8.3 Deaths and Explants 
8.3.1 Patient Deaths 
In the event of patient death, every effort should be made to obtain a copy of the autopsy report 
and/or death summary.  Information on the cause of death and its relationship to the 
investigational device or study procedure will be determined by the Investigator. Copies of an 
autopsy report, if available, and/or a death summary are to be forwarded to the Study Sponsor.  
If a device is explanted during autopsy, the device should be returned to the Study Sponsor for 
analysis.  Return kits for devices will be provided upon request by the clinical monitor.   
8.3.2 Device Explants 
In the event the study device(s) is explanted, in the intra-operative or early post-operative period 
a copy of the explant procedure report must be provided to the Study Sponsor. Information on 
the cause of explant and its relationship to the study devices will be determined by the 
Investigator. Explanted study devices during this period should be returned to Study Sponsor for 
analysis.   
In the event the study device is explanted, in the late post-operative period, every effort should 
be made to obtain a copy of the explant procedure report, as applicable. Information on the 
cause of explant and its relationship to the study device will be determined by the Investigator. 
Copies of an explant report, if available, are to be sent to the Study Sponsor. Explanted study 
devices during this period should be returned to Study Sponsor for analysis.  

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9 
STATISTICAL CONSIDERATIONS 
9.1 Study Design and Sample Size 
This is a multi-center, multi-national, prospective, and single arm study. A total of 60 patients will 
be enrolled in the study.  This sample size is adequate to evaluate the safety and performance 
of the PASCAL System. Recent studies for CE marking of novel mitral repair technologies 
(listed in Table 8 below) have used sample size of 30 to 35 patients. A sample size of 30 
patients is therefore appropriate to reasonably assess the safety profile and technical 
performance of the PASCAL device.  
 
The analysis population will consist of 60 patients. No site will be allowed to enroll more than 
20% of the analysis population in the primary cohort. In addition, the study allows for 0 to 3 roll-
in patients per site, for a total maximum of 60 roll-in patients. The overall study therefore allows 
for up to 120 patients: 60 in the analysis population, and up to 60 additional roll-in patients. 
 
 
 
 
 
Table 8. Safety and Performance studies for CE marking of novel devices for the treatment of 
mitral regurgitation. 
Month, Year  
(CE Mark) 
Study Title 
Sample 
Size 
Primary 
Outcome 
Assessment 
Device/Sponsor 
Sep, 2011  
AMADEUS™ (CARILLON Mitral 
Annuloplasty Device European 
Union Study)  
 
Source: European Society of Cardiology  
30 
30 Day 
Carillon /  
Cardiac 
Dimensions  
Sep, 2015 
Cardioband Adjustable 
Annuloplasty System for 
Transcatheter Repair of Mitral 
Valve Regurgitation 
 
Source: Clinical report on file at Edwards 
31 
30 Day 
Cardioband/  
Valtech, Inc. 
Feb, 2016 
Mitralign Percutaneous 
Annuloplasty First In Man Study 
 
Source: www.clinicaltrials.gov 
35 
30 Day 
MPAS Implant/          
Mitralign, Inc. 
 

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9.2 Analysis Population 
 
Intent-to-treat population  
The intention-to-treat (ITT) population includes all patients in whom the study procedure 
has been attempted (i.e., incision).   
 
Per-protocol population   
The per-protocol (PP) population includes all patients in whom the study device was 
introduced in the body, and do not have any major protocol deviations.  
 
Roll-in population   
Up to three roll-in patients per site may be allowed, but not required (e.g., for sites with 
sufficient prior experience with the system). The study Sponsor will review each situation 
to determine when a site may start enrolling in the ITT population. 
The PP population will be the primary analysis population for performance and safety 
assessment.  The ITT population will be used for additional safety analysis. Subgroup analysis 
by etiology may be performed. For patients with mixed etiology, the echo core lab will determine 
the dominant etiology for analysis. 
 
9.3 Statistical Analysis  
A first analysis will be performed when 30 patients complete 30-day follow-up, and a second 
analysis when all patients in the primary cohort complete their 30-day follow-up.  A pooled 
analysis of all patients from the primary cohort and additional cohort will also be performed. 
Descriptive statistics will be presented for all primary and secondary endpoints.  For quantitative 
variables, the mean values, standard deviation, maximum and minimum will be calculated. The 
95% confidence interval (CI) for the mean will be calculated when relevant.  
For qualitative variables, absolute and relative frequencies are determined. Exact binomial 95% 
confidence interval for proportions will be calculated when relevant.  
For combined and individual clinical endpoints the survival rate (and 95% CI) will be calculated 
using Kaplan-Meier estimator. Kaplan-Meier survival curves will also be presented when 
relevant. 
 

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9.4 Missing Data  
All possible steps will be taken to minimize missing data in the study, including monitoring of 
data forms for completeness and efforts to track and maintain contact with study patients during 
the follow-up period. 
10 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
10.1 Data Safety Monitoring Board (DSMB) and Clinical Events Committee (CEC) 
10.1.1 Data Safety Monitoring Board (DSMB)  
The Data Safety Monitoring Board (DSMB) will be the primary independent Data and Safety 
advisory board for the CLASP Study. The independent DSMB will have the responsibility to 
assess aggregate safety data (and if requested the critical performance endpoints) on an 
ongoing basis, evaluate trends of adverse events and their effect on trial conduct and device 
risk assessment, and to recommend to the sponsor whether to continue, suspend, modify or 
stop the clinical investigation.  The DSMB will communicate all safety-related trial 
recommendations to the Sponsor. 
The DSMB will consist of a minimum of three physician members that are medical experts in the 
areas of CV surgery, interventional cardiology, and heart failure. The DSMB will also include an 
experienced biostatistician. Its conduct will be governed by a written DSMB charter describing 
its rules of operation and responsibilities.   
10.1.2 Clinical Events Committee (CEC) 
The Clinical Events Committee (CEC) is an independent committee that will provide a standard, 
systematic and unbiased assessment of pre-determined endpoints to ensure that they are 
adjudicated uniformly by a single group, using the definitions specified in the Protocol and CEC 
Charter. 
The CEC will consist of a minimum of three members and will be comprised of physicians with 
expertise in CV surgery, interventional cardiology, heart failure, and neurology. 
The scope, procedures, and events classification system will be defined in a written CEC 
charter. 

