A Clinical Evaluation of the Safety and Effectiveness of the MitraClip® System for the Treatment of Functional Mitral Regurgitation in Symptomatic Heart Failure Subjects (COAPT Recruitment Closed). COAPT CAS (Recruitment Closed)
Phase: NA
Conditions: Mitral Regurgitation, Mitral Valve Regurgitation, Treatment of Functional Mitral Regurgitation in Symptomatic Heart Failure Subjects, Heart Failure
Sponsor: Abbott Medical Devices

 
 
The COAPT Trial 
 
Clinical Investigational Plan 11-512: Version 8.0 
 
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CLINICAL INVESTIGATIONAL PLAN 11-512 
Cardiovascular Outcomes Assessment of the MitraClip 
Percutaneous Therapy for Heart Failure Patients with 
Functional Mitral Regurgitation 
(The COAPT Trial) 
A Clinical Evaluation of the Safety and Effectiveness of the MitraClip® System for the 
Treatment of Functional Mitral Regurgitation in Symptomatic Heart Failure Subjects  
IDE Number  
G120024 
Version Number 
8.0 
Date 
October 12, 2016 
National Principal Investigator  
Michael J. Mack, MD 
(CT Surgeon) 
 
National Principal Investigator  
Gregg W. Stone, MD 
(Interventional Cardiologist) 
 
National Heart Failure Specialist  
Co-Principal Investigators 
William T. Abraham, MD 
JoAnn Lindenfeld, MD 
Trial Type 
Prospective, randomized, parallel-controlled, 
multicenter clinical evaluation of the MitraClip 
device for the treatment of clinically significant 
functional mitral regurgitation in symptomatic 
heart failure subjects who are treated per standard 
of care and who have been determined by the site’s 
local heart team as not appropriate for mitral valve 
surgery.  Eligible subjects will be randomized in a 
1:1 ratio to the MitraClip device (Device group) or 
to no MitraClip device (Control group). 
Sponsor  
Evalve, Inc. 
 
A subsidiary of Abbott Vascular Inc. 
 
4045 Campbell Avenue 
 
Menlo Park, CA 94025 USA 
Enrollment/Randomization Service 
Medidata RAVE 
Data Management and Analysis  
Abbott Vascular Inc.                                                   
 
3200 Lakeside Drive 
 
Santa Clara, CA 95054 USA 
Electronic Data Capture Software 
Medidata RAVE 

 
 
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Data Monitoring Committee 
Management 
Ionna Kosmidou, MD, PhD 
Director of Events Adjudication and Reporting 
Cardiovascular Research Foundation 
1700 Broadway, 9th Floor 
New York, NY 10019 
Clinical Events Committee 
Management 
Ionna Kosmidou, MD, PhD 
Director of Events Adjudication and Reporting 
Cardiovascular Research Foundation 
1700 Broadway, 9th Floor 
New York, NY 10019 
Echocardiography Core Laboratory 
MedStar Health Research Institute 
Neil Weissman, MD 
6495 New Hampshire Avenue, Suite 201 
Hyattsville, MD 20783 USA 
Steering Committee 
Chairpersons 
Michael J. Mack, MD 
Gregg W. Stone, MD  
 
Heart Failure Specialists 
William Abraham, MD  
JoAnn Lindenfeld, MD 
 
Cardio-Thoracic Surgeons 
Steven F. Bolling, MD 
Michael J. Mack, MD 
Patrick M. McCarthy, MD 
 
Interventional Cardiologists 
Ted E. Feldman, MD 
Samir Kapadia, MD  
Gregg W. Stone, MD 
 
Echocardiographer/Cardiologist 
Paul A. Grayburn, MD  
 
Sponsor Representative 
Gary Johnson 
Clinical Investigational Plan Author 
Jeffrey T. Ellis, PhD 

 
 
