Surgical Implantation of TRAnscatheter vaLve in Native Mitral Annular Calcification (SITRAL) Study
Phase: NA
Conditions: Mitral Annular Calcification
Sponsor: Baylor Research Institute

SITRAL 
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Baylor Scott & White Research Institute 
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STUDY TITLE:  Surgical Implantation of TRAnscatheter vaLve in native mitral annular calcification 
(SITRAL) Study 
Study Sponsor: 
Baylor Scott & White Research Institute 
3310 Live Oak, Ste. 501, 
Dallas, Texas 75204 
 
 
Proposed Study Clinical SITES: 
 
Cedars-Sinai Medical Center 
Los Angeles, CA 
 
Emory University Hospital 
Atlanta, Georgia 
 
St. Thomas West Hospital 
Nashville, Tennessee 
 
St. Vincent Hospital 
Indianapolis, Indiana 
 
The Heart Hospital Baylor Plano 
Plano, TX 
 
Hospital of the University of Pennsylvania 
Philadelphia, Pennsylvania 
 
University of Virginia Medical Center 
Charlottesville, Virginia 
 
Principal Investigator: Robert L. Smith II, MD 
 
Sub-Investigators: Gorav Ailawadi, MD, Raj Makkar, MD, David A. Heimansohn, MD, Evelio 
Rodriguez, MD, Wilson Szeto, MD, Vinod H. Thourani, MD, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SIGNATURE PAGE 
 
 
 
 
Surgical Implantation of TRAnscatheter vaLve in native mitral annular calcification (SITRAL) Study 
 
 
 
 
 
 
 
Investigator’s Signature 
 
 
 
I have read this protocol and agree to participate in the clinical investigation sponsored by Baylor Scott 
 
& White Research Institute. I agree to conduct this investigation according to the requirements of the 
study protocol and in accordance with Good Clinical Practice, applicable State and U.S. Federal 
regulations and conditions imposed by the reviewing Investigational Review Board. I agree to supervise 
all sub-investigators at my site as well as the use of all of the investigational devices at my institution and 
to ensure appropriate informed consent is obtained from all subjects prior to inclusion in this study. 
 
 
 
 
 
 
 
 
 
Investigator’s Signature 
Date 
 
 
 
 
 
 
 
Printed Name

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Table of Contents 
 
1.0 
BACKGROUND & STUDY RATIONALE……………………………………………………………………………………….4 
2.0 
DESCRIPTION OF STUDY PROCEDURE……………………………………………………………………………………..4 
3.0 
PURPOSE ………………………………………………………………………………………………………………………………..5 
4.0 
STUDY DESIGN…………………………………………………………………………………………………………………………5 
5.0 
STUDY POPULATION………………………………………………………………………………………………………………..6 
5.1 
INCLUSION CRITERIA…………………………………………………………………………………………………….6 
5.2 
EXCLUSION CRITERIA…………………………………………………………………………………………………….6 
6.0 
STUDY OBJECTIVES……………………………………………………………………………………………………………………7 
7.0 
STUDY METHODS………………………………………………………………………………………………………………………9 
8.0 
SUBJECT CONFIDENTIALITY………………………………………………………………………………………………………10 
9.0 
ENROLLMENT AND SCREENING……………………………………………………………………………………………..…10 
10.0 
BASELINE FUNCTIONAL ASSESSMENTS……………………………………………………………………………………..11 
11.0 
ANTICOAGULATION MEDICATION…………………………………………………………………………………………….11 
12.0 
STUDY DEVICES…………………………………………………………………………………………………………………………11 
13.0 
PREGNANCY TESTING AND CONTRACEPTION…………………………………………………………………………...12 
14.0 
ENROLLMENT AND STUDY PROCEDURES…………………………………………………………………………………..14 
15.0 
STUDY DATA MONITORING AND DATA AND SAFETY MONITORING BOARD………………………………18 
16.0 
DATA COLLECTION…………………………………………………………………………………………………………………….19 
17.0 
IMAGING CORE LAB………………………………………………………………………………………………………………..…20 
18.0 
SCREENING/ENROLLMENT LOG…………………………………………………………………………………………………20 
19.0 
DEVIATIONS FROM THE STUDY PROTOCOL……………………………………………………………………………….20 
20.0 
INVESTIGATOR RESPONSIBILITIES……………………………………………………………………………………………..21 
21.0 
WITHDRAWAL…………………………………………………………………………………………………………………………..21 
22.0 
POTENTIAL RISKS AND BENEFITS……………………………………………………………………………………………….22 
23.0 
STATISTICAL ANALYSIS & DATA MANAGEMENT…………………………………………………………………………28 
24.0 
ROLE OF BAYLOR RESEARCH INSTITUTE AS CLINICAL AND DATA COORDINATING CENTER………..29 
25.0 
TABLE OF EVENTS………………………………………………………………………………………………………………………30 
APPENDIX 1: 
 
INFORMED CONSENT TEMPLATE 
APPENDIX 2: MITRAL VALVE ACADEMIC RESEARCH CONSORTIUM DEFINITIONS 
APPENDIX 3: NYHA FUNCTIONAL CLASSIFICATION 
APPENDIX 4: KANSAS CITY CARDIOMYOPATHY QUESTINNAIRE 
REFERENCES 
 
 

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1.0 BACKGROUND & STUDY RATIONALE 
 
Extensive mitral annular calcification (MAC) poses a significant risk in elderly subjects undergoing mitral 
valve surgery. MAC has been associated with higher risk of cardiovascular disease, cardiovascular death, 
and all-cause death.1 Surgical replacement of such valves presents a technically challenging procedure 
with the potential for rupture at the atrial ventricular junction and of the left ventricular wall.2 Thus,  
new surgical and minimally invasive techniques for mitral replacement could improve treatment of high- 
risk subjects with MAC. 
 
Recently, isolated reports of deployment of the Edwards SAPIEN™ XT (Edwards Lifesciences, Irvine, CA, 
USA) valve in native mitral valves with extensive MAC have shown early anecdotal feasibility in a limited 
number of cases. There are several reports using transapical, transeptal, or transatrial approaches with 
varying degrees of success.3,4,5,6 The multi-center IDE Mitral Implantation of TRAnscatheter vaLves in 
native mitral stenosis (MITRAL) Study initiated by Northshore University Health System is currently 
studying this technique, primarily focusing on the transcatheter, transseptal approach. Early experience 
with this procedure demonstrates limited success with treatment of subjects with mitral stenosis and 
regurgitation associated with extensive MAC. However, technical challenges with this approach have 
included left ventricular outflow tract (LVOT) obstruction (11% of subjects), valve embolization (7%), and 
a 30-day mortality (34%) in the limited data available.7 In order to possibly mitigate some of the 
challenges with this approach, we propose to study a limited access surgical approach with the Edwards 
SAPIEN 3 valve placed in the mitral valve position under direct vision to optimize procedural safety and 
success. From our own limited experience with the successful treatment of 3 subjects with this 
approach, we feel that an expanded study in a larger number of subjects including other investigators is 
warranted. 
 
 
2.0 DESCRIPTION OF STUDY PROCEDURE 
 
Surgical access is allowed via any accepted heart team approach.  Any commercially approved delivery 
system for the SAPIEN 3 valve may be used. 
 
Surgical access is via a mini-anterolateral thoracotomy with the patient under general anesthesia and on 

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cardiopulmonary bypass support. Cannulation for cardiopulmonary bypass is typically achieved through 
the common femoral arterial and venous circulation, though axillary arterial cannulation is a suitable 
substitute for subjects in which there is concern for arterial occlusive disease. There are several  
methods to prepare for cardiac entry. These include a cardioplegic or cold, fibrillatory arrest, depending 
on the individual patient circumstances. A left atriotomy is performed to access the mitral valve. The 
mitral valve is then evaluated to determine whether conventional replacement is a reasonable 
depending upon the severity of MAC. If not, the anterior leaflet is then resected, leaving approximately 
0.5cm to 1cm of residual leaflet tissue adjacent to the annulus. Pledgetted mattress sutures are placed  
in both of the fibrous trigones and the mid-portion of the posterior leaflet. The valve is then sized with a 
25ml valvuloplasty balloon. If there is a reasonable fit with no gap between the inflated balloon and the 
annulus, then a 26mm Edwards SAPIEN 3 is selected. If there is a gap, then a 29mm Edwards SAPIEN 3 is 
selected. If there are concerns about the native annulus being too large, a cuff of felt material can be 
placed to minimize paravalvular leak. 
 
The valve implant is performed with thoracoscopic guidance (30 degree, 5mm-10mm endoscope). The 
 
commisures of the prosthetic valve are aligned with the fibrous trigones. To control the delivery, two 
separate operators are required. One slowly delivers the valve correcting for depth and orientation 
while the other inflates the balloon slowly within the native valve to maximal dilation for at least 10 
seconds, and thoracoscopic confirmation of a fully deployed valve is obtained. The fibrous trigone 
sutures are then placed through the skirt on the prosthetic valve and tied. The valve is tested with cold 
saline to ensure appropriate leaflet mobility and assess for paravalvular leak.  Following confirmation, a 
vent may be placed across the valve for de-airing, and the atrium is closed. 
 
 
3.0 PURPOSE 
 
The purpose of this study is to establish the safety and feasibility of the Edwards SAPIEN 3 valve in 
subjects with mitral annular calcification (MAC) associated with mitral stenosis (MS) and/or mitral 
regurgitation who are at high-risk for mitral valve surgery or deemed inoperable due to the extent of 
calcification. 
 
4.0 STUDY DESIGN 

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This is a multi-center, prospective feasibility study. The study cohort will comprise all consecutive 
subjects undergoing mitral valve replacement with the Edwards SAPIEN 3 heart valve by a standardized 
minimally invasive surgical approach at investigational centers and will consist of up to 30 subjects. 
Subjects will undergo follow-up visits at 30 days, 6 months and 12 months post procedure. 
 
 
 
5.1 STUDY POPULATION 
 
 
The study cohort will consist of up to 30 subjects who are candidates for mitral valve replacement using 
the Edwards SAPIEN 3 heart valve as per the inclusion and exclusion criteria below: 
 
5.2 Inclusion Criteria: 
 
• Subject has severe native mitral annular calcification associated with mitral stenosis and/or 
regurgitation. Qualifying echo must be within 60 days of the date of the procedure. 
• Subject has a clinical indication for mitral valve replacement, as demonstrated by reported 
New York Heart Association (NYHA) Functional Class II or greater. 
• The subject is at least 22 years old. 
 
• The Heart Team agrees that the subject is high-risk or inoperable for surgical mitral valve 
repair or replacement (MVR), based on a conclusion that the probability of death or serious, 
irreversible morbidity exceeds the probability of meaningful improvement.  The following 
concomitant procedures, are allowed MAZE, TVP, and AF ablation. 
• The study subject has been informed of the nature of the study, agrees to its provisions and 
has provided written informed consent as approved by the Institutional Review Board (IRB) of 
the respective clinical site. 
• The study subject agrees to comply with all required post-procedure follow-up visits 
 
 
5.3 Exclusion Criteria 
 
• Evidence of an acute myocardial infarction (MI) ≤ 30 days before the intended treatment 
[defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB ≥ twice normal 
in the presence of MB elevation and/or troponin level elevation (WHO definition)]. 
4.0 STUDY DESIGN

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• Untreated coronary artery disease in need of revascularization 
 
• Any therapeutic invasive cardiac procedure resulting in a permanent implant that is 
performed within 30 days of the index procedure (unless part of planned strategy for 
treatment of concomitant coronary artery disease). 
• Leukopenia (white blood cell count < 2000 cell/mL), acute anemia (hemoglobin < 8 g/dL), or 
thrombocytopenia (platelet count < 50,000 cell/mL). 
• Hemodynamic or respiratory instability requiring vasoactive medications, mechanical 
ventilation at time of procedure. 
• Need for emergency surgery for any reason. 
 