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10.2 Core Laboratory 
An echocardiography core laboratory will be used for the independent assessment of image 
findings. Standard measurement processes will be designed by the independent core laboratory 
and specified in written core laboratory guidelines. Each of the selected investigative sites will 
receive training on the acquisition, interpretation (in especially regarding patient selection) and 
transmission of images.  Any additional (unscheduled) imaging data should be documented and 
sent to Edwards.  
10.3 Monitoring 
All clinical sites will be monitored periodically by the Sponsor or designee to ensure compliance 
with the protocol and the Investigator’s Agreement and that all study patients have been 
properly consented.  The monitor will ensure that the completed eCRFs match the source 
documents and work with the site to resolve differences through electronically generated 
queries or formal action items.  
   
10.3.1 Monitoring Methods  
A study monitor will be assigned to monitor the progress of the study by the Study Sponsor.  
The study monitor will remain in close contact with the study center throughout the duration of 
the study to provide any needed materials, (e.g. study forms, etc.) answer any questions and 
ensure that proper staffing levels are being maintained by the Investigator .  The study monitor 
will be responsible for verifying that patients have signed the informed consent as required by 
regulations, reviewing the data recorded on the eCRFs and visiting the study center periodically 
to observe study progress and compliance with the study protocol and regulations applicable to 
this clinical study. 
Monitoring visits will be scheduled throughout the duration of the clinical study between the 
monitor and the Investigator at a mutually convenient and available time.  These visits will 
assure the study protocol is being followed, the Institutional Review Board/Ethical Committees 
and Competent Authorities have been notified of approved protocol changes as required, 
complete records are being maintained, appropriate timely reports have been made to the Study 
Sponsor and the IRB/EC, device and device inventory are controlled and the Investigator is 
carrying out all agreed activities. Any personnel changes must be reported to the study monitor 
immediately and a training program scheduled and documented.  

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Prior to patient enrollment, an initiation visit will be completed at the study center to ensure the 
following:   
 
Institutional Review Board/Ethics Committee and applicable regulatory body approvals 
have been obtained and documented,  
 
The Investigator (s) and study personnel are appropriately trained and clearly 
understand the study,  
 
The Investigator (s) and study personnel accept the obligations incurred in undertaking 
this clinical study, 
 
The Delegation of Authority form has been completed properly. 
Periodic monitoring visits will be made at the enrolling study center in accordance with center 
enrollment rates and / or the monitoring plan. Upon termination or conclusion of the study, the 
study monitor will perform a close-out visit.  Additional details will be included in the Monitoring 
Plan. 
10.4 Data Management 
A qualified third party service partner will be used to host the clinical study database.  The 
hosting facility will have a multi-level protected environment, restricted access with high-end 
user recognition technology, and multi-point backup of critical data. Passwords will be issued to 
appropriate data management personnel to ensure confidentiality and protection of the data. 
The Study Sponsor’s data management is responsible for providing a clean data set at the end 
of the clinical investigation. Queries should be resolved by the Investigator or a person 
designated by the Investigator in a timely manner. Data snapshots will be performed for interim 
analysis. When all data is complete, the database will be locked and data analyzed. 
10.4.1 Data Collection Methods 
The Study Sponsor will provide the study center with the clinical protocol, electronic case report 
forms, sample informed consent form, and all other necessary study-related documents.  Study 
Sponsor’s Clinical Affairs Department, or designee, will conduct all aspects of data quality 
control and assurance of the study center including but not limited to, data reviewing, data 
monitoring, and form collection. 
10.4.2 Case Report Forms (CRFs) 
Electronic case report forms (eCRFs) will be used to collect all patient data during the 
trial.  Electronic CRFs must be fully completed for each patient, and signed electronically by the 
Investigator and/or designee. The eCRFs should be completed at the first earliest opportunity. 

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The Investigator, or an individual designated by him/her, is responsible for recording all data 
from the trial onto the eCRFs on a dedicated website.  All data entered may be subjected to 
data type verification and range checking.  The operator is notified of queries that may occur, 
and depending on the data verification sub-routines (edit checks), the operator might need to 
resolve that queries before moving to the next entry field.  The Investigator is required to provide 
an electronic signature on the appropriate eCRF pages to verify that he/she has reviewed the 
recorded data. If for any reason the eCRFs are unavailable, or access to the electronic 
database is limited, paper CRF forms must be completed and submitted to the sponsor. 
Completed eCRFs will be reviewed at the investigational site and remotely by authorized 
Edwards Lifesciences or designee personnel at regular intervals throughout the trial. If a query 
is discovered, the Clinical Research Coordinator will be notified.  Corrections to the eCRFs will 
be made by the research Study Coordinator, approved by the Investigator or designee and 
verified by the sponsor. 
 
The cycle of data editing will be ongoing until all the data are clean.  If further data entry or 
source documentation errors are discovered during the site visit, additional queries will be 
generated and will have to be addressed by the clinical site. 
10.4.3 Source Documentation Requirements 
The Clinical Research Coordinator designated by the Investigator, and documented on the 
Delegation of Authority log, will perform primary data collection drawn from source 
documentation review (patient’s medical record). Data to be collected for the study purposes 
must not be entered directly onto eCRFs. The data shall be recorded from original source 
documents and available for review by the study monitor. Regulations require that Investigators 
maintain information in the study patient’s medical records that corroborate data collected on 
the eCRFs. The source documentation may consist of but is not limited to: operative or 
procedure reports, progress notes, discharge summaries, laboratory reports, radiographic 
reports, medication logs, and worksheets. Source Documents may be in electronic form and/or 
hard (paper) copies. 
10.5 Patient Visits 
The Investigator or designee shall inform study patients of the importance of returning for 
scheduled follow-up visits and reporting any address or telephone number changes. The 
Investigator shall make every attempt to follow the study patients. 

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The Investigator or designee shall keep a separate log of the patients’ names and current 
contact information to facilitate their record keeping and ability to contact the patients for future 
follow-up. If a patient cannot be reached for a follow-up assessment, the Investigator will 
document the missed visit and effort made to contact the patient or the patient’s primary health 
care provider.  Patients who miss a visit will not be considered withdrawn, and an effort to 
contact them at the next follow-up visit interval will be made by the Investigator.   
10.6 Vulnerable Population 
Children or patients under guardianships are perceived as vulnerable population. Both 
subgroups are excluded from this study. 
 