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Table of Contents 
TABLE OF CONTENTS ....................................................................................................... 3 
TABLE OF FIGURES ............................................................................................................ 8 
TABLE OF TABLES .............................................................................................................. 9 
CLINICAL TRIAL SUMMARY......................................................................................... 11 
1 INTRODUCTION ............................................................................................................ 20 
2 BACKGROUND INFORMATION ................................................................................ 20 
2.1 
MITRACLIP CLINICAL PROGRAM ............................................................................................................ 20 
2.2 
RESULTS ................................................................................................................................................. 22 
2.2.1 
EVEREST I Trial .......................................................................................................................... 22 
2.2.2 
EVEREST II RCT .......................................................................................................................... 22 
2.2.3 
EVEREST II High Risk Registry (HRR) Study .............................................................................. 24 
2.2.4 
EVEREST II REALISM Continued Access Study .......................................................................... 25 
2.2.5 
ACCESS-EU Study ....................................................................................................................... 25 
2.2.6 
Results in High Surgical Risk Patients ......................................................................................... 26 
2.3 
RATIONALE TO CONDUCT THE COAPT TRIAL ........................................................................................ 29 
2.3.1 
Intended Indication ....................................................................................................................... 30 
2.4 
SUMMARY OF INVESTIGATIONAL DEVICE AND CONTROL THERAPY ....................................................... 30 
2.4.1 
Name of the Investigational Device .............................................................................................. 30 
2.4.2 
Description of the Investigational Device (MitraClip System) ..................................................... 30 
2.4.3 
Description of the Control Group Therapy .................................................................................. 31 
2.4.4 
Procedures Involved in the Use of the Device .............................................................................. 32 
2.4.5 
Training Required for the Use of the Device ................................................................................ 32 
2.4.6 
Investigational Device Accountability .......................................................................................... 32 
3 TRIAL OBJECTIVES ..................................................................................................... 32 
3.1 
PRIMARY OBJECTIVES ............................................................................................................................. 33 
3.2 
SECONDARY OBJECTIVES ........................................................................................................................ 33 
4 TRIAL ENDPOINTS ....................................................................................................... 34 
4.1 
PRIMARY SAFETY ENDPOINT .................................................................................................................. 34 
4.2 
PRIMARY EFFECTIVENESS ENDPOINT ...................................................................................................... 34 
4.3 
SECONDARY SAFETY ENDPOINTS............................................................................................................ 34 
4.4 
SECONDARY EFFECTIVENESS ENDPOINTS ............................................................................................... 34 
4.5 
ADDITIONAL ENDPOINTS ........................................................................................................................ 35 
4.5.1 
Device or Procedure-Related Adverse Events .............................................................................. 35 
4.5.2 
Device and Procedure-Related Endpoints .................................................................................... 35 
4.5.3 
Echocardiographic Endpoints ...................................................................................................... 36 
4.5.4 
Clinical Endpoints ........................................................................................................................ 37 
4.5.5 
CPX Sub-Study Endpoint .............................................................................................................. 39 
4.5.6 
Health Economic Data ................................................................................................................. 40 
5 TRIAL DESIGN, SCOPE AND DURATION ............................................................... 40 
5.1 
TRIAL DESIGN ......................................................................................................................................... 40 
5.2 
NUMBER OF SUBJECTS TO BE REGISTERED.............................................................................................. 40 
5.3 
TRIAL DURATION .................................................................................................................................... 41 

 
 
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5.4 
PARTICIPATION OF WOMEN IN COAPT .................................................................................................. 41 
5.4.1 
Sex-Specific Prevalence of Valvular Heart Disease, Diagnosis and Treatment Patterns ............ 41 
5.4.2 
Proportion of Women Included in Past Studies for Target Indication ......................................... 42 
5.4.3 
Safety and Effectiveness Outcomes by Sex .................................................................................... 42 
5.4.4 
Representation of Women in the COAPT Trial ............................................................................. 42 
5.4.5 
Subgroup Analysis for Sex ............................................................................................................ 43 
6 CLINICAL TRIAL PROCEDURE ................................................................................ 43 
6.1 
SITE SELECTION ...................................................................................................................................... 43 
6.2 
SITE PERSONNEL SELECTION .................................................................................................................. 44 
6.2.1 
Investigator Experience Requirements ......................................................................................... 44 
6.3 
SUBJECT SELECTION ............................................................................................................................... 46 
6.3.1 
Defining Heart Failure Patients with Functional Mitral Regurgitation ....................................... 46 
6.3.2 
Eligibility Criteria ........................................................................................................................ 47 
6.3.2.1 
Inclusion Criteria ..................................................................................................................................... 47 
6.3.2.2 
Exclusion Criteria .................................................................................................................................... 49 
6.3.3 
Justification for Inclusion and Exclusion Criteria ........................................................................ 51 
6.4 
SUBJECT SCREENING AND INFORMED CONSENT ..................................................................................... 53 
6.5 
PRE-RANDOMIZATION ............................................................................................................................ 54 
6.5.1 
Roll-in Subjects ............................................................................................................................. 54 
6.5.2 
Screening and Baseline Assessments ............................................................................................ 54 
6.6 
SUBJECT REGISTRATION ......................................................................................................................... 57 
6.7 
RANDOMIZATION .................................................................................................................................... 57 
6.8 
“TREATMENT” VISIT (DEVICE GROUP OR ROLL-IN SUBJECTS) ............................................................... 58 
6.8.1 
Anticoagulation and Antibiotic Therapy ....................................................................................... 58 
6.8.1.1 
Anticoagulation Therapy ......................................................................................................................... 58 
6.8.1.2 
Clopidogrel .............................................................................................................................................. 58 
6.8.1.3 
Antibiotic Therapy .................................................................................................................................. 59 
6.8.2 
MitraClip Procedure .................................................................................................................... 59 
6.8.2.1 
Pre-Procedural TEE ................................................................................................................................. 59 
6.8.2.2 
Pre-Procedural ECG and Physical Exam ................................................................................................. 59 
6.8.2.3 
Baseline Activated Clotting Time ........................................................................................................... 59 
6.8.3 
Personnel ...................................................................................................................................... 59 
6.8.4 
Subject Preparation ...................................................................................................................... 60 
6.8.5 
Anticoagulation Therapy .............................................................................................................. 60 
6.8.6 
MitraClip Device Placement Procedure ....................................................................................... 60 
6.9 
POST-MITRACLIP PROCEDURE (DEVICE GROUP OR ROLL-IN SUBJECTS) ................................................ 61 
6.9.1 
Subject Management Guidelines .................................................................................................. 61 
6.9.2 
Antibiotic Therapy ........................................................................................................................ 61 
6.9.3 
Antiplatelet/Anticoagulation Regimen .......................................................................................... 62 
6.9.4 
Management of Hypertension ....................................................................................................... 62 
6.9.5 
Vital Signs ..................................................................................................................................... 62 
6.9.6 
Implant Identification Card .......................................................................................................... 63 
6.9.7 
Procedural and Discharge Data................................................................................................... 63 
6.10 “TREATMENT” VISIT (CONTROL GROUP) ................................................................................................ 64 
6.11 CLINICAL FOLLOW-UP (ALL REGISTERED SUBJECTS) .............................................................................. 64 
6.11.1 
1-Week Phone Contact ................................................................................................................. 65 
6.11.2 
30-Day, 6-Month, 12-Month, 18-Month and 24-Month Visits ...................................................... 65 
6.11.3 
3, 4 and 5 Year Visits .................................................................................................................... 66 
6.12 HEART-RELATED OFFICE VISITS ............................................................................................................ 73 
6.13 MITRACLIP INTERVENTION IN CONTROL GROUP SUBJECTS OR ADDITIONAL MITRACLIP INTERVENTION 
IN DEVICE GROUP OR ROLL-IN SUBJECTS ......................................................................................................... 73 
6.13.1 
30-Day Post-MitraClip Follow-up ............................................................................................... 73 
6.14 MITRAL VALVE SURGERY ...................................................................................................................... 74 