• Severe left ventricular dysfunction with Left Ventricular Ejection Fraction (LVEF) < 30%. 
 
• Severe right ventricular dysfunction 
 
• Pregnancy, lactation, or planning to become pregnant 
 
• Echocardiographic evidence of left ventricular mass, thrombus, or concerns of active 
infective endocarditis. 
• Active upper GI bleeding within 3 months prior to procedure without treatment or 30 days 
prior to procedure with definitive treatment. 
• A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to 
be maintained on oral anticoagulant following the study procedure. 
• An estimated Glomerular Filtration Rate (eGFR) <30 as calculated using the Modification of 
Diet in Renal Disease (MDRD) formula or End stage renal disease requiring dialysis 
• Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack 
(TIA) within 30 days of the procedure. 
• Estimated life expectancy < 12 months 
 
 
 
 
6.0 STUDY OBJECTIVES 
 
6.1 Primary Outcome Measures: 
 
a. Primary objective(s) 
 
  
Primary safety endpoints: 

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o Technical success at exit from cath lab/OR 
o Device success at 30 days 
o Procedural success at 30 days 
 
Technical Success: 
 Alive, with  
 Successful access, delivery and retrieval of the device delivery system, and  
 Deployment and correct positioning (including repositioning/recapture if needed) of 
the single intended device, and 
 No need for additional unplanned or emergency surgery or re-intervention related 
to the device or access procedure 
                         Device Success: 
 Alive and stroke free, with 
 Original intended device in place, and  
 No additional surgical or interventional procedures related to access or the device 
since completion of the original procedure (i.e., exit from the cath lab/OR), and 
 Intended performance of the device: 
- 
Structural performance:  No migration, embolization, detachment, fracture, 
hemolysis, thrombosis (including reduced leaflet motion) or endocarditis, 
etc, and 
- 
Hemodynamic performance:  Maintenance of relief of stenosis or 
insufficiency without producing the opposite (Stenosis = MVA < 1.5cm2 and 
MV gradient > 5mmHg, Insufficiency = MR >1+), and 
- 
Absence of para-device complications (e.g., PVL > mild, need for a PPM, 
erosion, Annular rupture or AV Groove disruption, LVOT gradient increase > 
10mmHg) 
Procedural Success: 
      Device success, and 
 No device or procedure related SAE’s (Life threatening bleed; major vascular or 
cardiac structural complications requiring unplanned reintervention or surgery; 
stage 2 or 3 AKI (includes new dialysis); MI or need for PCI/CABG; severe HF or 
hypotension requiring IV inotrope, ultrafiltration or mechanical circulatory support; 
prolonged intubation ( > 48 hours) 
  
6.2  Secondary objective(s) 
 
 Device Success (at 6 months and 1 year) 

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 Subject success  1 year 
  
 
                         Device Success: 
 Alive and stroke free, with 
 Original intended device in place, and  
 No additional surgical or interventional procedures related to access or the device 
since completion of the original procedure (i.e., exit from the cath lab/OR), and 
 Intended performance of the device: 
- 
Structural performance:  No migration, embolization, detachment, fracture, 
hemolysis, thrombosis (including reduced leaflet motion) or endocarditis, 
etc, and 
- 
Hemodynamic performance:  Maintenance of relief of stenosis or 
insufficiency without producing the opposite (Stenosis = MVA < 1.5cm2 and 
MV gradient > 5mmHg, Insufficiency = MR >1+), and 
- 
Absence of para-device complications (e.g., PVL > mild, need for a PPM, 
erosion, Annular rupture or AV Groove disruption, LVOT gradient increase > 
10mmHg) 
 
 
 
7.0 STUDY METHODS 
 
 
Methods for required study activities in the clinical investigational plan (CIP) are specified in the 
following subsections. Deviations from the CIP must be documented and reported to the Sponsor. All 
subjects must sign an IRB approved informed consent prior to performing any study activities described 
in this CIP. 
 
 
Study data supporting enrollment eligibility must be recorded on the applicable case report forms. 
Source documentation supporting all case report form entries must be maintained at the investigational 
site and copies of source documents may be maintained by the Sponsor to support monitoring activities. 

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Investigators are expected to complete all applicable case report forms within 5 business days of the 
related follow-up visit or study activity. To ensure CIP compliance, data integrity, and protection of 
Subjects’ rights, safety and welfare, Sponsor or its representative and other regulatory agencies may 
monitor the conduct of the study. 
 
 
 
8.0 SUBJECT CONFIDENTIALITY 
 
 
All Subject information collected during the study is kept strictly confidential. All data and information 
pertaining to the Subject and their participation in the study are considered confidential by Sponsor. All 
public reporting of study results must eliminate references to individual subjects. Information contained 
in paper form must be stored in secure areas. Electronic information that is kept on computers must be 
protected by secure passwords. 
 
 
 
9.0 ENROLLMENT AND SCREENING 
 
 
In order to protect the rights and welfare of subjects, the study is conducted in accordance with the 21 
CRF 50, Protection of Human Subjects. All subjects are required to sign and date an IRB approved 
consent prior to participation in the study. All Subjects who sign an informed consent are assigned a 
unique identification number in order to maintain Subject traceability. 
 
 
If during the course of the preoperative evaluations, the subject is found to be ineligible for study 
participation, the subject will be notified, and the reason for ineligibility will be documented on the 
Screening Log. Ineligible subjects are considered screen failures, and they will not be counted towards 
total enrollment and their subject ID number will not be reused. Sites are not required to enter data into 
the EDC system for any screen failures. 
 
 
After screening assessments are made, the study candidate’s qualifying criteria will be presented via the 
case review process where experienced study investigators will review the submitted criteria. Upon case 
review approval, the supporting evidence for approval and the names of the reviewer(s) will be 

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documented. Once the review and the eligibility criteria are documented, the subject can be enrolled in 
the study. 
 
 
Subjects are considered enrolled at the time of initial skin incision. 
 
 
 
 
10.0 BASELINE FUNCTIONAL ASSESSMENTS 
 
 
Functional Assessments such as 6 minute walk test (6MWT), NYHA classification, Quality of Life (QOL) 
assessments (Kansas City Cardiomyopathy Questionnaire [KCCQ]) and 5 meter walk test are collected as 
part of the screening activities for baseline comparative purpose against scheduled follow-ups post- 
procedure. 
 
 
 
11.0 ANTICOAGULATION MEDICATION 
 
 
Subjects should be maintained on a once daily dose of warfarin (Coumadin) for a minimum of 3 months 
post study procedure to maintain an international normalized ratio (INR) of between 2.5 and 3.5. If a 
subject is not eligible for warfarin, the subject should be maintained on appropriate anticoagulation per 
investigator. If the subject was on novel oral anticoagulation (NOAC) pre-study procedure, that 
medication may be continued in lieu of warfarin at the investigators discretion. 
 
 
 
12.0 STUDY DEVICES 
 
 
Investigators selected to participate in the study will have prior experience with Edwards SAPIEN 3 
system. The Edwards SAPIEN 3 valve is approved by the Food and Drug Administration (FDA). The study 
sites will be authorized to utilize devices for the study procedure after receiving IRB approval and signing 
the clinical study agreement. 
 
 
 

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13.1 PREGNANCY TESTING AND CONTRACEPTION 
 
13.2 Pregnancy Testing 
 
A Woman of Child Bearing Potential (WOCBP) who is planning pregnancy should not participate in 
the study.  For participation in this study, pregnancy  has to be excluded in any  female study 
participant below age 60. 
 
 
 
13.3 Contraception 
 
WOCBP (Women of Child Bearing Potential) who are considering participation in the study must be 
informed about the study related risks to pregnancy/embryonic development and must receive 
contraceptive counseling. WOCBP must agree to use effective contraception while participating in 
the study. 
 
 
 
Female subjects who are considered WOCBP and who are engaging in intercourse with a male 
partner(s), must begin using an acceptable method of contraception as soon as feasible prior to 
enrollment and must continue throughout the duration of their study enrollment 
 
 
13.4 
Female subjects are considered non-WOCBP if they are either: 
 
A. Post-menopausal (12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of 
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL) 
 
B. Have had surgical bilateral oophorectomy (with or without hysterectomy) at least six 
weeks prior to enrollment into the study. In the case of surgical bilateral oophorectomy 
only, this will only be acceptable when the reproductive status of the woman has been 
confirmed by a follow up hormone level assessment 

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14.1 ENROLLMENT AND STUDY PROCEDURES 
 
14.2 Baseline/Screening 
 
The following information will be collected for all study subjects prior to procedure. Baseline 
assessments must be completed within 30 days of subject enrollment unless otherwise specified. 
Subjects are considered enrolled at the time of initial skin incision. 
A. Society of Thoracic Surgeons (STS) Risk Score Assessment 
 
B. Medical History and Physical Exam including Cardiac Medications 
 
C. Cardiopulmonary: 
 
1. Cardiac Catheterization (within 6 months prior to consent) 
 
2. 3D Computed Tomography scan with contrast of chest, heart and peripheral 
vasculature with assessment of degree and pattern of MAC 
3. Transthoracic echocardiogram (TTE) 
 
4. 12 Lead Electrocardiogram (ECG) 
 
5. Chest X-Ray 
 
6. Pulmonary Function Test (PFT) within 1 year prior to consent 
 
A. Functional Assessments: 
 
1. 6 minute walk test (6MWT) 
 
2. NYHA classification 
 
3. QOL assessments: KCCQ 
 
4. 5 meter walk test (5MWT) 
 
B. Subject Clinical Laboratory Tests 
 
1. Complete Blood Count (CBC) and platelet count 
 
2. Complete metabolic panel (CMP) including Albumin 
 
3. B-type natriuretic peptide (BNP) 
 
4. PTT or PT/INR (if applicable) 

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5. A blood or urine pregnancy test will be performed at screening for females with 
childbearing potential. A positive pregnancy test will render the subject ineligible 
for study participation. 
 
 
 
14.3 Intra-Procedure Assessments 
 
Total procedure time is defined as the time from skin incision to the time of skin incision access 
closure. The following invasive hemodynamic data must be collected pre and post implant: 
A. Transesophageal echocardiogram (TEE) assessments: 
 
1. To be collected prior to placement of valve 
 
i. 
Mitral valve gradient (peak and mean) 
 
ii. 
Quantify severity of mitral regurgitation (ERO, vena contracta width) 
 
iii. 
Left ventricular outflow tract (LVOT) width in millimeters (mm) and 
gradient 
iv. 
Presence of other valvular heart disease 
 
v. 
Left ventricular ejection fraction 
 
2. To be collected following placement of valve: 
 
i. 
central or paravalvular mitral regurgitation 
 
ii. 
transmitral gradient 
 
iii. 
left ventricular outflow tract (LVOT) gradients 
 
B. Cardiac output and cardiac index 
 
C. Adverse Event Assessment 
 
 
14.4 Discharge Procedures 
 
The following data will be collected for all study subjects within 24 hours of the date of 
discharge from the index hospitalization. However, subjects discharged within 48 hours of 
exiting the cath lab / operating room are not required to repeat tests collected during the Post 
Procedure period that are also required for the discharge visit. See Table 1.0. If subject is 
discharged over a weekend or holiday, the discharge tests may be completed on the last 
weekday prior to discharge. 