11 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
11.1 Protocol Deviation  
If an Investigator or designee contacts a Clinical Affairs representative to obtain prior approval 
for a change to the clinical study requirements, the approval or disapproval will be documented 
in writing. A copy of the approval or disapproval will be forwarded to the Investigator and a copy 
will be maintained in the study files.  
 
A major protocol deviation or noncompliance are those that may have a significant impact on 
subject safety, well-being, the subject’s willingness to participate in the study, or that may 
compromise the integrity of the study data and analysis, including:  
a) Subject implanted/treated with study device not having met eligibility criteria at the 
time of implant/treatment.  
b) Informed Consent not signed or signed after the initiation of non-standard of care, 
research related assessments.  
c) UADE not reported to IRB/EC/Sponsor within the required timeframe  
d) Unauthorized use/implant of an investigational device  
 
A minor protocol deviation or noncompliance is unlikely to have a significant impact on subject 
safety, wellbeing, or is unlikely to compromise the integrity of the study data and analysis.  All 
protocol deviations or noncompliances will be reported to the IRB/EC, as required.  
 

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11.2 Audits / Inspections 
Study centers may be audited during the course of and after completion of the clinical 
investigation by Edwards or Edwards’ designees, IRB/EC, competent authority or other 
applicable regulatory authorities.  
The Investigator must provide the auditor with all clinical investigation documents including the 
medical records for all enrolled patients.  
Edwards will evaluate any non-compliance and issue corrective actions, discontinue enrolment 
or, as last measure, close the clinical investigation site.  
11.3 Communication Procedures 
During the course of the study, all study relevant correspondence (letters, telephone call, emails 
and faxes) regarding the study must be maintained in the study binder provided by the Study 
Sponsor.  This binder must be made available during monitoring visits and audits. 
 
12 
STATEMENTS OF COMPLIANCE 
12.1  Applicable Regulations and Guidelines  
This clinical investigation will be conducted in compliance with the applicable regulations for the 
conduct of clinical investigations with human beings, especially with regard to: 
• 
The Declaration of Helsinki (2013)  
• 
ISO 14155:2011  
• 
ICH/GCP current version  
• 
All applicable local and national requirements in the participating countries 
12.2  Ethics and Regulatory Bodies 
Prior to start of the study, the CIP and other relevant study documents will be submitted for 
approval by the ethics and regulatory bodies per applicable regional regulations. Edwards will 
record changes to the CIP in amendments and submitted to ethics and regulatory bodies as 
applicable. Investigators and study personnel will be trained on all amendments. 
All patients must be provided with a written informed consent which is approved by the site’s 
ethics body. Edwards will provide a master English informed consent form and patient 
information sheet to be used in the study. Each site must provide Edwards with a copy of the 
clinical site’s ethics approval letter or vote and the approved informed consent. The approval 

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letter must specify the documents for which approval has been granted.   Approvals for the 
continuation of the trial at each clinical site must be kept current and notifications forwarded to 
Edwards. 
12.3  Insurance 
Patients who participate in this study will be insured for study related injuries according to local 
regulatory requirements. Edwards will organize appropriate insurance coverage which will be 
available throughout the entire study. 
12.4  Data Protection and Patient Confidentiality 
The Study Sponsor is dedicated to maintaining the confidentiality and privacy of patients who 
volunteer to participate in the study.  Passwords are issued to appropriate personnel to insure 
confidentiality and protection of the database by allowing variable levels of access to the 
computer system. In addition, the Principal Investigator is responsible for ensuring 
confidentiality throughout the clinical study. Hard copies of source documents are to be 
maintained in a secure area with limited access and duration according to country specific 
guidelines and regulations.  All patient identifiers will be obliterated from all copies of source 
documents that have been removed from the study site.  Patient identifiers include, but are not 
limited to: patient’s name, social security number or equivalent, and medical / hospital number.  
All study documents for the clinical study will identify the patient by a patient study identification 
number assigned by the Sponsor and patient initials (if applicable). Subject to the same 
confidentiality obligations as described above, patient data (including, but not limited to, imaging 
assessments) collected during the course of this investigation may be used in other Edwards 
research and development efforts. 
12.5  Study Termination  
Edwards will monitor the progression of the clinical investigation. If warranted, the clinical 
investigation may be suspended or discontinued early if there is an observation of serious 
adverse reactions presenting an unreasonable risk to the clinical investigation population. 
Edwards may terminate Investigator and site participation in the clinical investigation if there is 
evidence of failure to maintain adequate clinical standards, failure to comply with the clinical 
investigational plan, fraud or any other forms of misconduct. 
In the event of clinical investigation termination or suspension, Edwards will send a report 
outlining the circumstances to the corresponding IRB/EC, regulatory body and all Investigators. 

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A suspended or terminated clinical investigation may not be re-initiated without approval of the 
corresponding IRB/EC and competent authority. 
12.6  Investigator Reimbursement and Contracting  
Edwards will reimburse efforts undertaken for inclusion and follow-up of patients, and 
documentation of patient data within the study. A contract with the principal Investigator and/or 
the respective hospital will be agreed on and signed prior to study start. Within this, an overall 
fee per patient, broken down to individual visits, will be included. 
This patient fee will cover all expenses for material used and procedures to be performed 
according to the CIP.  
The CIP, and any future changes thereof, will be part of the contract. 
 
13 
INVESTIGATOR RESPONSIBILITIES 
13.1.1 General Duties 
The Investigator shall ensure that all work and services described herein, or incidental to those 
described herein, shall be conducted in accordance with the highest standards of medical and 
clinical research practice and the applicable regulations.  The Investigator shall be responsible 
for the day to day conduct of the clinical study and for the safety and well-being of patients 
enrolled. The Investigator will provide copies of the current study protocol to all staff responsible 
for study conduct. 
 
The Investigator is responsible for obtaining and maintaining IRB approval for the study at 
his/her study center.   
 
If there is a change or addition of an Investigator, an amended Clinical Study Agreement must 
be completed promptly. 
13.1.2  Investigator Records 
The Investigator will maintain the accurate, complete, and current records relating to 
participation in this clinical study.  Study records including CRFs and supporting data, signed 
Clinical Study Agreement, protocols and protocol amendments, signed informed consents,  
device tracking logs, IRB approval letters, IRB submissions, correspondence, including required 
reports, and other documents pertaining to the conduct of the study must be kept on file by the 

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Investigator.  If the Investigator wishes to assign the responsibility of maintaining the study files 
to someone else or move them to another location, he/she should consult with the Study 
Sponsor in writing regarding the change.   
 