 
 
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6.14.1 
30-Day Post-Mitral Valve Surgery Follow-up ............................................................................. 74 
6.15 EXPLANTED MITRACLIP DEVICE ............................................................................................................ 75 
6.16 SUBJECT DISCONTINUATION ................................................................................................................... 75 
6.16.1 
Lost-to-Follow-up ......................................................................................................................... 76 
6.17 EARLY TERMINATION OF THE CLINICAL TRIAL ....................................................................................... 76 
6.18 TRIAL COMPLETION ................................................................................................................................ 77 
6.19 TRIAL CLOSURE ...................................................................................................................................... 77 
7 STATISTICAL METHODS ............................................................................................ 77 
7.1 
ANALYSIS POPULATIONS ........................................................................................................................ 78 
7.1.1 
Intention to Treat (ITT) Population .............................................................................................. 78 
7.1.2 
Per Protocol Population ............................................................................................................... 78 
7.1.3 
As Treated Population .................................................................................................................. 78 
7.2 
PRIMARY ENDPOINTS .............................................................................................................................. 78 
7.2.1 
Primary Safety Endpoint............................................................................................................... 78 
7.2.2 
Primary Effectiveness Endpoint.................................................................................................... 79 
7.3 
SECONDARY SAFETY ENDPOINTS............................................................................................................ 80 
7.3.1 
Composite 30-Day Secondary Safety Endpoint ............................................................................ 80 
7.3.2 
All-Cause Mortality at 12 Months ................................................................................................ 81 
7.4 
SECONDARY EFFECTIVENESS ENDPOINTS ............................................................................................... 81 
7.4.1 
MR Severity at 12 Months ............................................................................................................. 81 
7.4.2 
Change in Six-Minute Walk Test Distance (6MWD) at 12 Months over Baseline ........................ 82 
7.4.3 
Change in Quality of Life (Kansas City Cardiomyopathy Questionnaire, KCCQ) at 12 Months 
over Baseline ............................................................................................................................................... 82 
7.4.4 
Change in LVEDV at 12 Months over Baseline ............................................................................ 83 
7.4.5 
NYHA Functional Class at 12 Months .......................................................................................... 83 
7.4.6 
Finkelstein-Schoenfeld Analysis of All-Cause Death and Recurrent HF Hospitalization ............ 84 
7.4.7 
Recurrent Hospitalization - All-Cause ......................................................................................... 84 
7.5 
ADJUSTMENT FOR MULTIPLE TESTING ................................................................................................... 85 
7.6 
ADDITIONAL ENDPOINTS ........................................................................................................................ 85 
7.6.1 
Device or Procedure-Related Adverse Events .............................................................................. 85 
7.6.2 
Device and Procedure-Related Endpoints .................................................................................... 86 
7.6.3 
Echocardiographic Endpoints ...................................................................................................... 86 
7.6.4 
Clinical Endpoints ........................................................................................................................ 87 
7.7 
POWER AND SAMPLE SIZE ....................................................................................................................... 89 
7.8 
TRIAL SUCCESS ....................................................................................................................................... 90 
8 ADVERSE EVENTS ........................................................................................................ 90 
8.1 
DEFINITION OF ADVERSE EVENT AND SERIOUS ADVERSE EVENT ........................................................... 90 
8.1.1 
Adverse Event (AE) ....................................................................................................................... 90 
8.1.2 
Serious Adverse Event .................................................................................................................. 91 
8.1.3 
Anticipated Adverse Events .......................................................................................................... 91 
8.1.4 
Unanticipated Adverse Device Effect ........................................................................................... 93 
8.2 
DEVICE DEFICIENCY/PRODUCT EXPERIENCE .......................................................................................... 93 
8.3 
DEVICE OR PROCEDURE-RELATIONSHIP ................................................................................................. 93 
8.4 
ADVERSE EVENT/DEVICE DEFICIENCY/PRODUCT EXPERIENCE REPORTING ........................................... 94 
8.4.1 
Adverse Event Monitoring ............................................................................................................ 94 
8.4.2 
Serious Adverse Event Reporting to Sponsor and IRB/EC ........................................................... 94 
8.4.3 
Unanticipated Adverse Device Effect (UADE) Reporting to Sponsor and IRB/EC ...................... 95 
8.4.4 
Unanticipated Serious Adverse Device Effect (USADE) Reporting to Sponsor and IRB/EC ....... 95 
8.4.5 
Device Deficiency/Product Experience Reporting ....................................................................... 95 
8.4.6 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .............................. 96 
8.5 
ANTICIPATED ADVERSE EVENT RATES ................................................................................................... 96 