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A. Systems: 
 
1. Pertinent physical examination [includes blood pressure, height, weight, major 
systems findings] including clinical assessment for Stroke and/or TIA; 
2. Medications given for cardiovascular effect including anti-platelet/anti-thrombins; 
 
3. Adverse Event assessment; 
 
B. Cardiac: 
 
1. Transthoracic echocardiogram (TTE). 
 
2. NYHA classification; 
 
3. Standard 12-lead ECG; 
 
4. Chest X-ray examination 
 
C. 
Clinical Laboratory Tests: 
 
1. B-type natriuretic peptide (BNP). 
 
2. CBC and platelet count; 
 
3. PT/INR; 
 
4. Metabolic Panel 
 
 
14.5 Follow-Up Procedures 
 
 
Follow-up procedures will be conducted at the intervals specified in Table 1.0. Blood draws will 
be performed at the specified intervals and according to hospital standard or medication 
regimen. Subjects will be informed that some of the data that are collected at scheduled follow- 
ups as well as at unscheduled visits, including the echocardiogram and CT scan may be sent to 
the respective independent core lab for analysis. 
 
If a subject cannot be reached for a follow-up visit, the investigator will document on the follow- 
up data form, the efforts undertaken to contact the subject. These efforts should include 3 
attempts of telephone contacts at separate dates and times, and a registered letter. If the 
subject cannot be reached in any way for their follow-up visits and misses the scheduled visit, 
new efforts will be undertaken to locate them at subsequent follow-up visits. In the event that 

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the subject’s implanted valve is explanted, the subject needs to be continued to be followed for 
the duration of the study. 
 
Follow-up visit intervals are as follows: 30 days (-7/+14 days), 6 months (±30 days), 12 months 
(+60 days). Additional phone follow-ups may be performed as needed to obtain up to date 
survival information for use in regulatory submissions. 
 
For all subjects at all visits, the time clock starts on the date of the first implant attempt, whether 
or not the implant is successful and site visits will be scheduled accordingly. 
 
14.4.1 One Month Follow-Up Visit 
 
 
The following data will be collected for all study subjects at one month (within 7 days 
before and 14 days after the 30 days date) 
 
 
A. Systems: 
 
1. Pertinent physical examination [includes blood pressure, height, weight, major systems 
findings] including clinical assessment for Stroke and/or TIA; 
 
2. Medications given for cardiovascular effect including anti-platelet/anti-thrombins; 
 
3. Adverse Event assessment 
 
B. Cardiac: 
 
1. 4D Computed Tomography scan with contrast of the heart to include valve assessment 
 
2. NYHA classification 
 
3. Standard 12-lead ECG 
 
4. Transthoracic echocardiogram (TTE) 
 
C. Functional Assessments: 
 
1. 6MWT 
 
2. QOL: KCCQ 
 
D. Clinical Laboratory Tests: 
 
1. CBC and platelet count 

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2. Complete Metabolic Panel (CMP) 
 
3. B-type natriuretic peptide (BNP) 
 
4. Plasma free hemoglobin 
 
5. Haptoglobin 
 
6. PT/INR 
 
E. Non-Invasive Studies: 
 
1. Chest X-ray examination 
 
 
14.4.2 Six Month Follow-Up Visit 
 
The following data will be collected for all study subjects at 6 months: (±30 days). 
 
 
A. Systems: 
 
1. Pertinent physical examination [includes blood pressure, weight, major systems 
findings] including clinical assessment for Stroke and/or TIA; 
 
2. Medications given for cardiovascular effect including anti-platelet/anti-thrombins; 
 
3. Adverse Event assessment 
 
B. Cardiac: 
 
1. 4D Computed Tomography scan with contrast of heart to include valve assessment if 
 
any of the following have occurred: 
 
A. presence of thrombus on 30 day 4DCT scan 
 
B. Increase in mitral gradient as measured on TTE 
 
C. Clinical deterioration or clinical event including: 
 
i. neurological or peripheral embolic event 
 
ii. Rehospitalization for heart failure 
 
2. NYHA classification 
 
3. Transthoracic echocardiogram (TTE) 
 
 
 
C. Clinical Laboratory Tests: 
 
1. Plasma free hemoglobin 
2. Haptoglobin 
3. PT/INR (if applicable)
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3. PT/INR (if applicable) 
 
 
 
14.4.3 Twelve Month Follow-Up Visit 
 
The following data will be collected for all study subjects at 1 year (365 days) +60 days. 
 
 
A. Systems: 
 
C. Pertinent physical examination [includes blood pressure, weight, major systems 
findings] including clinical assessment for Stroke and/or TIA; 
D. Medications given for cardiovascular effect including anti-platelet/anti-thrombins 
 
E. Adverse Event assessment 
 
 
B. Cardiac: 
 
F. NYHA classification 
 
G. Standard 12-lead ECG 
 
H. Chest X-ray examination 
 
I. Transthoracic echocardiogram (TTE) 
 
 
C. Clinical Laboratory Tests: 
 
J. CBC and platelet count 
 
K. Complete metabolic panel 
 
L. B-type natriuretic peptide (BNP) 
M.Plasma free hemoglobin 
N. Haptoglobin. 
 
O. PT/INR (if applicable) 
 
 
D. Functional Assessments: 
 
P. 6MWT 
 
Q. QOL: KCCQ 
 
 
 
 
 
 
 
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15.0 STUDY DATA MONITORING AND DATA AND SAFETY MONITORING BOARD 
 
The purpose of the monitoring plan is to facilitate compliance with GCP guidelines (GCP 5.18.1), FDA 
guidelines and FDA regulations (21 CFR 812). The monitoring plan for this study includes use of 
monitoring services and institution of a Data and Safety Monitoring Board. . A Data Safety and 
Monitoring Board (DSMB) will be constituted for this study to provide additional safety review. The 
DSMB is an independent advisory group of experts with a mandate to periodically review and evaluate 
safety and evaluate data for continuing validity. 
 
 
The DSMB will be responsible for assuring that research subjects are not exposed to unnecessary or 
unreasonable risks. Ongoing responsibilities of the DSMB will be to evaluate the progress of the study, 
including periodic assessments of adverse events and serious adverse events. The DSMB will report on 
the safety and scientific progress of the study. 
 
 
On site monitoring will be completed at regular intervals at each site commensurate with enrollment of 
the first subject and completion of the index procedure. As an electronic data capture system will be 
used to collect the data, the data entered into the database will be remotely reviewed to evaluate for 
potential safety issues such as unanticipated adverse device effects. Compliance with the study 
milestones for each enrolled subject will be reviewed, as well. Sites will be contacted for source 
information as indicated. 
 
Reports  from  each  monitoring  visit  will  be  provided  to  the  site  Investigator  and  the  sponsor  at 
completion of the monitoring. 
 
16.0 DATA COLLECTION 
 
 
All required data for this investigation are to be collected on standardized electronic case report forms 
(eCRFs) for individual enrolled subjects; sample eCRFs are provided. The eCRF must be electronically 
signed by the Principal Investigator or co-Investigator listed in the Clinical Studies Agreement and/or 
Delegation of Authority Log. If for any reason the eCRFs are unavailable and/or inaccessible, paper CRFs 
will be provided by the Sponsor to be completed, signed by the Principal Investigator or designee and 
submitted to the Sponsor. 
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Case Report Form Instructions will be provided to assist the Investigator(s) and appropriate 
investigational staff in the completion of the required eCRFs. Source documents are original documents, 
data, and records from which the subject’s CRF data are obtained. These include, but are not limited to, 
hospital records, clinical and office charts, laboratory records, and correspondence. Electronic CRFs must 
be kept current to reflect enrolled subject status during the course of the investigation. 
 
17.0 IMAGING CORE LAB 
 
 
All baseline and follow-up transthoracic echocardiograms, transesophageal echocardiograms and CT 
scans will be evaluated at The Baylor Scott & White Research Institute Imaging Core Lab, under the 
direction of Paul Grayburn, M.D and Ambarish Gopal M.D. 
 
 
Follow-up Doppler echocardiograms will be evaluated by the designated Echo Core Lab. A standardized 
written report generated by the Core Lab for each Doppler echocardiogram will be entered into an 
electronic database maintained by the Sponsor. The Clinical Site Manager or Sponsor designee shall 
notify the Investigator should there be any indication of a complication or discrepancy that the 
Investigator may not have noted. This will allow the Investigator an opportunity to further review the 
test results and clarify the findings if necessary. 
 
18.0 SCREENING/ENROLLMENT LOG 
 
 
All subjects considered for the study will be recorded on the Screening Log. A Screening Log will be 
provided to the investigational sites to maintain a cumulative log of all screened subjects. For subjects 
who are ineligible for participation in the clinical investigation, a reason supporting the disqualification 
of the subject must be entered on the Screening Log. 
 
 
19.0 DEVIATIONS FROM THE STUDY PROTOCOL 
 
 
The Investigator will not deviate from the protocol without the prior written approval of the Sponsor 
except in medical emergencies or in unforeseen, isolated instances where minor changes are made that 
will not increase the subject’s risk or affect the validity of the study. Any subsequent revisions to the 
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protocol, including the Informed Consent Form and the Case Report Forms, other than very minor 
revisions, must be approved by the Sponsor, the FDA, and the IRB. In medical emergencies, prior 
approval for protocol deviations will not be required, but the Sponsor or its designee and IRB must be 
notified within 5 working days of the incident. Periodic monitoring of protocol compliance will be 
performed for each site. Deviations will be documented on the appropriate case report form. The 
sponsor has the right to suspend enrollment at sites deemed to have excessive protocol compliance 
issues. 
 
 
20.0 INVESTIGATOR RESPONSIBILITIES 
 
 
The Investigator is responsible for ensuring that this clinical study is conducted according to the 
Investigator Agreement, Protocol, all conditions of FDA and IRB approval and applicable FDA regulations. 
Written IRB approval of the protocol and ICF must be provided to the Sponsor prior to the enrollment of 
any subject in the clinical study at each investigational site. The Investigator is responsible for ensuring 
that informed consent is obtained from all subjects prior to any diagnostic tests or treatments that are 
outside the standard course of treatment that would be followed if this subject was not being considered 
for enrollment in this clinical study. Subjects must be informed that their medical records will be subject 
to review by the Sponsor, its authorized designee or representatives of FDA. Subjects will be informed 
that they are free to refuse participation in this clinical study without loss of benefits to which they are 
otherwise entitled, and, that if they choose to participate, they may withdraw at any time without 
prejudice to future care. The informed consent provided by each investigational site’s IRB must be signed 
prior to study participation. The original signed informed consent for each subject must be retained by 
the Investigator and is subject to review by the Sponsor and the FDA. A copy of the informed consent will 
be provided to the subject. 
 