Upon Study completion, the study files must be maintained in a known location for a period in 
accordance with local regulatory requirements.   
13.1.3  Investigator Reports 
The Investigator will prepare and submit the following accurate and complete reports to the 
Study Sponsor and IRB/EC in a timely manner: 
 
Anticipated and unanticipated serious adverse device effects occurring during the study will be 
reported as described in section 8.1.   
Withdrawal of IRB/EC approval will be reported to the Sponsor within 5 working days  
Annual progress reports will be submitted to the IRB/EC.   
Deviation from the clinical study protocol. Deviations to protect the patient’s life or physical well-
being in an emergency will be reported to the Study Sponsor within 5 working days and to the 
IRB/EC according to their reporting policy. 
Use of the study device without informed consent will be reported within 5 working days after 
the use occurs.   
A final written report within three months of completion or termination of the trial.   
Upon request by a reviewing IRB/EC or the pertinent regulatory agencies, the Principal 
Investigator will provide current information about any aspect of the investigation. 
13.2  Sponsor Responsibilities 
13.2.1 General Duties 
As the Study Sponsor of this clinical study, Edwards Lifesciences has the overall responsibility 
for the conduct of the study, including assurance that the study meets the regulatory 
requirements of the pertinent regulatory agencies.   
 
In addition, the Study Sponsor declares that no employee/affiliate of the Sponsor or Investigator 
will be included or encouraged to participate in this investigational study. 
 

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The Study Sponsor will inform the Investigator of any new information about the study that may 
affect the health, safety or welfare of the patients or which may influence patient’s decision to 
continue participating in the study. 
 
14 
STUDY CHANGES 
Changes in the protocol may be made only by written amendment agreed upon by the Study 
Sponsor, the regulatory agency and IRB/EC.  As appropriate, the Study Sponsor will submit 
protocol amendments to the pertinent regulatory agencies and Investigators to obtain IRB/EC 
approval prior to implementation. 
 
15 
PUBLICATION POLICY 
 
 
 
 
 
 
 
 
 
 
 

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16 
ACRONYMS 
Acronym 
Definition 
ACE 
Angiotensin converting enzyme 
ACT 
Activated clotting time  
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AR 
Aortic Regurgitation 
ASA 
Acetylsalicyclic acid 
ASE 
American Society of Echocardiography 
AV 
Atrioventricular 
BNP 
B-type Natriuretic Peptide  
CBC 
Complete Blood Count 
CEC 
Clinical events committee 
CI 
Confidence interval  
CIB 
Clinical Investigator’s Brochure 
CIP 
Clinical Investigation Plan. 
CK 
Creatinine Kinase 
CKMB 
Creatinine Kinase Muscle/Brain 
cm 
Centimeter 
Cr 
Creatinine 
CRF 
Case Report Form 
CRT 
Cardiac resynchronization therapy  
dl 
Deciliter 
DSMB 
Data Safety Monitoring Board 
DMR 
Degenerative/Primary Mitral Regurgitation  
DVI 
Doppler Velocity Index  
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECHO 
Echocardiography 
EDC 
Electronic Data Capture  
EROA 
Effective Regurgitant Orifice Area 
EQ-5D 
Five Dimensions Quality of Life Questionnaire 
F 
French 
FDA 
U.S. Food and Drug Administration  
FIH 
First-in-Human 
FMR  
Functional/Secondary Mitral Regurgitation 
FUP 
Follow-Up 
Hg 
Mercury 
IABP 
Intra-Aortic Balloon Pump 

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ICH/GCP 
International Conference on Harmonization / Good Clinical Practice 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
INR 
Internationalized Normalized Ratio 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent-to-Treat 
IV 
Intravenous 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LV 
Left Ventricle 
LVAD 
Left Ventricular Assist Device 
LVEDD 
Left Ventricular End Diastolic Diameter 
LVEDV 
Left Ventricular End Diastolic Volume 
LVEF 
Left Ventricular Ejection Fraction 
LVESV 
Left Ventricular End Systolic Volume 
LVOT 
Left Ventricular Outflow Tract 
m 
Meter 
MAE 
Major Adverse Events 
MD 
Medical Doctor 
mg 
Milligram 
MI 
Myocardial Infarction 
MLWHF 
Minnesota Living With Heart Failure 
mm 
Millimeter 
MR 
Mitral Regurgitation 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
MV 
Mitral Valve 
MVA 
Mitral Valve Area  
MVARC 
Mitral Valve Academic Research Consortium 
MVR 
Mitral Valve Replacement 
N 
Number 
NIH 
National Institutes of Health 
NIHSS 
National Institutes of Health Stroke Scale 
NT-proBNP 
N-terminal pro b-type natriuretic peptide  
NYHA 
New York Heart Association 
OR 
Operating Room 
PCI 
Percutaneous Coronary Intervention 
PET 
Polyethylene Terephthalate 
PI 
Principal Investigator  

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PP 
Per-protocol  
PT 
Prothrombin Time 
PTFE 
Polytetrafluoroethylene 
PTT 
Partial Thromboplastin Time 
QoL 
Quality of Life 
Qp 
Pulmonary Blood Flow  
Qs 
Systemic Blood Flow  
RBC 
Red Blood Cell(s) 
rHFH 
Recurrent heart failure hospitalization 
s 
Second(s) 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAVR 
Surgical Aortic Valve Replacement 
SC 
Steering Committee 
Six (6) MWT 
Six minute walk test. 
STS 
Society of Thoracic Surgeons 
TEE 
Trans-Esophageal Echocardiogram 
TF 
Transfemoral 
TIA 
Transient Ischemic Attack 
TMVr 
Transcatheter Mitral Valve Repair  
TTE 
Transthoracic Echocardiogram 
USADE 
Unanticipated Serious Device Effect 
VSD 
Ventricular Septal Defect  
WBC 
White Blood Cell(s)  
 
 
 

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17 
DEFINITIONS 
Access site  
(VARC-1) 
Any location (arterial or venous) traversed by a guide-wire, a 
catheter or a sheath 
Access site related 
complication 
(VARC-1) 
Any adverse clinical consequence possibly associated with any 
of the access sites used during the procedure 
Access site and 
Vascular 
Complications  
(M-VARC 2015) 
 