 
 
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8.6 
ADJUDICATION OF EVENTS ..................................................................................................................... 96 
9 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................ 96 
10 QUALITY CONTROL AND QUALITY ASSURANCE ............................................. 96 
10.1 STEERING COMMITTEE............................................................................................................................ 97 
10.2 CENTRAL ELIGIBILITY COMMITTEE ........................................................................................................ 97 
10.3 CENTRAL ECHOCARDIOGRAPHY CORE LABORATORY (ECL).................................................................. 97 
10.4 CLINICAL EVENTS COMMITTEE............................................................................................................... 97 
10.5 DATA MONITORING COMMITTEE ............................................................................................................ 98 
10.6 PUBLICATION COMMITTEE ...................................................................................................................... 98 
10.7 TRAINING ................................................................................................................................................ 98 
10.7.1 
Site Training ................................................................................................................................. 98 
10.7.2 
Training of Sponsor’s Monitors .................................................................................................. 101 
10.7.3 
Training of Sponsor’s Designees or Vendors ............................................................................. 101 
10.8 MONITORING ........................................................................................................................................ 101 
10.8.1 
Designated Monitors .................................................................................................................. 101 
10.8.2 
Monitoring Visits ........................................................................................................................ 101 
10.8.2.1 
Pre-study Qualification Visit ............................................................................................................ 102 
10.8.2.2 
Initiation Visit .................................................................................................................................. 102 
10.8.2.3 
On-Site Interim Monitoring Visits ................................................................................................... 102 
10.8.2.4 
Final Monitoring Review ................................................................................................................. 103 
10.9 QUALITY ASSURANCE AUDIT ............................................................................................................... 103 
10.10 PROTOCOL DEVIATIONS ........................................................................................................................ 103 
10.10.1 Deviations with Expedited Reporting Requirements .................................................................. 103 
10.10.2 Non-Critical Deviations.............................................................................................................. 104 
10.11 DEVICE MALFUNCTION ......................................................................................................................... 104 
10.12 DEVICE MISUSE .................................................................................................................................... 104 
10.13 SPONSOR SUPPORT TO CLINICAL TRIAL/INVESTIGATION SITE FOR REGULATORY BODY INSPECTION .. 104 
10.14 MEASURES TAKEN TO AVOID AND MINIMIZE BIAS DURING STUDY CONDUCT .................................... 105 
10.14.1 Subject Recruitment and Randomization .................................................................................... 105 
10.14.2 Maintaining Similar Levels of Follow-up ................................................................................... 105 
10.14.3 Administration of Assessments ................................................................................................... 106 
10.14.4 Review of Echocardiography Images ......................................................................................... 106 
10.14.5 Safety and Effectiveness Monitoring ........................................................................................... 106 
10.14.6 Follow-Up Compliance .............................................................................................................. 106 
10.14.7 Analysis ....................................................................................................................................... 107 
10.15 SUBJECT CONFIDENTIALITY .................................................................................................................. 107 
11 DATA HANDLING AND RECORD KEEPING ........................................................ 108 
11.1 SOURCE DOCUMENTATION ................................................................................................................... 108 
11.2 ELECTRONIC CASE REPORT FORM COMPLETION .................................................................................. 109 
11.3 SITE RECORD RETENTION ..................................................................................................................... 109 
12 ETHICAL CONSIDERATION .................................................................................... 109 
12.1 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE REVIEW ............................................................ 109 
13 RISK ANALYSIS ........................................................................................................... 110 
13.1 POTENTIAL RISK ................................................................................................................................... 110 
13.2 RISK MANAGEMENT PROCEDURES ....................................................................................................... 114 
13.2.1 
Device Design ............................................................................................................................. 114 
13.2.2 
Investigator Selection and Training ........................................................................................... 115 
13.2.3 
Ensuring Strict Adherence to the Clinical Investigational Plan ................................................. 115 

 
 
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13.2.4 
Data Monitoring Committee (DMC) .......................................................................................... 115 
13.3 POTENTIAL BENEFIT ............................................................................................................................. 115 
APPENDIX A: DEFINITIONS ......................................................................................... 117 
APPENDIX B: ECHOCARDIOGRAPHY PROTOCOL ............................................... 132 
APPENDIX C: MONITORING EXPOSURE TO IONIZING RADIATION .............. 136 
APPENDIX D: COMPONENTS OF FRAILTY ............................................................. 138 
APPENDIX E: ATS 6 MINUTE WALK TEST GUIDELINES ..................................... 140 
APPENDIX F:  RATES OF FORESEEABLE ADVERSE EVENTS ........................... 147 
 