21.0 WITHDRAWAL 
 
 
Subjects may voluntarily withdraw from the study at any time. If such withdrawal occurs, or if the 
subject fails to return for visits, the site investigator must determine the primary reason for a subject’s 
premature withdrawal from the study and record this information in the subject’s study records. 

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For subjects who are lost to follow-up, the site investigator should show "due diligence" by documenting 
in the subject record steps taken to contact the subject, e.g., dates of telephone calls, registered letters, 
etc. 
 
Subjects who are prematurely withdrawn from study treatment or from the study will not be replaced. 
 
 
22.1 POTENTIAL RISKS AND BENEFITS 
 
 
The risks associated with the use of the system are similar to those encountered with standard cardiac 
catheterization, use of anesthesia, mitral valve replacement (MVR) and the use of bioprosthetic heart 
valves, in addition to risks associated with study-related procedures (e.g. Transesophageal 
echocardiography, MSCT scan, etc.). A list of anticipated or potential adverse events is provided below. 
 
 
22.2 Adverse Events 
 
 
An adverse event is any undesirable clinical occurrence in a study subject, whether or not it is 
related to the study intervention. Any condition that was recorded as pre-existing is not an AE 
unless there is a change in the nature, severity or degree of the condition. Furthermore, for a pre- 
existing condition that is not protocol defined to be reported as an adverse event, a change in 
severity must meet the criteria for being serious (see definition below). 
 
22.3 Serious Adverse Event 
 
 
Serious adverse events are defined by FDA regulation as any experience that results in a fatality or 
is life threatening; results in significant or persistent disability; requires or prolongs a 
hospitalization; results in a congenital anomaly/birth defect; or represents other significant 
hazards or potentially serious harm to research subjects or others, in the opinion of the 
investigators. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 

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22.4 Unanticipated Serious Adverse Event 
 
 
An unanticipated (unexpected) serious adverse event is any serious adverse event that is not 
protocol-defined. Expedited reporting is required for serious adverse events that are unexpected. 
 
 
22.5 Event Recording 
 
 
The following adverse events will be captured throughout the period of study participation: 
 
A. Protocol-defined (as described below) 
 
B. Serious unanticipated events (serious “Other” adverse events) 
 
 
22.6 Causality 
 
 
The investigator will assess the relationship of an adverse event to the surgical intervention. If 
possible, the investigator should distinguish the relationship between the event and (a) the 
surgical procedure and (b) the investigational intervention (implant of Edwards SAPIEN 3 valve). 
Causality will be defined as follows: 
A. Probable 
 
Adverse events that, after careful medical evaluation, are considered with a high degree 
of certainty to be related to the surgical intervention 
The following characteristics will apply: 
 
1. A reasonable temporal relationship exists between the event and the 
surgical intervention, and 
2. The event is a known reaction to the surgical intervention and cannot 
be explained by an alternative etiology commonly occurring in the 
population/individual. 
B. Possible 
 
Adverse events that, after careful medical evaluation, do not meet the criteria for a 
probable relationship to the surgical intervention, but for which a connection cannot be 
ruled out with certainty. 
The following characteristics will apply: 

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1. 
The event occurs after surgical intervention, and 
 
2. 
The event is not a known reaction to surgical intervention, but 
cannot be explained by a commonly occurring alternative etiology. 
 
 
C. Unlikely 
 
Adverse events that, after careful medical evaluation, do not meet the criteria for a 
possible or probable relationship to surgical intervention and for which a connection is 
unlikely. 
The following characteristics will apply: 
 
3. The event does not follow a reasonable temporal sequence from 
administration of the surgical intervention, or 
4. May have been produced by environmental factors, and there is no 
apparent pattern of response to the surgical intervention. 
 
 
22.7 Reporting of Serious Adverse Events 
 
 
All investigators must report both expected (protocol-defined) and unexpected serious adverse 
events. All serious protocol defined adverse events must be reported directly to the clinical 
center’s IRB and the sponsor within 10 working days of knowledge of the event, or as dictated by 
the specific IRB policy, whichever is sooner. All unexpected serious adverse events must be 
reported to the sponsor within 24 hours of knowledge of the event and the clinical center’s IRB as 
dictated by the specific IRB policy. 
 
 
22.8 Eliciting adverse effect information 
 
Investigators are responsible for preparing and submitting all reports as summarized on Table 1.0. 
 
 
 
Case Report Forms should be entered within 10 days after the corresponding visit. Investigators are 
responsible for notifying the Sponsor of any changes to previously reported data. Upon request of the 
reviewing IRB, FDA, the Investigator must provide accurate, complete, and current information about 
any aspect of the study. 

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22.9 Table 1.0: Investigator Report Requirements 
 
Report title/description 
Requirement(s) 
Submit to: 
Adverse events (AE) 
Immediately but no later than 10 
days of becoming aware 
Sponsor 
Serious Adverse Event (SAE) 
Report should be submitted 
immediately after the Investigator 
first learns of the event but no 
longer than 10 days hours 
Sponsor 
If applicable, IRB 
Unanticipated Adverse Device 
Effect (UADE) 
Report should be submitted 
immediately after the Investigator 
first learns of the event but no 
longer than 10 working days 
Sponsor 
IRB 
Withdrawal of IRB approval 
Report must be submitted 
immediately after the Investigator 
learns of the withdrawal but no 
longer than 5 working days. 
Sponsor 
Progress Report 
Report must be submitted 
annually, or as required by the IRB, 
for the duration of the clinical 
study. The Sponsor may also 
prepare this report. 
If applicable, IRB 
CIP Deviations 
Deviations from the investigational 
plan must be approved by the 
Sponsor prior to implementation 
NOTE: If the deviation affects 
the scientific soundness of the 
CIP or the rights, safety or 
welfare of the Subjects, the 
deviation must be approved by 
the Sponsor and IRB, if 
applicable. 
Sponsor 
If Applicable IRB 
In the event that a CIP deviation 
occurs and the sponsor cannot 
be notified ahead of time (e.g., if 
the notification was to protect 
the life or physical well-being of 
the Subject), 
Sponsor 
IRB 

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22.9 Anticipated or Potential Adverse Events 
 
 
 
The list below provides anticipated or potential adverse events that may occur during the study. 
The potential adverse events are those that are expected to occur during the study because they 
are associated with the surgical procedure, stress-induced tests (e.g. TEE/TOE, TTE, MSCT scan, 
exercise tolerance, etc.), or the heart failure population over time. It is anticipated that subjects 
may require temporary medical and/or mechanical hemodynamic support in the peri and/or early 
post-op period. These events are not considered adverse events. 
• Abnormal Lab values 
 
• Allergic Reaction to Anesthetic, Anti- 
coagulant Therapy, Contrast or Cobalt 
Chromium 
• Anaphylactic Shock or Toxic Reaction 
 
• Anemia 
 
• Angina 
 
• Annulus Rupture/ A-V Groove Disruption 
 
• Aortic Valve Impairment/Damage 
 
• Arrhythmias 
 
• Atrial Fibrillation 
 
• Atrio-ventricular Node Block 
 
• A-V fistula or pseudo-aneurysm 
 
• Bleeding diathesis 
 
• Cardiac Arrest 
 
• Cardiac Failure or Decompensation 
 
• Cardiac Perforation 
 
• Cardiac Tamponade/ Pericardial Effusion 
 
• Cardiogenic Shock 
 
• Chordal Rupture 
• Conduction System Injury (defect) which 
may require pacemaker 
• Conversion to Open Sternotomy 
 
• Coronary Artery Obstruction 
 
• Death 
 
• Dissection, Any Vessel 
 
• Dyspnea 
 
• Edema 
 
• Electrolyte Imbalance 
 
• Electro-mechanical Dissociation 
 
• Embolization including air, particulate, 
calcific material, or thrombus 
• Emergent PCI 
 
• Emergent Cardiac Surgery 
 
• Endocarditis 
 
• Esophagus Irritation/Perforation (TEE 
related) 
• Fever 
 
• Frame Strut Fracture 
 
• GI Bleeding 
 
• Heart Failure 

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• Hematoma 
 
• Hemolysis / Hemolytic Anemia 
 
• Hemorrhage require transfusion/surgery 
 
• Infection at the access site 
 
• Inflammation 
 
• Leaflet tearing 
 
• Left Ventricle Failure 
 
• Local and Systemic Infection 
 
• LVOT Obstruction 
 
• Mal-positioning of Prosthesis 
 
• Multi-system Failure 
 
• Myocardial Infarction 
 
• Myocardial Ischemia 
 
• Pacemaker Implantation 
 
• Pannus Formation 
 
• Papillary Muscle Damage 
 
• Peripheral Ischemia 
 
• Pleural effusion 
 
• Pneumonia 
 
• Prosthesis Dislodgement/Embolization 
 
• Prosthesis Leaflet Entrapment 
• Prosthesis Migration 
 
• Prosthesis Paravalvular Leak 
 
• Prosthesis Regurgitation 
 
• Prosthetic Valvular Endocarditis 
 
• Prosthetic Valvular Thrombosis 
 
• Pulmonary Edema 
 
• Pulmonary Vein Obstruction 
 
• Reintervention or reoperation 
 
• Renal Failure or Insufficiency 
 
• Respiratory Failure 
 
• Retroperitoneal Bleed 
 
• Septicemia 
 
• Stroke, TIA, or other Neurological Event 
 
• Structural Deterioration 
 
• Systolic Anterior Motion 
 
• Thromboembolism 
 
• Valve Stenosis 
 
• Vascular trauma, dissection, or occlusion 
 
• Ventricular Perforation by Frame 
 
• Vessel Spasm 
 
• Wound Dehiscence 
 
 
 
22.10 Risk Minimization 
 
 
Efforts to minimize risks associated with performing the procedure include the following: 
 
A. Selection of qualified Investigators 
 
B. Comprehensive Investigator training to insure that Investigators have a thorough 
knowledge of the CIP and the proper technique for implantation of the study device, 
including the following elements of instruction: 

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1. Providing CIP training to all Investigators and study staff noted on the 
Delegation of Authority log (DOA) 
2. Clearly defining the subject inclusion and exclusion criteria 
 
3. Monitoring echocardiographic and hemodynamic parameters during placement 
of the implant 
4. Ensuring data collection is consistent with the CIP 
 
5. Ensuring treatment and follow-up of subjects is consistent with the CIP and 
standard and current medical practice 
 
 
22.11 Potential Benefits 
 
 
The clinical benefits of using the SAPIEN 3 valve in subjects with mitral annular calcification (MAC) 
associated with mitral stenosis and/or regurgitation are not known at the present time. There are 
no guaranteed benefits from participation in this clinical study and being treated with the study 
device. 
 
 
Mitral valve replacement with the SAPIEN 3 valve may result in one or more of the following 
benefits for subjects typically considered high risk or inoperable for surgical MVR: decrease in 
mitral stenosis, decrease in mitral regurgitation, acute alleviation of symptoms related to mitral 
insufficiency and/or stenosis, and/or improved morbidity and mortality. Information gained from 
the conduct of this study may be of benefit to other people with the same medical condition in 
the future as the indication for the system is expanded. 
 
 
 
23.0 STATISTICAL ANALYSIS & DATA MANAGEMENT 
 
 
To describe procedural success and device success at 30 days, and subject success at 12 Months 
descriptive statistics (e.g. percentage) and plots will be estimated. 
 