I. Vascular complications 
A. Major access site vascular complications, including: 
i. Aortic dissection or aortic rupture, or 
ii. Access site-related† arterial or venous injury 
(dissection, stenosis, ischemia, arterial, or venous 
thrombosis including pulmonary emboli, perforation, 
rupture, arteriovenous fistula, pseudoaneurysm, 
hematoma, retroperitoneal hematoma, atrial septal 
defect‡), irreversible nerve injury, or compartment 
syndrome resulting in death; hemodynamic compromise; 
life-threatening, extensive, or major bleeding (MVARC 
bleeding scale); visceral ischemia; or neurological 
impairment, or 
iii. Distal embolization (noncerebral) from a vascular 
source requiring surgery or resulting in amputation or 
irreversible end-organ damage, or 
iv. Unplanned endovascular or surgical interventions 
resulting in death; life-threatening, extensive, or major 
bleeding (MVARC bleeding scale); visceral ischemia; or 
neurological impairment 
B. Minor access site vascular complications, including: 
i. Access site arterial or venous injury (dissection, 
stenosis, arterial, or venous thrombosis including 
pulmonary emboli, ischemia, perforation, rupture, 
arteriovenous fistula, pseudoaneurysm, hematoma, 
retroperitoneal hematoma, atrial septal defect‡) not 
resulting in death; life-threatening, extensive, or major 
bleeding (MVARC scale); visceral ischemia; or 
neurological impairment, or 
ii. Distal embolization treated with embolectomy and/or 
thrombectomy not resulting 
in amputation or irreversible end-organ damage, or 
iii. Any unplanned endovascular stenting or unplanned 
surgical intervention not meeting the criteria for a major 
vascular complication, or 
iv. Vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 

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II. Cardiac structural complications due to access-related issues 
A. Major cardiac structural complications, including: 
i. Cardiac perforation* or pseudoaneurysm resulting in 
death, life-threatening bleeding, hemodynamic 
compromise, or tamponade, or requiring unplanned 
surgical or percutaneous intervention 
B. Minor cardiac structural complications, including: 
i. Cardiac perforation* or pseudoaneurysm not meeting 
major criteria 
 
*Including the left ventricle, left atrium, coronary sinus, right 
atrium, and right ventricle. †May arise from the access 
procedure per se or complications from vascular closure 
devices. ‡Meeting pre-specified criteria for a hemodynamically 
significant shunt, or requiring unplanned percutaneous or 
surgical closure. 
Acute Kidney Injury 
(AKI)  
(M-VARC 2015) 
 
Acute kidney injury defined as maximal change in sCr from 
baseline to 7 days post-procedure 
Stages: 
Stage 1- Increase in sCr to 150%–199% (1.50–1.99× increase 
vs. baseline), increase of ≥0.3 mg/dl (≥26.4 mmol/l) within 48 h, 
or urine output <0.5 ml/kg/h for ≥6 h but <12 h 
Stage 2- Increase in sCr to 200%–299% (2.00–2.99× increase 
vs. baseline) or urine output <0.5 ml/kg/h for ≥12 h but <24 h 
Stage 3- Increase in sCr to ≥300% (>3.0× increase vs. 
baseline), sCr of ≥4.0 mg/dl (≥354 mmol/l) with an acute 
increase of ≥0.5 mg/dl (44 mmol/l), urine output <0.3 ml/kg/h for 
≥24 h, or anuria for ≥12 h; patients receiving renal replacement 
therapy are considered stage 3 irrespective of other criteria. 
Adverse Device 
Effect (ADE)  
(ISO 14155:2011) 
 
Adverse event related to the use of an investigational medical 
device 
NOTE 1- This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
NOTE 2- This definition includes any event resulting from use 
error or from intentional misuse of the investigational medical 
device. 

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Adverse Event (AE) 
(ISO 14155:2011) 
 
Any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory 
findings) in patients, users or other persons, whether or not 
related to the 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. 
Bleeding  
(M-VARC 2015) 
 
I. Minor 
Any overt, actionable sign of hemorrhage (e.g., more bleeding 
than would be expected for a clinical circumstance, including 
bleeding found by imaging alone) that meets ≥1 of the following: 
requiring nonsurgical medical intervention by a health care 
professional; leading to hospitalization or increased level of 
care; prompting evaluation; or requires 1 or 2 U of whole blood 
or packed RBC transfusion and otherwise does not meet criteria 
for major, extensive, or life threatening bleeding. 
II. Major 
Overt bleeding either associated with a drop in the hemoglobin 
of ≥3.0 g/dl or requiring transfusion of ≥3 U of whole blood or 
packed RBCs AND does not meet criteria of life-threatening or 
extensive bleeding. 
III. Extensive 
Overt source of bleeding with drop in hemoglobin of ≥4 g/dl or 
whole blood or packed RBC transfusion ≥4 U within any 24-h 
period, or bleeding with drop in hemoglobin of ≥6 g/dl or whole 
blood or packed RBC transfusion ≥4 U (BARC type 3b) within 
30 days of the procedure. 
IV. Life-threatening 
Bleeding in a critical organ, such as intracranial, intraspinal, 
intraocular, or pericardial necessitating surgery or intervention, 
or intramuscular with compartment syndrome OR bleeding 
causing hypovolemic shock or hypotension (systolic blood 
pressure <90 mm Hg lasting >30 min and not responding to 
volume resuscitation) or requiring significant doses of 
vasopressors or surgery. 
V. Fatal 
Bleeding adjudicated as being a proximate cause of death. 
Severe bleeding adjudicated as being a major contributing 
cause of a subsequent fatal complication, such as MI or cardiac 
arrest, is also considered fatal bleeding. 
Cardiac Tamponade 
Pressure on the heart that occurs when blood or fluid builds up 

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in the space between the heart muscle (myocardium) and the 
outer covering sac of the heart (pericardium). 
Clinical Success 
Procedural success with evidence of MR reduction ≤ MR2+ and 
without MAEs at 30 days. Per patient analysis.  
Coagulopathy  
A pathologic condition that affects the ability of the blood to 
coagulate. Examples include hemophilia, drug-induced clotting 
disorder, thrombocytopenia and Von Willebrand's disease  
Congestive Heart 
Failure (CHF) 
(STS) 
Diagnosis requires physician documentation or report of any of 
the following:   
 
Unusual dyspnea on light exertion  
 
Recurrent dyspnea occurring in the supine position 
 
Fluid retention; or the description of rales, jugular 
venous distension 
 
Pulmonary edema on physical exam, or pulmonary 
edema on chest x-ray presumed to be cardiac 
dysfunction 
 
A low ejection fraction alone, without clinical evidence of heart 
failure does not qualify as heart failure.  
An elevated BNP without other supporting documentation 
should not be reported as CHF 
Death  
 
(M-VARC 2015 
Definition and Hicks 
JACC 2014) 
 
All events with an outcome of death will be classified to 
determine whether the death was related to cardiovascular (CV) 
or non-cardiovascular (non-CV) cause.  
 