 
 
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Table of Figures 
Figure 1: 
Timeline for Clinical Trials with the MitraClip System ..................................... 21 
Figure 2 
12-Month Mortality in EVEREST High Risk Patients and Comparators .......... 29 
Figure 3: 
Trial Flowchart.................................................................................................... 68 
 
 

 
 
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Table of Tables 
Table 1: 
Follow-up Schedule* and Windows for Registered Subjects ............................. 69 
Table 2: 
Clinical Evaluation Schedule for Registered Subjects ........................................ 71 
Table 3: 
Anticipated Adverse Events (MitraClip Procedure) ........................................... 92 
 
 
 

 
 
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 Clinical Trial Summary 
Trial Name and Number 
Cardiovascular Outcomes Assessment of the MitraClip 
Percutaneous Therapy for Heart Failure Patients with 
Functional MR (The COAPT Trial) 
 
CIP No. 11-512 
Investigational Device 
MitraClip System 
Title 
Cardiovascular Outcomes Assessment of the MitraClip 
Percutaneous Therapy for Heart Failure Patients with 
Functional MR (The COAPT Trial)  
Objective 
To evaluate the safety and effectiveness of the MitraClip 
System for the treatment of moderate-to-severe or severe 
functional mitral regurgitation (FMR) in symptomatic heart 
failure subjects who are treated per standard of care and who 
have been determined by the site’s local heart team as not 
appropriate for mitral valve surgery.  This randomized 
controlled trial will provide the opportunity to strengthen or 
add labeling claims regarding safety and clinical benefits of 
the MitraClip System for symptomatic heart failure patients 
with moderate-to-severe or severe functional mitral 
regurgitation.   
Design 
Prospective, randomized, parallel-controlled, multicenter 
clinical evaluation of the MitraClip device for the treatment of 
clinically significant functional mitral regurgitation in 
symptomatic heart failure subjects who are treated per 
standard of care and who have been determined by the site’s 
local heart team as not appropriate for mitral valve surgery.  
Eligible subjects will be randomized in a 1:1 ratio to the 
MitraClip device (Device group) or to no MitraClip device 
(Control group).  Randomization will be stratified by study 
site and cardiomyopathy etiology (i.e. ischemic or non-
ischemic). 

 
 
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Key Inclusion Criteria 
• Symptomatic functional MR (≥3+) due to cardiomyopathy 
of either ischemic or non-ischemic etiology  
• Subject has been adequately treated per applicable 
standards, including for coronary artery disease, left 
ventricular dysfunction, mitral regurgitation and heart 
failure 
• Subject has had at least one hospitalization for heart 
failure in the 12 months prior to subject registration and/or 
a corrected BNP ≥300 pg/ml or corrected NT-proBNP 
≥1500 pg/ml  
• New York Heart Association (NYHA) Functional Class 
II, III or ambulatory IV 
• Surgery will not be offered as a treatment option and 
medical therapy is the intended therapy for the subject 
• Left Ventricular Ejection Fraction (LVEF) is ≥20% and 
≤50% 
• Left Ventricular End Systolic Dimension (LVESD) is ≤70 
mm 
Key Exclusion Criteria 
• Untreated clinically significant coronary artery disease 
requiring revascularization 
• Coronary artery bypass grafting (CABG) within prior 30 
days  
• Percutaneous coronary intervention within prior 30 days 
• Tricuspid valve disease requiring surgery 
• Aortic valve disease requiring surgery 
• Chronic Obstructive Pulmonary Disease (COPD) 
requiring continuous home oxygen therapy or chronic 
outpatient oral steroid use 
• Cerebrovascular accident within prior 30 days  
• Severe symptomatic carotid stenosis (> 70% by 
ultrasound) 
• Carotid surgery within prior 30 days  
• Mitral valve orifice area < 4.0 cm2 
• Leaflet anatomy which may preclude MitraClip 
implantation, proper MitraClip positioning on the leaflets 
or sufficient reduction in MR by the MitraClip 

 
 
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Primary Endpoints 
Safety:  Composite of Single Leaflet Device Attachment 
(SLDA), device embolizations, endocarditis requiring surgery, 
Echocardiography Core Laboratory confirmed mitral stenosis 
requiring surgery, LVAD implant, heart transplant, and any 
device related complications requiring non-elective 
cardiovascular surgery at 12 months 
 
Effectiveness:  Recurrent heart failure (HF) hospitalizations 
through 24 months (analyzed when the last subject completes 
12 months of follow-up) 
Secondary Endpoints 
Secondary Safety: 
• Composite of death (all-cause), stroke, myocardial 
infarction (MI), or non-elective cardiovascular surgery for 
device related complications at 30 days post-procedure in 
the Device group   
• All-cause mortality at 12 months 
 
Secondary Effectiveness: 
• Mitral Regurgitation (MR) severity at 12 months  
• Change in distance walked on the 6 Minute Walk Test 
(6MWT distance or 6MWD) at 12 months over baseline  
• Change in quality of life (QoL) at 12 months over 
baseline, as measured by the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) 
• Change in Left Ventricular End Diastolic Volume 
(LVEDV) at 12 months from baseline  
• New York Heart Association (NYHA) Functional Class 
I/II at 12 months 
• Hierarchical composite of death and recurrent HF 
hospitalization (analyzed when the last subject completes 
12 months of follow-up) 
• Recurrent hospitalizations - all-cause (analyzed when the 
last subject completes 12 months of follow-up)  