All tasks will be performed in compliance with HIPAA regulations. Patients’ identifiers will be encrypted 
for study data shared with other study personnel. All data for the proposed study will be stored in the 

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secure database we will develop and periodic back-up will protect against catastrophic loss. All hard 
copy materials (summary printouts) will be stored by the principal investigator in locked file cabinets; 
disks and other removable storage media files will be stored as per HIPAA regulations. The Principal 
Investigator will be responsible for the data management operations. 
 
 
 
24.1 ROLE OF BAYLOR RESEARCH INSTITUTE AS CLINICAL AND DATA COORDINATING CENTER 
 
 
Baylor Research Institute is the sponsor of this study. The Sponsor is responsible for ensuring that this 
study will be conducted in compliance with all applicable U.S. Federal regulations pertaining to 
investigational devices including but not limited to: 21 CFR Part 50, Part 54, Part 56, Part 812, Good 
Clinical Practice (GCP) standards, and Health and Insurance Portability and Accountability Act (HIPAA). 
 
 
Baylor Research Institute Regulatory Affairs and Data Management departments have quality assurance 
procedures to ensure that complete, accurate and timely data are collected, that the Investigational Plan 
requirements are followed and that all complications and adverse events are reported in a timely 
manner. 
 
 
Electronic CRFs are used for collecting and recording of data for enrolled subjects at all investigational 
sites. Investigators or their designees are responsible for the timely completion of these forms.  
Entered data are reviewed to identify inconsistent or missing data and adverse events. Data problems 
will be addressed by phone or written communication with the investigational sites and/or during site 
visits. All forms and data files will be secured to ensure confidentiality. Investigators are to maintain all 
source documents required by regulation, including diagnostic test reports, laboratory results, 
completed CRFs, supporting medical records and informed consents. The source documents will be 
referenced during regular monitoring visits to verify the information documented on the CRFs. 
 
 
Pre-operative diagnostic tests will be evaluated by the Investigator and other appropriate professionals 
at the investigational site to determine the subject’s eligibility for the clinical study. 

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25.0 Table of Events (Table 2.0) 
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Screening/ 
During 
Discharge 
1 
6 
12 
Month Month 
Month 
(-7/+14 
(+/- 30 
(+ 60 
Baseline 
Procedure 
days) 
days) 
days) 
Informed 
Consent 
X 
Medical History 
X 
Physical Exam 
X 
X 
X 
X 
X 
Cardiac 
Medications 
X 
X 
X 
X 
X 
Cardiac 
Catheterization 
X 
CT Scan with 
contrast 
X1 
X4 
X5 
TTE 
X 
X 
X 
X 
X 
PFT
2 
X 
Chest X-ray 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
6 Minute Walk 
Test 
X 
X 
X 
5 Meter Walk 
Test 
X 
NYHA 
Classification 
X 
X 
X 
X 
X 
STS Risk Score 
X 
Quality of Life 
(KCCQ) 
X 
X 
X 
X 
Intra-Procedure 
assessments 
X 
Adverse Event 
Assessment 
X 
X 
X 
X 
X 

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Table of Events (Table 2.0) continued 
 
 
Lab 
Measurements 
CBC and Platelet 
Count 
X 
X 
X 
X 
CMP 
X 
X 
X 
X 
BNP 
X 
X 
X 
X 
PTT or PT/INR 
X 
X 
X 
X 
X 
Blood or urine 
pregnancy3 
X 
Plasma Free 
Hemoglobin 
X 
X 
X 
Haptoglobin 
X 
X 
X 
1. 3D Computed Tomography scan with contrast of chest, heart and peripheral vasculature with assessment 
 
of degree and pattern of MAC 
 
2. Pulmonary Function Test within 1 year of consent 
 
3. A blood or urine pregnancy test will be performed at screening for females with childbearing potential. A 
positive pregnancy test will render the subject ineligible for study participation. 
4. 4D Computed Tomography scan with contrast of the heart to include valve assessment 
 
5. 4D Computed Tomography scan with contrast of heart to include valve assessment if any of the following 
have occurred: 
A. presence of thrombus on 30 day 4DCT scan 
 
B. Increase in mitral gradient as measured on TTE 
 
C. Clinical deterioration or clinical event including: 
 
i. neurological or peripheral embolic event 
 
ii. Rehospitalization for heart failure 

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Appendix 1 Informed Consent Form Template 
 
BAYLOR RESEARCH INSTITUTE 
 
Investigational Site Name 
 
 
 
 
PARTICIPATION EXPLANATION AND CONSENT FORM 
 
 
 
 
PROJECT TITLE: 
Surgical Implantation of TRAnscatheter vaLves in native mitral stenosis (SITRAL) Trial 
 
 
 
 
INVESTIGATORS: 
 
 
 
 
TELEPHONE NUMBER: 
 
 
 
 
Introduction: 
 
 
 
 
Before you say that you will be in this clinical trial (a kind of research study) you need to read this form. It is 
important for you to understand all the information in this form. This form will tell you what the clinical trial is 
about and how it will be done. It will tell you about some problems that might happen during the clinical trial.  It 
will also tell you about the good things that might happen for you during the clinical trial. When you read a paper 
like this to learn about a clinical trial it is called “informed consent.” The people who are doing this clinical trial 
are giving you very important information about the clinical trial. When you give your consent for something, it is 
the same as giving your permission. This consent form may contain words that you do not understand. Please 
talk with one of the doctors or their staff if you have questions. Do not sign this consent form unless all your 
questions have been answered and you feel comfortable with the information you have read. You will be given a 
copy of the form to keep. 
 
 
You are being asked to take part in this study because you have been diagnosed as having mitral stenosis and 
mitral annular calcification (MAC) and are high-risk or inoperable for mitral valve surgery. 
 
 
Why is this study being done? 

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The purpose of this study is to establish the safety and feasibility of the Edwards SAPIEN 3 valve in subjects with 
mitral stenosis and mitral annular calcification (MAC) who are high-risk or inoperable for mitral valve surgery. 
 
 
What is the Status of the Drugs (Devices or Procedures) involved in this study? 
 
 
The Edwards SAPEIN 3 valve is currently approved by the US Food and Drug Administration for the treatment of 
aortic stenosis. 
 
 
 
 
How Many People Will Take Part In The Study? 
 
 
About 30 people will take part in this study at six sites worldwide. About 5 of these people will take part at this 
location. 
 
 
What Is Involved In The Study? 
 
 
The following information will be collected for all study subjects prior to procedure. Baseline assessments must 
be completed within 30 days of subject enrollment unless otherwise specified. 
 
• 
Medical History and Physical Exam including Cardiac Medications 
• 
Blood tests (about 2-3 teaspoons) 
• 
Society of Thoracic Surgeons (STS) Risk Score Assessment 
• 
Heart catheterization with an x-ray dye (contrast media) to evaluate your heart. This test will take about 2 
hours. 
• 
Computed tomography (CT) scan of chest, heart and abdomen with assessment of degree and pattern of 
MAC with an x-ray dye (contrast media). This test will take about 1-2 hours. 
• 
Transthoracic echocardiogram (TTE: a probe is placed on your chest and images of your heart are 
recorded). The TTE does not require anesthesia and takes about 45 minutes. 
• 
12 Lead Electrocardiogram (ECG) (a test which measures the electrical activity of your heart) 
• 
Chest X-Ray which will take about 15 minutes 
• 
Pulmonary Function Test (PFT) 
• 
6 minute walk test (measures how far you can walk in six minutes) 
• 
New York Heart Association classification (this is a score based on severity of your heart failure symptoms) 
• 
Quality of Life questionnaire which will take about 10 minutes 
• 
5 meter walk test (this measure how fast you walk) 
 
 
What Happens during the procedure? 
The  study  doctor  will  perform  your  mitral  valve  surgery  in  a  cardiac  operating  room  (OR)  under  general 
anesthesia. An incision will be made on your right side so that the study doctor can access your heart. 

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You will be placed on cardiopulmonary bypass during your procedure. This is sometimes called a “heart-lung 
machine”. The machine will remove the blood from your body through tubes and add oxygen to it. The machine 
then returns the blood to your body. The study doctor will try to minimize the time you spend on this machine. 
The study doctor will explain the entire procedure to you, including all the risks and the steps he will take to 
minimize those risks. 
 
 
 
 
Once the study doctor has access to your mitral valve, a small portion will be removed from your valve leaflet and 
the study doctor will choose an Edwards Sapien 3 valve that is appropriately sized. A camera will be used to help 
visualize the procedure to confirm that the valve is in a good position and that there are no leaks. Once the valve 
is confirmed to be in a good positioned and well seated, sutures will be used to secure the valve in position and 
the heart will be closed. 
 
The valve function will be assessed by transesophageal echocardiogram (TEE) during the procedure. If the valve 
appears to be functioning well with little to no paravalvular leak (blood flowing around the valve). The patient will 
be weaned from the “heart lung machine” and transferred to the ICU for further care. 
 
 
The following information will be collected during you procedure: 
 
 
• 
Transesophageal echocardiogram (TEE) assessments: 
o Mitral valve gradients 
o Quantify severity of mitral regurgitation 
o Left ventricular outflow tract (LVOT) width in millimeters (mm) and gradient 
o Presence of other valvular heart disease 
o Left ventricular ejection fraction 
o central or paravalvular mitral regurgitation 
o transmitral gradient 
• 
Cardiac output and cardiac index 
 
 
The following data will be collected within 24 hours of the date of your discharge. If you are discharged within 48 
hours of leaving the operating room, the tests collected during the Post Procedure period will not be repeated at 
discharge. If you are discharged over a weekend or holiday, the discharge tests will be completed on the last 
weekday prior to your discharge. 
 
• 
Physical examination 
• 
A list of current Medicines will be collected 
• 
Transthoracic echocardiogram 
• 
NYHA classification 
• 
Standard 12-lead ECG 
• 
Chest X-ray examination 
• 
Blood tests (about 2-3 teaspoons) 

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Follow-Up Procedures: 
 
 
Follow-up procedures will be conducted at the intervals list below. Blood draws will be performed at the specified 
intervals and according to hospital standard or medicine regimen. You will be informed that some of the 
information collected at scheduled follow-ups as well as at unscheduled visits, including the echocardiogram, CT 
scan, ECG and the Quality of Life questionnaires, may be sent to the respective independent core lab for analysis. 
 
Follow-up visit intervals are as follows: 30 days (-7, +14) days, 6 months (±30 days), 12 months (+ 60 days). 
Additional phone follow-ups may be performed as needed to obtain up to date survival information. 
 
30 day Follow-Up Visit: 
 
 
The following data will be collected for all study subjects at 30 days (within 7 days before and 14 days after the 30 
days date) 
 
 
 
• 
Physical examination 
• 
A list of current Medicines will be collected 
• 
Transthoracic echocardiogram 
• 
4D Computed tomography (CT) scan of heart with an x-ray dye (contrast media). This test will take about 
1-2 hours. 
• 
NYHA classification 
• 
Standard 12-lead ECG 
• 
Chest X-ray examination 
• 
Blood tests (about 2-3 teaspoons) 
 
 
• 
6 minute walk test 
• 
Quality of life questionnaire which will take about 10 minutes 
 
 
 
 
 
Six Month Follow-up Visit: 
 
 
• 
Physical examination 
• 
A list of current Medicines will be collected 
• 
Transthoracic echocardiogram 
• 
NYHA classification 
• 
Blood tests (about 2-3 teaspoons) 
• 
A 4D Computed tomography (CT) scan of heart with an x-ray dye (contrast media) will be completed if any 
of the following have occurred: 
A. presence of thrombus (blood clot) on 30 day 4DCT scan 
B. Increase in mitral gradient as measured on TTE 

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C. Clinical deterioration or clinical event including: 
i. neurological or peripheral embolic event 
ii. Rehospitalization for heart failure 
 
 
 
12 Month Follow-Up Visit 
 
 
The following data will be collected for all study subjects at +60 days. 
 