Although categorizing the initiating or proximate cause of 
cardiovascular death may be difficult, major complications 
contributing to death should be identified. A diagnosis of non-
cardiovascular death requires the primary cause to be clearly 
related to another condition (e.g., trauma, cancer, or suicide). 
For this study purpose, all deaths that are not unequivocally 
related to a non-cardiovascular condition are considered 
cardiovascular death. 
 
CV Death 
The primary cause of CV death will be categorized using the 
following choices: 
o Arrhythmia and/or conduction system disturbance 
o Cardiovascular infection and sepsis (e.g. Endocarditis) 
o Device failure  
o Heart failure  
o Major bleeding 
o Myocardial Infarction 

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o Stroke 
o Sudden, unexpected death / unknown 
o Tamponade  
o Thromboembolism  
o Other CV cause 
 
If death was due to a heart failure, it will be sub-classified into: 
o LV dysfunction 
o RV dysfunction 
o Biventricular dysfunction 
 
Non-CV Death 
A diagnosis of non-CV death requires the primary cause to be 
clearly related to another condition due primarily to an 
identifiable non-CV cause or etiology. Specific diagnoses may 
include respiratory failure, pneumonia, trauma, suicide, or any 
other non-cardiovascular defined causes (e.g., liver disease, 
malignancies etc.) not included in the previous categories. 
 
Primary cause of non-CV death 
The primary cause of non-CV death will be categorized using 
the following choices: 
o Adverse drug reaction or overdose 
o Cancer  
o Gastrointestinal 
o Liver failure  
o Non-cardiovascular infection and sepsis (e.g. pneumonia) 
o Pancreatic 
o Renal failure  
o Respiratory Failure 
o Trauma  
o Other non-CV cause 
Degenerative/ 
Primary Mitral 
Regurgitation  
(M-VARC 2015) 
Abnormal backflow of blood from left ventricle to left atrium due 
to underlying degenerative/structural mitral valve pathology.  
Severity is as defined by ASE.  
Device success 
Device is deployed as intended and the delivery system is 
successfully retrieved as intended at the time of the patient’s 
exit from the cardiac catheterization laboratory. Per device 
analysis. 
Conversion to open 
mitral valve surgery 
during a 
transcatheter 
Sub-classified as: 
o Secondary to mitral valve apparatus damage or dysfunction, 
requiring surgical valve repair or replacement, or 

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procedure  
o Secondary to procedural complications (such as cardiac 
perforation, removal of an embolized device, and so on) 
Effective Regurgitant 
Orifice Area (ASE) 
Cross-sectional area of the vena contracta of the regurgitant jet  
Enrollment 
Patient enrollment in this clinical study is established when a 
patient has signed the informed consent form agreeing to 
participate in the study and has been deemed eligible for study 
participation by meeting the study criteria.   
Explant  
Removal of the study device for any reason. 
Functional/ 
Secondary Mitral 
Regurgitation  
(M-VARC 2015) 
Abnormal backflow of blood from left ventricle to left atrium 
principally caused by global or regional left ventricular 
remodeling and/or severe left atrial dilation. 
Severity is as defined by ASE. 
Heart Team 
Multidisciplinary team consisting of local experts experienced in 
the care of patients with mitral valve disease.  At a minimum, 
the heart team should include a heart failure/valve cardiologist, 
an interventional cardiologist skilled in the relevant access and 
device implantation procedures, a mitral valve cardiac surgeon, 
and an imaging specialist.   
Implant procedure 
(Index procedure) 
The procedure in which placement of the investigational device 
in the mitral valve regurgitant orifice takes place 
Infection 
Known infection requiring intravenous antibiotics for other than 
prophylaxis, and/or extended hospitalization 
KCCQ 
Kansas City Cardiomyopathy Questionnaire is an instrument 
used to quantify physical function, symptoms, social function, 
self-efficacy and knowledge, and quality of life.  
Major Adverse 
Events (MAE) 
Cardiac mortality, stroke, myocardial infarction, new need 
for renal replacement therapy, severe bleeding, and non-
elective cardiovascular surgery for device related 
complications. 
Mitral regurgitation 
The condition in which incompetency of the mitral valve causes 
abnormal backflow of blood from the left ventricle to the left 
atrium during the systolic phase of the cardiac cycle. 

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Myocardial Infarction 
(M-VARC 2015) 
 
I. Periprocedural MI (≤48 h after the index procedure) 
A. In patients with normal baseline CK-MB (or cTn): The 
peak CK-MB measured within 48 h of the procedure 
rises to ≥10× the local laboratory ULN plus new ST-
segment elevation or depression of ≥1 mm in ≥2 
contiguous leads (measured 80 ms after the J-point), or 
to ≥5xULN with new pathological Q waves in ≥2 
contiguous leads or new persistent LBBB, OR in the 
absence of CK-MB measurements and a normal 
baseline cTn, a cTn (I or T) level measured within 48 h 
of the PCI rises to ≥70× the local laboratory ULN plus 
new ST-segment elevation or depression of≥1 mm in ≥2 
contiguous leads (measured 80 ms after the J-point), or 
≥35× ULN with new pathological Q waves in ≥2 
contiguous leads or new persistent LBBB. 
B. In patients with elevated baseline CK-MB (or cTn): 
The CK-MB (or cTn) rises by an absolute increment 
equal to those levels recommended above from the 
most recent pre-procedure level plus, new ECG changes 
as described. 
II. Spontaneous MI (>48 h after the index procedure)  
Detection of rise and/or fall of cardiac biomarkers (preferably 
cTn) with at least 1 value above the 99th percentile URL (or 
ULN in the absence of URL) together with at least 1 of 
the following: 
A. Symptoms of ischemia 
B. ECG changes indicative of new ischemia (new ST-
segment or T-wave changes or new LBBB) or new 
pathological Q waves in $2 contiguous leads 
C. Imaging evidence of a new loss of viable myocardium 
or new wall motion abnormality 
III. MI associated with sudden, unexpected cardiac death 
Sudden cardiac death or cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by 
presumably new ST-segment elevation or new LBBB and/or 
evidence of fresh thrombus by coronary angiography and/or at 
autopsy, but death occurs before blood samples could be 
obtained or at a time before the appearance of cardiac 
biomarkers in the blood 
IV. Pathological findings of an acute myocardial infarction 
New York Heart 
Association 
Classification (NYHA 
Class) 
Class I: Patients with cardiac disease but without resulting 
limitations of physical activity. 
Class II: Patients with cardiac disease resulting in slight 
limitation of physical activity. Patients are comfortable at rest. 