 
 
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Additional Endpoints 
Device or Procedure-Related Adverse Events:  Adverse 
events that are adjudicated by the Clinical Events Committee 
as probably, possibly or definitely device and/or procedure 
related, regardless of temporal relationship to the MitraClip 
procedure. Examples of device-related adverse events are:  
• Myocardial perforation 
• Single Leaflet Device Attachment  
• Embolization of the MitraClip device or MitraClip System 
components 
• Iatrogenic atrial septal defect 
• Mitral valve stenosis 
• Need for mitral valve replacement instead of repair due at 
least in part to the MitraClip procedure or the presence of 
the MitraClip device 
 
Device and Procedure-Related Endpoints: The following 
device and procedure-related acute endpoints will be reported 
for the Device group:  
• Implant Rate: defined as the rate of successful delivery 
and deployment of the MitraClip device(s) with 
echocardiographic evidence of leaflet approximation and 
retrieval of the delivery catheter 
• Device Procedure Time: defined as the time elapsed from 
the start of the transseptal procedure to the time the 
Steerable Guide Catheter is removed 
• Total Procedure Time: defined as the time elapsed from 
the first of any of the following: intravascular catheter 
placement, anesthesia or sedation, or transesophageal 
echocardiogram (TEE), to the removal of the last catheter 
and TEE 
• Device Time: defined as the time the Steerable Guide 
Catheter is placed in the intra-atrial septum until the time 
the MitraClip Delivery System (CDS) is retracted into the 
Steerable Guide Catheter 
• Fluoroscopy duration: defined as the duration of exposure 
to fluoroscopy during the MitraClip procedure   

 
 
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Additional Endpoints 
(Continued) 
Echocardiographic Endpoints:  The following 
echocardiographic endpoints will be reported for the Device 
and Control groups at baseline, discharge (or 30 days if 
discharge echocardiogram is not available), 6 months, 12 
months, 24 months and then yearly through 5 years. For 
continuous variables, change from baseline to each follow-up 
will also be reported:  
• MR Severity Grade 
• Effective Regurgitant Orifice Area 
• Regurgitant Volume 
• Regurgitant Fraction 
• Left Ventricle End Diastolic Volume (LVEDV) 
• Left Ventricular End Systolic Volume (LVESV) 
• Left Ventricular End Diastolic Dimension (LVEDD) 
• Left Ventricular End Systolic Dimension (LVESD) 
• Left Ventricular Ejection Fraction (LVEF) 
• Right Ventricular Systolic Pressure (RVSP) 
• Mitral Valve Area  
• Mean Mitral Valve Gradient 
• Systolic Anterior Motion of the mitral valve (present or 
absent) 
• Cardiac Output  
• Forward Stroke Volume 

 
 
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Additional Endpoints 
(Continued) 
Clinical Endpoints:  The following clinical endpoints will be 
reported for the Device and Control groups: 
• Kaplan-Meier freedom from the components of the 
primary safety composite at 12 months, 24 months and 
yearly through 5 years (Device group only) 
• Kaplan-Meier freedom from the primary safety composite 
at 24 months and yearly through 5 years (Device group 
only) 
• Kaplan-Meier freedom from all-cause mortality at 12 
months, 24 months and yearly through 5 years 
• Kaplan-Meier freedom from: (1) cardiovascular mortality 
(2) the first HF related hospitalization (3) the first 
cardiovascular hospitalization (4) the first HF related 
hospitalization or all-cause mortality at 12 months and 24 
months and then yearly through 5 years  
• NYHA Functional Class at baseline, 30 days, 6 months, 
12 months, 24 months and then yearly through 5 years  
• 6MWD at baseline, 30 days, 6 months, 12 months and 24 
months (and change from baseline to follow-up)  
• KCCQ QoL scores at baseline, 30 days, 6 months, 12 
months and 24 months (and change from baseline to 
follow-up) 
• SF-36 QoL scores at baseline, 30 days, 6 months, 12 
months and 24 months (and change from baseline to 
follow-up) 
• Mitral valve surgery (including type of surgery), new use 
of CRT, new use of single or dual chamber pacemaker, 
permanent LVAD implant, heart transplant, additional 
MitraClip device intervention in Device group or de novo 
MitraClip device intervention in Control group, including 
reason for intervention through 5 years 
• Responder analysis for 6MWD, where responder is 
defined as alive and experiencing an improvement of 24 
meters and 50 meters (difference in proportion of 
responders between Device and Control groups) at 12 
months and 24 months  
• Responder analysis for LVEDV Index, where responder is 
defined as alive and experiencing an improvement of 12 
ml/m2 (difference in proportion of responders between 
Device and Control groups) at 12 months, 24 months and 
then yearly through 5 years 
• Responder analysis for QoL (KCCQ), where responder is 
defined as alive and experiencing an improvement of 5 
points (difference in proportion of responders between 
Device and Control groups) at 12 months and 24 months 

 
 