 
• 
Physical examination 
• 
A list of current Medicines will be collected 
• 
Transthoracic echocardiogram 
• 
NYHA classification 
• 
Standard 12-lead ECG 
• 
Chest X-ray examination 
• 
Blood tests (about 2-3 teaspoons) 
 
 
• 
6 minute walk test 
• 
Quality of life questionnaire which will take about 10 minutes 
 
 
 
 
How Long Will I Be In The Study? 
 
 
You will be in the study for about 1 year or 12 months. 
 
 
The researcher may decide to take you off the study if any of the following occur: 
 
 
• 
He/She feels that it is in your medical best interest. 
• 
Your condition worsens. 
• 
New information becomes available. 
• 
The study is stopped by the sponsor. 
 
 
You can stop taking part in this study at any time. However, if you decide to stop taking part in the study, we 
encourage you to talk to the researcher and your regular doctor first. 
 
 
What Are The Risks of The Study? 
 
 
While on the study, you are at risk for these bad reactions. You should discuss these with the researcher and/or 
your regular doctor.  There also may be other bad reactions that we cannot predict. 
 
 
Risks and bad reactions related to the procedure we are studying include: 

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• 
abnormal lab values (reduced number of red blood cells, abnormal white blood cells, low platelets, elevated 
renal (kidney) function), hematologic dyscrasia (abnormal blood cells), hepatic enzyme changes (changes in 
liver lab) 
• 
access site arteriovenous fistula or pseudoaneurysm; (hole or abnormal connection between the arteries and 
veins at the access site); 
• 
allergic reaction to anesthesia or to contrast media (x-ray dye); 
• 
anemia(reduced number of red blood cells); 
• 
angina (chest pain); 
• 
arrhythmia (irregular heart beat); 
• 
bleeding (loss of blood); 
• 
cardiovascular or vascular (involving the heart and blood vessels)  injury including perforation (a hole), 
obstruction (blockage), or dissection (damage) of valvular structures that may require intervention, including 
access sites; 
• 
conduction system (the system that controls the heart to contract and pump blood) injury (defect) which may 
require permanent pacemaker; 
• 
death; 
• 
dyspnea (e.g. orthopnea) (shortness of breath); 
• 
electrolyte imbalance; 
• 
embolization (obstruction) including air, particulate, calcific material (plaque); or thrombus (clot formation) ; 
• 
exercise intolerance (unable to do exercise that is expected for one’s physical condition) or weakness; 
• 
fever; 
• 
heart failure; 
• 
heart murmur; 
• 
hematoma (blood accumulation or bruising); 
• 
hemorrhage (a rapid loss of blood) requiring transfusion or intervention; 
• 
leaflet tearing; 
• 
hypertension(high blood pressure)/hypotension(low blood pressure); 
• 
infection, including septicemia (infection in the blood),  and endocarditis (inflammation of the heart); 
• 
inflammation (swelling); 
• 
myocardial infarction (heart attack); 
• 
pain or changes at the access site; 
• 
paralysis; 
• 
pericardial effusion/cardiac tamponade (bleeding into the heart sac); 
• 
permanent disability; 
• 
pleural effusion(fluid accumulation in the lungs); 
• 
prosthesis nonstructural dysfunction (poor function of the study device); 
• 
prosthesis pannus (a hanging flap of tissue from device); 
• 
pulmonary edema(fluid in the lungs); 
• 
renal failure (poor kidney function requiring dialysis); 

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• 
renal insufficiency (poor kidney function); 
• 
reoperation(having another operation); 
• 
restenosis (narrowing of the mitral valve); 
• 
retroperitoneal bleed (bleeding into a space in the abdomen); 
• 
syncope (fainting or brief loss of consciousness); 
• 
systemic (body) or peripheral (arms and legs) ischemia (decreased blood flow)/nerve injury; 
• 
thromboembolic events, stroke, transient ischemic attack (mini-strokes), clusters (type of mini stroke), or 
neurological (brain, spinal cord and nerves) changes. 
 
 
 
Complications with the investigational device you may experience may include, but are not necessarily limited to, 
the following: 
 
 
 
 
• 
Cardiac arrest(heart stops beating); 
• 
cardiac dysrhythmias (irregular heart beat) requiring permanent pacemaker; 
• 
cardiac failure/low cardiac output (poor heart function); 
• 
cardiogenic shock (heart muscle is unable to supply blood to the body); 
• 
cardiovascular or vascular (involving the heart and blood vessels) injury including perforation (a hole), 
obstruction(blockage), or dissection (damage) of valvular structures that may require intervention, including 
access sites; 
• 
chordal rupture (tearing of a portion of the native valve); 
• 
device degeneration(device breakdown); 
• 
device explants (removal of the device); 
• 
device migration (movement), malposition (implanted in unintended position) or embolization (obstruction) 
requiring intervention; 
• 
device thrombosis (clot formation)  requiring intervention; 
• 
emergency cardiac (heart) surgery; 
• 
hemolysis (disruption of blood cells); 
• 
infection including endocarditis (inflammation of the heart); 
• 
leak (transvalvular or paravalvular) (blood leakage through or around the device); 
• 
Left Ventricular Outflow Tract obstruction (blocking the path of blood leaving the heart); 
• 
non-emergent reoperation (need for another operation that is not an emergency); 
• 
nonstructural Mitral THV dysfunction (poor function of the study device); 
• 
papillary muscle damage; 
• 
pulmonary vein obstruction (blocking the path of blood entering part of the heart); 
• 
structural deterioration (poor function of the aortic valve) (wear, fracture, calcification, leaflet tear/tearing, 
leaflet retraction (valve parts stop working), stent creep, suture line disruption, thickening, stenosis, or other); 
• 
thromboembolism (permanent or transient neurological events); 
• 
transvalvular (across the valve) flow disturbances or aortic valve impairment/damage; 

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• 
valvular regurgitation (leakage); 
• 
ventricular or atrial (chambers of the heart) wall damage, abrasion (injury), or perforation (hole); 
• 
worsening of heart failure; 
• 
worsening of valvular insufficiency (valve function). 
 
 
 
With any investigational device there may be unforeseeable risks, which are not known at this time.  Medical and 
/ or surgical intervention may be required to correct clinical complications associated with the device and / or 
study procedure. 
 
 
 
 
Pregnancy Risks 
 
Women who are pregnant may not take part in this study. The effects of this treatment and follow-up requirements 
to an embryo or fetus are currently unknown. If you are a woman of child-bearing potential, and are not sterile, 
a small amount of blood or urine will be collected, to confirm you are not pregnant, before the study procedure. 
A urine pregnancy test is not as sensitive as a blood pregnancy test and a negative urine test does not completely 
rule out an early pregnancy in progress. 
 
 
 
A serum pregnancy test will be given to if you  are considered  of child-bearing potential (WOCBP). To be considered 
as non-WOCBP, you must be post-menopausal (12 months of natural amenorrhea with an appropriate clinical profile 
[e.g., age appropriate, history of vasomotor symptoms] or six months of spontaneous amenorrhea with serum FSH 
levels > 40mIU/mL) 
 
 
 
Other study procedure risks: 
• 
Possible nausea and vomiting from general anaesthesia 
 
• 
Possible bruising at blood draw site 
 
 
If you have additional questions about these risks, ask the researcher. 
 
 
Please notify the study doctor or study staff if you experience any side effects or complications during the 
study. You will be monitored throughout the study in order to minimize risks. 
 
 
 
 
Radiation Risks: 
 
If you take part in this study, you will undergo several medical imaging procedures involving exposure to 
radiation. The following lists these procedures: 
 
• 
a CT scan (also known as a CAT scan) to help visualize the heart valves and blood vessels in and around 
your heart, done during the screening assessment as well as the 30 days and 6 month visits. 

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• 
Heart catheterization under fluoroscopy (fluoroscopy is like an x-ray “movie”) during the screening 
assessment (standard of care that you would have likely had even if not in the study) 
• 
Fluoroscopy during the procedure to replace your mitral value if the replacement is performed with a 
catheter (research only procedure) 
• 
Chest x-ray 
 
 
 
If you have concerns about the radiation exposure associated with this study, please speak with your doctor. 
 
 
 
Conflict of Interest 
 
 
Your doctor may be an investigator in this research study. If so, s/he is interested both in your medical care and in 
the conduct of this research. Before you sign up for this study or at any time during the research, you may discuss 
your care with another doctor who is not associated with this research project. You are not under any obligation 
to take part in any research study offered by your doctor. 
 
 
The people working on this study may be paid for their work on this research study from money provided by the 
company sponsoring this research study. The people working on this study may be paid for other work that is 
unrelated to this research study, such as consulting with the sponsor company or speaking at educational 
programs at the request of the sponsor company or other companies that may have an interest in the study. The 
people working on this study may have public stock holdings as an investment in the company sponsoring this 
research study. 
 
 
 
Are There Benefits to Taking Part in The Study? 
 
 
If you agree to take part in this study, there may or may not be direct medical benefit to you. We hope that the 
information learned from this study will benefit other subjects with this disease in the future. 
 
 
What Other Options Are There? 
 
 
Instead of being in this study, you have the following options: 
 
 
• 
You may choose to receive no therapy at this time and receive only care to help you feel more 
comfortable. 
• 
You may choose not to take part in the study. 
 
 
Please talk to your regular doctor about these and other options. 
 
 
What About Confidentiality? 

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You have a right to privacy. This means that all the information about you from this study will only be shown to 
the people working on the study. The results of this study may be published in a scientific book or journal.  If this 
is done, your name will not be used. All information about you from this research project will be kept in a locked 
office or other locked area. Information that is kept on computers will be kept safe from access by people who 
should not see it. 
 
 
The privacy law requires that (Insert Site Name here) get your permission before giving any of your health 
information to other people. There are people who need to review your information to make sure the study is 
done correctly. These people may look at or copy your information while they are doing this review. When you 
sign this form you give permission to (Insert Site Name here) to give other people information about your health 
as needed for the research project. These groups include people who work for (Insert Site Name here) (including 
the Institutional Review Board), the US Food and Drug Administration, the Office for Human Research Protections 
and the Association for the Accreditation of Human Research Protection Programs. This also includes the  
following groups of people who are working with the sponsor of the study: Baylor Scott & White Research 
Institute, Baylor Scott & White Research Institute Imaging Core Lab, Edwards Lifesciences, (list additional groups 
as applicable).  Even though we usually remove your name from the information, the people who get this 
information may be able to figure out who you are. The kinds of health information that might be given to these 
people include results from lab tests or other tests like x-rays. This information might also be notes written by 
your doctor from your medical record or notes written by your doctor asking for tests to be done on you. 
 
 
 
 
You do not have to give this permission and it is all right to refuse to sign this form.  Your doctor will still treat you 
and your insurance company will still pay your medical bills (according to their policy) even if you do not give your 
permission for us to release this information. However, since it is important for the people listed above to have 
access to your information, if you do not sign this form, you cannot be in the research study. 
 