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Ordinary physical activity results in fatigue, palpitation, dyspnea, 
or anginal pain. 
Class III: Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. 
Less than ordinary physical activity causes fatigue, palpitation 
dyspnea, or anginal pain. 
Class IV: Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. Symptoms of 
cardiac insufficiency or of the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is 
increased. 
Nonstructural 
Dysfunction 
Abnormality extrinsic to the repair device that results in valve 
dysfunction (stenosis, regurgitation or both) 
Patient 
A person with the disease (mitral regurgitation) being 
screened to participate in the clinical study. 
Pre-existing 
condition  
A pre-existing condition is one that is present prior to enrollment 
in the trial 
Procedural Success 
Device success with evidence of MR reduction ≤ MR2+ at 
discharge and without the need for a surgical or percutaneous 
intervention prior to hospital discharge. Per patient analysis. 
 
Rehospitalization  
(M-VARC 2015 
Definition and 
Sponsor) 
Rehospitalization  
For the purpose if this trial, rehospitalization is defined as any 
unplanned admission to the hospital (including an emergency 
department visit) for either a diagnostic or therapeutic purpose 
following discharge from the index hospitalization. ER 
(Emergency Room) visits will be explicitly presented separately 
from the inpatient hospitalizations. 
Rehospitalizations will be classified as either:  
o Admission to an inpatient unit (treated by a physician in 
a hospital for at least a 24 hour period)  OR   
o Visit to an ER unit (typically less than 24 hours) AND 
diagnostic procedure and/or therapeutic intervention 
Additionally, duration of admission will be indicated as lasting: 
o < 24 hours OR 
o ≥ 24 hours 
All rehospitalizations will be classified to determine whether the 
hospitalization was related to: 

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o CHF (Congestive Heart Failure) hospitalization: a 
hospital stay for ≥ 24 hours with signs and/or laboratory 
evidence of worsening heart AND administration of 
intravenous or mechanical heart failure therapies. An ER 
stay for ≥ 24 hours would qualify as a CHF 
hospitalization endpoint, even absent formal hospital 
admission, as such a prolonged stay represents a 
severe episode of heart failure. 
o Other CV hospitalization: hospitalization due for 
coronary artery disease, acute myocardial infarction, 
hypertension, cardiac arrhythmias, cardiomegaly, 
pericardial effusion, atherosclerosis, stroke, or peripheral 
vascular disease without qualifying heart failure. 
o Non-CV hospitalization: hospitalization that is not due 
to heart failure or other cardiovascular causes, as 
defined above. 
Diagnostic Criteria of Heart Failure  
The diagnosis of worsening heart failure is on the basis of:  
1)  Symptoms of worsening heart failure such as increased 
dyspnea, orthopnea, paroxysmal nocturnal dyspnea, 
fatigue, decreased exercise tolerance, and/or history of 
weight gain 
2)  Physical examination evidence of worsening heart failure 
such as neck vein distention, the presence of a third 
heart sound, pulmonary rales, ascites or pedal edema, 
and/or hypotension or signs of worsening end-organ 
perfusion; and/or  
3)  Diagnostic evidence of worsening heart failure such as 
radiographic pulmonary congestion, natriuretic peptide 
levels greater than the upper limit of normal in the 
absence of conditions known to affect these values (e.g., 
renal dysfunction, infection), arterial oxygen desaturation 
or increasing oxygen requirements, and/or acidosis.  
 
No single finding is necessarily diagnostic, and classification 
should be on the basis of all available clinical evidence.  
 
Examples of intravenous Heart Failure therapies contributing 
to this definition would include: 
o Bolus or continuous infusion of loop diuretic agents 
o Continuous infusion of vasodilators such as Nitroglycerin, 
Nitroprusside, or Nesiritide 

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o Inotropic agents such as Dobutamine 
o Inodilators such as Milrinone 
o Beta-agonists 
o Vasopressors such as Dopamine, Epinephrine, and 
Norepinephrine 
Also included would be other invasive or mechanical heart failure 
treatments such as: 
o Ultrafiltration 
o CRT (Cardiac Resynchronization Therapy) 
o Hemodynamic assist devices including intra-aortic 
balloon counterpulsation or left ventricular (LV) or 
biventricular assist devices  
Treatment with intravenous antiarrhythmic medications or 
electrical cardioversion and/or ablation in the absence of other 
intravenous or invasive heart failure treatments would not per se 
constitute criteria for CHF hospitalization (but would qualify as a 
cardiovascular hospitalization). Similarly, a CHF exacerbation 
that can be managed solely by augmentation of oral heart 
failure therapies does not meet the pre-defined criteria for heart 
failure hospitalization. 
Patients hospitalized with heart failure meeting these criteria 
should further be subclassified into:   
o Primary (cardiac related) heart failure: this may be 
due to any cardiac cause, including primary LV 
dysfunction with or without medication or dietary 
noncompliance, acute MI, arrhythmias, and worsening 
valve dysfunction 
o Secondary (non-cardiac related) heart failure: when a 
non-cardiac primary condition is present such as 
pneumonia, urinary tract infection, or renal failure, which 
results in fluid overload or myocardial failure. 
 
Investigator may need to determine which diagnosis is of 
prevailing importance (e.g., exacerbation of COPD with 
bronchospasm and some element of heart failure, or major 
heart failure exacerbation with secondary bronchospasm). Only 
primary heart failure should be considered a valid criterion 
for heart failure hospitalization.  
Re-intervention 
Any intervention on the previously implanted study device 
(repair, alteration, or replacement) or study procedure access 
site post-implant procedure. 
Renal Failure 
See “Acute Kidney Injury (AKI)” 

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Renal Replacement 
Therapy 
Treatment that replaces the normal blood-filtering function of the 
kidneys (e.g. dialysis) due to renal failure (typically Stage 3 AKI) 
Serious Adverse 
Device Event (SADE) 
Per ISO 14155:2011: 
adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event 
Serious Adverse 
Event (SAE) 
Per ISO 14155:2011: 
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 CIP, without serious deterioration in 
health, is not considered a serious adverse event. 
Severe Bleeding  
Severe bleeding is a major, extensive, life-threatening or fatal 
bleeding, as defined by MVARC. 
 