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Additional Endpoints 
(continued) 
• Each subscale for QoL (KCCQ) (difference in means 
between Device and Control groups) at 12 months and 24 
months  
• Length of index hospitalization for MitraClip procedure 
(Device group) 
• Number of hospitalizations and reason for hospitalization 
(i.e., heart failure, cardiovascular, non-cardiovascular) at 
12 months and 24 months in each of the Device and 
Control groups  
• Number of days alive and out of hospital from the time of 
randomization (difference in medians between Device and 
Control groups) to 12 months, 24 months and then yearly 
through 5 years 
• Number of days hospitalized from the “Treatment” visit 
(difference in medians between Device and Control 
groups) at 12 months, 24 months and then yearly through 
5 years 
• Proportion of alive time in hospital will be summarized 
and compared between Device and Control groups at 12 
months, 24 months and then yearly through 5 years 
• Proportion of subjects living in the baseline location at 12 
months, 24 months and then yearly through 5 years   
• Mitral valve replacement rates will be summarized and 
compared between Device and Control groups at 12 
months, 24 months and then yearly through 5 years 
• New onset of permanent atrial fibrillation at 12 months, 24 
months and then yearly through 5 years 
• Mitral stenosis at 12 months, 24 months and then yearly 
through 5 years 
• Clinically significant atrial septal defect (ASD) that 
requires intervention at 12 months, 24 months and then 
yearly through 5 years 
• Device-related complications in Device group subjects 
and Control group subjects who undergo the MitraClip 
procedure through 5 years  
• BNP (Brain Natriuretic Peptide) or NT-proBNP (N-
terminal prohormone of Brain Natriuretic Peptide) levels 
at baseline, 30 days and 12 months 
• Modified Rankin Scale Score at baseline, 30 days, 6 
months, 12 months 
• Major bleeding at 30 days 
• Prolonged ventilation at 30 days 

 
 
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Additional Endpoints 
(continued) 
• Average dosages of Guideline Directed Medical Therapy 
(GDMT) at baseline, 30 days, 6 months, 12 months, 24 
months, and then yearly through 5 years 
• The number and reasons for (1) any changes in GDMT 
and GDMT dosage from baseline at 30 days, 6 months, 12 
months, 24 months, and then yearly through 5 years and  
(2) any changes in GDMT from baseline that result in a 
greater than 100% increase or greater than 50% decrease 
in dose at 30 days, 6 months, 12 months, 24 months, and 
then yearly through 5 years 
• Peak VO2 from cardiopulmonary exercise testing (CPX) 
in the subset of patients participating in the CPX sub-
study at baseline and 12 months 
Sample Size / Targeted 
Number of Subjects to 
Receive Study Device 
Approximately 610 subjects will be randomized with 
approximately 305 subjects targeted to receive the study 
device. 
 
Up to an additional 150 roll-in subjects, up to 3 per site, may 
be treated by operators without prior or recent experience 
using the MitraClip device to gain hands-on experience before 
randomizing subjects in the trial. 
Subject Follow-up 
All subjects will be scheduled for a “Treatment” visit.  At the 
“Treatment” visit, Device group subjects will undergo the 
MitraClip procedure and Control group subjects will be seen 
by a Heart Failure specialist for a physical exam, including 
vital signs, cardiac health status and evaluation of heart failure 
medications. 
 
Subjects will have required follow-up evaluations at these 
time points post-“Treatment” visit: 1-week (phone contact), 
30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter through 5 years 
Primary Analytical 
Population 
The primary safety analysis set will consist of all Device 
group subjects in whom the MitraClip procedure is attempted. 
The primary effectiveness analysis set will consist of the 
Intention-to-Treat (ITT) randomized population.  This 
analysis set is defined as all subjects who are registered.  
Subjects will be considered registered when informed consent 
has been obtained and they have been randomized to either 
the Device group or the Control group. 

 
 
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Safety Monitoring 
The Data Monitoring Committee (DMC) will monitor the 
safety of subjects from subject registration to the required 
follow-up on an on-going basis.  The composition, guiding 
policies, and operating procedures governing the DMC are 
described in a separate DMC charter. 

 
 
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1 Introduction 
The purpose of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous 
Therapy for Heart Failure Patients with Functional MR (COAPT) Trial is to evaluate the 
safety and effectiveness of the MitraClip System for the treatment of moderate-to-severe or 
severe functional mitral regurgitation (FMR) in symptomatic subjects who are treated per 
standard of care and who have been determined by the site’s local heart team as not 
appropriate for mitral valve surgery.  Eligible subjects will be randomized in a 1:1 ratio to the 
MitraClip device (Device group) or to no MitraClip device (Control group).  
As the Sponsor of this clinical trial, Abbott Vascular has the overall responsibility for the 
conduct of the trial, including assurance that the trial will be performed according to this 
Clinical Investigational Plan and US Food and Drug Administration (FDA) and Health 
Canada regulations.  Abbott Vascular will have direct and indirect responsibilities for day-to-
day trial management and may delegate responsibilities for some trial management activities 
to a Contract Research Organization (CRO).   
This Clinical Investigational Plan describes the requirements for the COAPT Trial. 
2 Background Information 
The MitraClip System was developed as a percutaneous technology to provide an option for 
treatment of patients with significant mitral regurgitation (MR).  The MitraClip System has 
been in clinical use since July 2003.  The MitraClip System received CE approval in 2008 
and is approved and commercially available in over 40 countries.  As of August 30, 2013, 
more than 10,000 patients have undergone the MitraClip procedure worldwide. 
2.1 
MitraClip Clinical Program  
Over the last 10 years, the Sponsor has collaborated with FDA to develop robust clinical 
trials to establish the safety and effectiveness of the MitraClip device.  More than 2,000 
patients have been enrolled in clinical trials as of August 30, 2013, of whom 1,200 have 
undergone the MitraClip procedure in the US Clinical Trial Program (Figure 1). 