 
If you give permission to (Insert Site Name here) to give other people information about your health and the other 
people are not part of the group that must obey this law, your health information will no longer be protected by 
the privacy law. However, we will take all reasonable measures to protect your information from being misused. 
 
 
If you change your mind and later want to withdraw your permission, you may do so. You must notify (Insert 
appropriate name and address here)  If you decide to do this, it will not apply to information that was given 
before you withdrew your permission and you will no longer be able to take part in the study. 
 
 
Unless permission is withdrawn, this permission will not expire at the end of the study. 
 
 
What Are the Costs? 
 
 
Taking part in the study may lead to added costs to you or your insurance company.  Please ask about any 
expected added costs or insurance problems. 

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• 
You or your insurance company will be required to pay for all expenses related to the implantation 
procedure and your other hospital care. 
 
The sponsor of this study is paying (Insert Site Name here) a specific amount of money for each person who 
agrees to take part in the study. This money is to cover the cost of doing the study and pay for such things as 
study supplies, staff salaries, etc. 
 
 
Will I Be Paid For Taking part in This Study? 
 
 
You will not be paid for being in this study. 
 
 
What if I am Injured or Become Ill While Taking part in this Study? 
 
 
The people doing this research project will do everything they can to make sure you do not get hurt during the 
project. If you do get hurt, there are some things that you need to know: 
 
 
 
 
• 
The people doing the research project have not set funds aside to pay you money if you are hurt. 
• 
Baylor Health Care System, Baylor Research Institute and The Heart Hospital at Baylor Hospital have not 
set funds aside to pay you money if you are hurt. 
• 
The sponsor, Baylor Scott & White Research Institute, has not set funds aside to pay you money if you are 
hurt. 
• 
If you have an emergency illness during the project, the people working with you will provide emergency 
care. You or your insurance company may need to pay for the emergency care if that happens. 
• 
You have not given up any of your legal rights by signing this form. 
 
 
What are My Rights As a Participant? 
 
 
Taking part in this study is voluntary. You may choose not to take part or may leave the study at any time. If you 
agree to take part and then decide against it, you can withdraw for any reason. Deciding not to be in the study, or 
leaving the study early, will not result in any penalty or loss of benefits that you would otherwise receive. 
 
 
We will tell you about any new information that may affect your health, welfare, or willingness to stay in this 
study. 
 
 
All of the people working on the project must be careful not to carelessly harm you. If you are hurt during this 
project, you have the right to seek legal counsel. Nothing in this consent form takes away that right if you are hurt 
during this research. 

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Whom Do I Call If I have Questions or Problems? 
 
 
If you have concerns, complaints or questions about the study or have a research-related injury, contact the 
Principal Investigator, 
at 
. 
 
 
For concerns, complaints or questions about your rights as a research subject or if you simply wish to speak with 
someone who is not a part of the research staff, contact 
_, M.D., IRB Chair, at 
  
_. 
 
 
 
Statement of Person Obtaining Consent: 
 
 
I have explained to 
the purpose of the research project, the procedures required and the possible 
risks and benefits to the best of my ability. They have been encouraged to ask questions related to taking part. 
 
 
 
 
 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
 
 
Confirmation of Consent by Research Subject: 
 
 
 
 
You are making a decision about being in this research study.  You will be asked to give your written consent if you want 
to be in the study. Giving consent is like giving permission. You should not give your permission to be in this study until 
you have read and understood all the pages in this form. If you cannot read, then someone can read the form to you. 
Make sure that all your questions about this research project have been answered before you sign this form. When you 
sign this form, you are giving your permission to be in the study. By signing this form, you have not given up any of your 
legal rights or released anyone from liability for negligence. 
 
  
has explained to me the purpose of the research project, the study procedures 
that I will have, and the possible risks and discomforts that may happen.  I have read (or have been read) this consent 
form. I have been given a chance to ask questions about the research study and the procedures involved. I believe 
that I have enough information to make my decision.  I have also been told my other options. To the best of my 
knowledge, I am not in any other medical research.  Therefore, I agree to give my consent to take part as a subject in 
this research project. 
 
 
 
 
Signature of Subject 
Date 
Time 
 

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Appendix 2: VALVE ACADEMIC RESEARCH CONSORTIUM DEFINITIONS 
 
TERM 
DESCRIPTION 
 
 
 
 
Cardiovascular Mortality 
(M-VARC) 
Any of the following criteria: 
 
• Death due to proximate cardiac cause (e.g., myocardial 
 
infarction, cardiac tamponade, worsening heart failure) 
 
 
 
• Death caused by non-coronary vascular conditions such 
as neurological events, pulmonary embolism, ruptured 
aortic aneurysm, dissecting aneurysm, or other vascular 
disease 
 
 
• All procedure-related deaths, including those related to 
a complication of the procedure or treatment for a 
complication of the procedure 
 
 
• Sudden or unwitnessed death 
 
 
 
• Death of unknown cause 
Procedure-related death (M-VARC) 
Procedure-related death is defined by any intra-procedural 
events that result in immediate or consequent death (within 
48 hours). 
Non-cardiovascular mortality (M-VARC) 
Any death in which the primary cause of death is clearly 

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related to another condition (e.g., trauma, cancer, suicide). 
 
 
 
Myocardial Infarction (M-VARC) 
Peri-procedural MI (≤ 72 hours after the index procedure): 
 
New ischemic symptoms (e.g. chest pain or shortness of 
breath), or new ischemic signs (e.g. ventricular 
arrhythmias, new or worsening heart failure, new ST- 
segment changes, hemodynamic instability, new 
pathological Q waves in at least two contiguous leads, 
imaging evidence of new loss of viable myocardium or 
new wall motion abnormality), 
 
 
AND 
 
 
 
Elevated cardiac biomarkers within 72 h after the index 
procedure consisting of at least one sample post- 
procedure with a peak value exceeding 15x upper 
reference limit (troponin) or 5x for CK-MB. 
If cardiac biomarkers are increased at baseline (>99th 
 
percentile), a further increase of at least 50% post- 
procedure is required AND the peak value must exceed 
the previously stated limit. 
 
 
Spontaneous MI (> 72 hours after the index procedure): 
 
Any one of the following criteria: 
 
1) Detection of rise and/or fall of cardiac biomarkers 
(preferably troponin) with at least one value above the 
99th percentile URL, together with evidence of 
myocardial ischemia with at least one of the following: 
– Symptoms of ischemia 

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– ECG changes indicative of new ischemia [new ST-T 
changes or new left bundle branch block (LBBB)] 
– New pathological Q waves in at least two 
contiguous leads 
– Imaging evidence of new loss of viable myocardium 
or new wall motion abnormality 
 
 
2) Sudden, unexpected cardiac death, involving cardiac 
arrest, often with symptoms suggestive of myocardial 
ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and/or evidence of fresh 
thrombus by coronary angiography and/or at autopsy, 
but death occurring before blood samples could be 
obtained, or at a time before the appearance of cardiac 
biomarkers in the blood. 
 
 
3) Pathological findings of an acute myocardial 
infarction. 
 
 
 
 
Bleeding 
(M-VARC) 
Life-threatening Bleeding: 
 
• Fatal bleeding (BARC type 5) OR 
 
• Bleeding in a critical organ, such as intracranial, intraspinal, 
intraocular, or pericardial necessitating pericardiocentesis, or 
intramuscular with compartment syndrome (BARC type 3b and 
3c) OR 
• Bleeding causing hypovolemic shock or severe hypotension 
 
requiring vasopressors or surgery (BARC type 3b) OR 
 
• Overt source of bleeding with drop in hemoglobin of ≥ 5 g/dL 

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or whole blood or packed red blood cells (RBCs) transfusion ≥ 
 
4 units* (BARC type 3b) 
 
 
 
Major Bleeding: 
 
• Over bleeding either associated with a drop in the 
hemoglobin level of at least 3.0 g/dL or requiring transfusion 
of 2 or 3 units of whole blood/RBC AND 
• Does not meet criteria of life-threatening or disabling 
 
bleeding 
 
 
 
Minor Bleeding: 
 
• Any bleeding worthy of clinical mention (e.g. access site 
hematoma) that does not qualify as life-threatening, disabling, 
or major. 
 
 
Acute Kidney Injury 
(M-VARC) 
Change in serum creatinine (up to 7 days) compared with 
baseline 
• Stage 1 Increase in serum creatinine to 150–200% (1.5–2.0 × 
increase compared with baseline) or increase of ≥0.3 mg/dL 
(≥26.4 mmol/L) within 48 hours. 
• Stage 2 Increase in serum creatinine to 200–300% (2.0–3.0 × 
increase compared with baseline) 
• Stage 3* Increase in serum creatinine to >300% (>3x 
increase compared with baseline) or serum creatinine of 
>4.0 mg/dL (>354 mmol/L) with an acute increase of at least 
 
0.5 mg/dL (44 mmol/L) 
 
*Subjects receiving renal replacement therapy are considered 
to meet Stage 3 criteria irrespective of other criteria 

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Vascular access site and site related 
Major Vascular Complications:
complications 
(M-VARC) 
• Any thoracic aortic dissection, aortic rupture, annulus 
rupture, left ventricle perforation, or new apical 
aneurysm/pseudo-aneurysm 
• Access site or access-related vascular injury (dissection, 
stenosis, perforation, rupture, arterio-venous fistula, 
pseudoaneurysm, hematoma, irreversible nerve injury, 
compartment syndrome, percutaneous closure device failure) 
leading to death, major bleeding*, visceral ischemia or 
neurological impairment 
• Distal embolization (non-cerebral) from a vascular source 
 
requiring surgery or resulting in amputation or irreversible 
end-organ damage 
• The use of unplanned endovascular or surgical intervention 
associated with death, major bleeding, visceral ischemia or 
neurological impairment 
 
 
Minor Vascular Complications: 
 
• Access site or access-related vascular injury (dissection, 
stenosis, perforation, rupture, arterio-venous fistula, 
pseudoaneurysm, hematomas, percutaneous closure device 
failure) not leading to death, major bleeding*, visceral 
ischemia or neurological impairment 
• Distal embolization treated with embolectomy and/or 
thrombectomy and not resulting in amputation or irreversible 
end-organ damage 
• Any unplanned endovascular stenting or unplanned surgical 
 
intervention not meeting the criteria for a major vascular 
complication 

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Percutaneous Closure Device Failure: 
 
• Access site or access-related vascular injury (dissection, 
stenosis, perforation, rupture, arterio-venous fistula, 
pseudoaneurysm, hematomas, percutaneous closure device 
failure) not leading to death, major bleeding*, visceral 
ischemia or neurological impairment 
• Distal embolization treated with embolectomy and/or 
 
thrombectomy and not resulting in amputation or irreversible 
end-organ damage 
• Any unplanned endovascular stenting or unplanned surgical 
intervention not meeting the criteria for a major vascular 
complication 
Vascular Complications: 
 
• Major vascular complications: 
 
– Hematoma at the access site > 6 cm; 
 
– Retroperitoneal hematoma; 
 
– Arterio-venous fistula; 
 
– Symptomatic peripheral ischemia/nerve injury with 
clinical signs or symptoms and lasting > 24 hours; 
– Vascular surgical repair at catheter access sites; 
 
– Ipsilateral deep vein thrombus; or 
 
– Access site-related infection requiring intravenous 
antibiotics and/or extended hospitalization. 
 