Screen Failure 
A patient who has signed the consent but, does not meet the 
inclusion criteria or who meets at least one of the exclusion 
criteria 
Subject Withdrawal  
A subject who decides not to participate in the study after  
signing an informed consent form and being enrolled. 
Stroke and TIA  
(M-VARC 2015)  
 
Stroke Diagnostic Criteria:  
1) Acute episode of a focal or global neurological deficit with at 
least one of the following:  
 
Change in level of consciousness 
 
Hemiplegia 
 
Hemiparesis 
 
Numbness 
 
Sensory loss affecting one side of the body 
 
Dysphasia or aphasia 
 
Hemianopia 
 
Amaurosis fugax 
 
Other neurological signs or symptoms consistent with 
stroke 

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2) Duration of symptoms: 
 
A focal or global neurological deficit ≥ 24 hours 
 
A focal or global neurological deficit < 24 hours if 
available neuroimaging indicates a new intracranial or 
subarachnoid hemorrhage (hemorrhagic stroke) or 
central nervous system infarction (ischemic stroke) 
 
The neurological deficit results in death 
3) 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 
designated neurologist.* 
4) Confirmation of the diagnosis by at least one of the 
following:  
 
Neurologist or neurosurgical specialist, or 
 
Neuroimaging procedure (CT scan or brain MRI) 
 
Non-neurologist physician (if neurologist is not available) 
 
Clinical presentation alone 
 
Stroke types will be classified as: 
 
Ischemic: an acute symptomatic episode of focal cerebral, 
spinal, or retinal dysfunction caused by an 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 
 
Undetermined: if there is insufficient information to allow 
categorization as ischemic or hemorrhagic 
 
TIA 
Acute episode of a focal or global neurological deficit fulfilling 
the following criteria:  
1) Resulting in at least one of the following: 
 
Change in level of consciousness 
 
Hemiplegia 
 
Hemiparesis 
 
Numbness 
 
Sensory loss affecting one side of the body 
 
Dysphasia or aphasia 
 
Hemianopia 
 
Amaurosis fugax 
 
Other neurological signs or symptoms consistent with 
stroke 

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2) Duration of deficit could be one of the following: 
 
A focal or global neurological deficit < 24 hours  
 
Any available neuroimaging does not demonstrate a 
new hemorrhage or infarct 
3) 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 
designated neurologist.* 
Notes:  
*Patients with non-focal global encephalopathy will not be reported as a stroke 
without unequivocal evidence based upon neuroimaging studies. 
#If a stroke is reported without evidence of confirmation of the diagnosis by 
one of these methods, the event may still be considered a stroke on the basis 
of the clinical presentation alone. 
Tricuspid 
Regurgitation 
Tricuspid Regurgitation (TR), tricuspid insufficiency or tricuspid 
incompetence describes a condition in which blood flow through 
the tricuspid valve flows in the incorrect direction during part of 
the cardiac cycle. 
Unanticipated 
Adverse Device 
Effect (UADE)  
21 CFR part 812.3 (s) 
Serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or 
any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
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 
NOTE Anticipated serious adverse device effect (ASADE) is an 
effect which by its nature, incidence, severity or outcome has 
been identified in the risk analysis report. 
 

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18 
CHRONIC MR SEVERITY GRADING BY ECHOCARDIOGRAPHY 
This table is derived from the 2017 American Society of Echocardiography Native Valve Regurgitation Guidelines.   
The only modification of note to the guidelines is the addition of a separate category for Trace MR.  This category will be used 
to characterize regurgitation that is clinically insignificant and too little to quantify.  In addition, the core lab overall has also 
subdivided the moderate MR category into mild-moderate and moderate-severe subcategories. 
 
 
Trace (0-1+) 
Mild (1+) 
Mild-Moderate (2+) 
Moderate-Severe (3+) 
Severe (4+) 
Structural 
 
 
 
 
 
  MV morphology 
None or mild leaflet 
abnormality 
None or mild leaflet 
abnormality 
Moderate leaflet 
abnormality or 
moderate tenting 
Moderate leaflet 
abnormality or moderate 
tenting 
Severe valve lesions 
  LV and LA size 
Usually normal 
Usually normal 
Normal or mild dilation 
Normal or mild dilation 
Dilated 
Qualitative Doppler 
 
 
 
 
 
  Color flow jet area 
Small, central, 
narrow, brief 
Small, central, narrow, 
brief 
Variable 
Variable 
Large central jet (>50% of 
LA) or eccentric wall-
impinging jet of variable size 
  Flow convergence 
Not visible 
Not visible, transient or 
small 
Intermediate in size 
and duration 
Intermediate in size and 
duration 
Large throughout systole 
  CW Doppler jet 
Faint 
Faint/partial/parabolic 
Dense but partial or 
parabolic 
Dense but partial or 
parabolic 
Holosystolic/dense/ 
triangular 
Semiquantitative 
 
 
 
 
 
  Vena contracta width 
(cm) 
< 0.3 
< 0.3 
Intermediate 
Intermediate 
> 0.7 
  Pulmonary vein flow 
Systolic dominance 
Systolic dominance 
Normal or systolic 
blunting 
Normal or systolic 
blunting 
Minimal to no systolic flow / 
systolic flow reversal 
  Mitral inflow 
A wave dominant 
A wave dominant 
Variable 
Variable 
E wave dominant (> 1.2 
m/sec) 
Quantitative 
 
 
 
 
 
  EROA (cm2) 
< 0.2 
< 0.2 
0.20 – 0.29 
0.30 – 0.39  
> 0.40 (may be lower in 
secondary MR with elliptical 
EROA) 
  Regurg Vol (ml) 
< 30 
< 30 
30 – 44  
45 – 59  
> 60 (may be lower in low 
flow conditions) 
  Regurg Fract (%) 
< 30 
< 30 
30 – 39  
40 – 49  
> 50 
 
 
Reference:  Zoghbi et al.  Recommendations for Noninvasive Evaluation of Native Valve Regurgitation.  Journal of the American Society of Echocardiography.  Volume 30, 
Number 4. 

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19 
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