 
Device Failure 
Device failure, defined as the absence of device success, is 
subclassified as: 
• Delivery failure (i.e., technical failure) 
 
• Structural failure: the device does not perform as intended 
due to a complication related to the device (e.g., fracture, 

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Specific device-related technical failure 
issues and complications Paravalvular 
leak 
migration or embolization, frozen leaflet, device 
detachment, and so on) 
• Functional failure: the device performs as intended without 
complication but does not adequately reduce the degree of 
MR (MR . moderate [2+], or fails to relieve or creates new 
mitral stenosis [EROA ,1.5 cm2 or transmitral gradient .5 
mm Hg]). 
Paravalvular leak 
 
• Major: moderate or severe (2+, 3+, or 4+), or associated 
with haemolysis, or requiring intervention or surgery 
• Minor: trace or mild (1+), without haemolysis 
 
 
 
Iatrogenic atrial septal defect 
 
• Major: significant left-to-right shunt (Qp:Qs ≥2:1) or 
symptomatic requiring the need for closure 
• Minor: nonsignificant shunt that is still present at ≥6 months 
 
 
 
Coronary vessel compression or obstruction 
 
• Angiographic evidence of any reduction in coronary artery 
luminal diameter or coronary sinus diameter due to either 
external compression, thrombosis, embolism, dissection, or 
other cause, subclassified as: 
- 
Major (≥50% diameter stenosis) or minor (<50%) 
 
- 
Symptomatic or not 
 
- 
Requiring treatment or not 
 
- 
Transient (intraprocedural only, resolved at 
procedure end) or persistent 

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Pericardial effusion 
 
• Major: leading to cardiac tamponade or requiring 
intervention 
• Minor: not leading to cardiac tamponade and not requiring 
intervention 
 
 
Conversion to open mitral valve surgery during a 
transcatheter procedure, subclassified as 
• Secondary to mitral valve apparatus damage or dysfunction, 
requiring surgical valve repair or replacement, or 
• Secondary to procedural complications (such as cardiac 
perforation, removal of an embolized device, and so on) 
 
 
Device malpositioning 
 
• Ectopic device placement: permanent deployment of a 
device in a location other than intended 
• Device migration: after initial correct positioning, the device 
moves within its initial position but not leading to device 
embolization 
• Device embolization: the device moves during or after 
deployment such that it loses contact with its initial position 
 
 
Device detachment 
 
• Partial: detachment of part of the device from the initial 
position without embolization 
• Complete: detachment leading to device embolization or 
ectopic device placement 
 
 
 
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Device fracture 
• Major: a break, tear, perforation, or other structural defect 
in the device (stent, housing, leaflet, arm, and so on) 
resulting in device failure, resulting in recurrent symptoms, 
or requiring reintervention, or 
• Minor: a break, tear, perforation, or other structural defect 
in the device (stent, housing, leaflet, arm, and so on) not 
resulting in device failure, not resulting in recurrent 
symptoms, and not requiring reintervention 
 
 
Damage to the native mitral valve apparatus 
 
• Chords 
 
• Papillary muscles 
 
• Leaflets 
 
• Mitral annulus 
 
 
 
Interaction with non-mitral valve intracardiac structures 
 
• Left ventricular outflow tract obstruction (gradient increase 
 
≥10 mm Hg from baseline) 
 
• Aortic valve regurgitation (≥ moderate or 2+) 
• Other 
 
 
 
Device thrombosis, defined as any thrombus attached to or 
near an implanted valve, subclassified as: 
• Major: occludes part of the blood flow path, interferes with 
valve function (e.g., immobility of 1 or more leaflets), is 
symptomatic, or is sufficiently large to warrant treatment, 
or 
• Minor: incidental finding on echocardiography or other 
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Protocol Version 1.1 
 
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Confidential 
Baylor Scott & White Research Institute 
 
 
 
imaging test that is not major 
 
 
 
Endocarditis 
 
Any 1 of the following: 
 
• Fulfilment of the modified Duke endocarditis criteria11, or 
 
• Evidence of abscess, paravalvular leak, pus, or 
vegetation confirmed as secondary to infection by 
histological or bacteriological studies during an 
operation or autopsy. 
-   Should be further subclassified by organism, and 
early (<1 yr) vs. late (>1 yr) 
 
 
Haemolysis 
 
• The presence of a paravalvular leak on 
transoesophageal or transthoracic echocardiography 
plus anaemia requiring transfusion plus increased 
haptoglobin and/or LDH levels; should be confirmed by a 
 
haematologist 
 
 
 
Other device-specific endpoints 
 
• The number of devices (e.g., clips, neochords) used by 
intent to achieve the desired reduction in MR 
• The need for unplanned use of additional devices (e.g., 
valves, clips, neochords) as a result of failed device 
delivery, device detachment, device fracture, 
or other device system failure 
 
• If surgery is required, inability to perform mitral valve 
repair because of the presence of or anatomic changes 
from the device 
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Baylor Scott & White Research Institute 
 
 
Appendix 3: NYHA FUNCTIONAL CLASSIFICATION 
 
The Criteria Committee of the New York Heart Association.10 
 
 
 
 
NYHA FUNCTIONAL 
CLASSIFICATION 
Class I: Subjects with cardiac disease but without resulting limitation of physical 
activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
Class II: Subjects with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Class III: Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Class IV Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
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Rev. 2012-04-11 
Kansas City Cardiomyopathy Questionnaire (KCCQ-12) 
 
The following questions refer to your heart failure and how it may affect your life. Please read and complete the following 
questions. There are no right or wrong answers. Please mark the answer that best applies to you. 
 
1. Heart failure affects different people in different ways. Some feel shortness of breath while others feel fatigue. Please 
indicate how much you are limited by heart failure (shortness of breath or fatigue) in your ability to do the following 
activities over the past 2 weeks. 
Activity 
Extremely 
Limited 
Quite a bit 
Limited 
Moderately 
Limited 
Slightly 
Limited 
Not at all 
Limited 
Limited for 
other reasons 
or did not do 
the activity 
a. Showering/bathing 
O 
O 
O 
O 
O 
O 
b. Walking 1 block on 
level ground 
O 
O 
O 
O 
O 
O 
c. Hurrying or jogging 
(as if to catch a bus) 
O 
O 
O 
O 
O 
O 
 
1 
2 
3 
4 
5 
6 
 
2. Over the past 2 weeks, how many times did you have swelling in your feet, ankles or legs when you woke up in the 
morning? 
Every morning 
3 or more times 
per week but 
not every day 
1-2 times per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
 
 
 
1 
2 
3 
4 
5 
 
 
 
3. Over the past 2 weeks, on average, how many times has fatigue limited your ability to do what you wanted? 
 
All of 
the time 
Several times 
per day 
At least 
once a day 
3 or more times 
per week but 
not every day 
1-2 times 
per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
6 
7 
 
 
4. Over the past 2 weeks, on average, how many times has shortness of breath limited your ability to do what you 
wanted? 
All of 
the time 
Several times 
per day 
At least 
once a day 
3 or more times 
per week but 
not every day 
1-2 times 
per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
6 
7 
 
 
5. Over the past 2 weeks, on average, how many times have you been forced to sleep sitting up in a chair or with at 
least 3 pillows to prop you up because of shortness of breath? 
 
Every night 
3 or more times 
per week but 
not every day 
1-2 times 
per week 
Less than 
once a week 
Never over the 
past 2 weeks 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
 
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Appendix 4: KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE

KCCQ-12 
Page 2 of 2 
 
 
Rev. 2012-04-16 
6. Over the past 2 weeks, how much has your heart failure limited your enjoyment of life? 
 
It has extremely 
limited my enjoyment 
of life 
It has limited my 
enjoyment of life 
quite a bit 
It has moderately 
limited my enjoyment 
of life 
It has slightly 
limited my enjoyment 
of life 
It has not limited 
my enjoyment 
of life at all 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
 
 
7. If you had to spend the rest of your life with your heart failure the way it is right now, how would you feel about this? 
 
Not at all 
satisfied 
Mostly 
dissatisfied 
Somewhat 
satisfied 
Mostly 
satisfied 
Completely 
satisfied 
O 
O 
O 
O 
O 
 
 
1 
2 
3 
4 
5 
 
 
8. How much does your heart failure affect your lifestyle? Please indicate how your heart failure may have limited your 
participation in the following activities over the past 2 weeks. 
 
Activity 
Severely 
Limited 
Limited 
quite a bit 
Moderately 
limited 
Slightly 
limited 
Did not 
limit at all 
Does not apply 
or did not do for 
other reasons 
a. Hobbies, recreational 
activities 
O 
O 
O 
O 
O 
O 
b. Working or doing 
household chores 
O 
O 
O 
O 
O 
O 
c. Visiting family or 
friends out of your 
home 
O 
O 
O 
O 
O 
O 
 
1 
2 
3 
4 
5 
6 
 
Page 56 of 57

 
 
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Confidential 
Baylor Scott & White Research Institute 
 
References 
 
 
1 CS Fox et al. Mitral Annular Calcification Predicts Cardiovascular Morbidity and Mortality: The 
Framingham Heart Study. Circulation. 2003;107:1492‐1496. 
2 Y Okada Surgical management of mitral annular calcification. Gen Thorac Cardiovasc Surg. 
2013;61:619‐625. 
3 JM Sinning et al. Transcatheter mitral valve replacement using a balloon‐expandable prosthesis in a 
subject with calcified native mitral valve stenosis. Eur Heart J. 2013;254:2609. 
4 AA Fassa et al. Transseptal Transcatheter Mitral Valve Implantation for Severely Calcified Mitral 
Stenosis. JACC. 2014;7(6):696‐697. 
5 R Hasan et al. First in Human Transapical Implantation of an Inverted Transcatheter Aortic Valve 
Prosthesis to Treat Native Mitral Valve Stenosis. Circulation. 2013;128:e74‐76. 
6 HB Ribeiro et al. Transapical Mitral Implantation of a Balloon‐Expandable Valve in Native Mitral Valve 
Stenosis in a Subject with Previous Transcatheter Aortic Valve Replacement. JACC 2014;7(10):e137‐139. 
7 M Guerrero Transcatheter mitral valve replacement with balloon expandable valves in native mitral 
valve disease due to severe mitral annular calcification: Results from the First Global Registry. TCT 2015. 
8 Stone GW, Vahanian AS, Adams DH, et al. Clinical study design principles and endpoint definitions for 
transcatheter mitral valve repair and replacement: part 1: clinical study design principles: a consensus 
document from the Mitral Valve Academic Research Consortium. J Am Coll Cardiol. 2015;66:278‐307. 
9Stone GW, Adams DH, Abraham WT, et al. Clinical study design principles and endpoint definitions for 
transcatheter mitral valve repair and replacement: part 2: endpoint definitions: a consensus document 
from the Mitral Valve Academic Research Consortium.J Am Coll Cardiol. 2015;66:308‐321. 
10 Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, 
Mass: Little, Brown & Co; 1994:253‐256. 
11Durack DT, Lukes AS, Bright DK et al. New criteria for diagnosis of infective endocarditis: utilization of 
specific echocardiographic findings. Am J Med 1994; 96:200–209. 
 
 
 
 
 
 
 
 
 
 
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