 
 
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Figure 1: Timeline for Clinical Trials with the MitraClip System 
Early in the Clinical Trial Program, a randomized comparison of the MitraClip System to the 
standard of care for the reduction of MR was considered necessary to demonstrate the safety 
and effectiveness of the MitraClip device.  Per the ACC/AHA Guidelines for the 
Management of Patients with Valvular Heart Disease1 (“ACC/AHA Guidelines”), the 
recommended treatment for moderate-to-severe (3+) or severe (4+) MR is mitral valve 
surgery for many patients.  The EVEREST II randomized controlled trial (RCT) therefore 
compared the MitraClip System to mitral valve repair or replacement surgery in patients who 
were indicated for and could undergo mitral valve surgery. 
Due to the innovative nature of the device and procedure, the safety of the MitraClip 
procedure and the effect of the MitraClip device on clinical outcomes were unclear or 
unknown at the time the RCT was designed.  Examples of these unknowns included the 
ability of the device to successfully capture and coapt the leaflets; safety of the procedure and 
the device; adequacy and durability of MR reduction; impact of MitraClip implant on 
subsequent mitral valve surgery; and durability and clinical benefit experienced by patients 
with residual MR of 2+ or less.  After careful consideration of these challenges, the 
EVEREST II RCT was designed and conducted to collect data to evaluate procedural 
success, safety of the procedure in comparison to mitral valve surgery, durability of MR 
reduction through 12 months and 24 months in comparison with mitral valve surgery, clinical 
benefit of the MitraClip implant in comparison with mitral valve surgery, and type of surgery 
post-MitraClip procedure. 
                                                 
1 Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused Update Incorporated Into the ACC/AHA 2006 
Guidelines for the Management of Patients With Valvular Heart Disease. A Report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 
1998 Guidelines for the Management of Patients With Valvular Heart Disease), JACC. 2008;52:e1-142. 
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
EVEREST I Feasibility (N=55)
EVEREST II Roll-in (N=60) + RCT (N=279)
EVEREST II High Risk Study (N=78)
REALISM (N=720)
(594 HR, 272 NHR)
ACCESS-EU I (N=567) & II (N=286)

 
 
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The Clinical Trial Program was expanded when the EVEREST II Investigational Device 
Exemption was amended to add the High Risk single-arm self-controlled study 
contemporaneous with the initiation of a dual-arm pivotal trial for another percutaneous 
valve device (TAVR).  The High Risk study was designed to evaluate the performance of the 
MitraClip System in patients who were too high risk for mitral valve surgery as determined 
by a cardiothoracic surgeon.  EVEREST II High Risk (HR) patients were screened 
concurrent with enrollment in the RCT and patients were treated in the arm in which they 
were eligible (RCT or HR).  After the RCT and HR trials were fully enrolled, a continued 
access study of the MitraClip System (REALISM) was approved and the study began 
enrolling patients in 2009.  The REALISM Study consists of two arms, one arm for RCT 
eligible (non-high surgical risk) patients and one arm for HR eligible (high surgical risk) 
patients.  The REALISM Study stopped enrolling in the non-high surgical risk arm in late 
2011. 
In 2008, after the MitraClip device received CE mark, the ACCESS EU post-approval study 
was initiated to study the use of the MitraClip System in patients treated in the commercial 
setting (“commercial use patients”) in Europe.  In September 2011, the ACCESS-EU II 
Study was initiated to continue to study patients treated in commercial use in the EU with 
Echocardiography Core Laboratory adjudication of baseline and follow-up echocardiograms.  
As of August 30, 2013, more than 9,000 patients have been treated under the CE mark with 
acute procedural results available for all patients. 
2.2 
Results 
The results presented in this section are a brief summary of results previously reported in 
PMA P100009 and its amendments.  The clinical data and reports supporting these results are 
on file at Abbott Vascular and available upon request.  These results have been updated 
through August 30, 2013 and will be updated as required in subsequent Clinical 
Investigational Plan amendments.  
2.2.1 EVEREST I Trial 
The EVEREST I trial (N=55) demonstrated evidence of the feasibility of the percutaneous 
approach utilizing the MitraClip System.  The trial met its primary endpoint, demonstrating 
that the MitraClip System was safe and mechanistically feasible, which allowed for the 
design and initiation of the EVEREST II pivotal trial.  The last patient has completed 5-year 
follow-up and the study is now closed. 
2.2.2 EVEREST II RCT 
The EVEREST II RCT (N = 60 Device roll-in, N = 184 Device randomized and N = 95 
Control randomized) was conducted in patients who were indicated for and could undergo 
mitral valve surgery.  The trial enrolled both degenerative (DMR) and functional (FMR) MR 

 
 
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etiologies (73% DMR, 27% FMR).  The trial was intended to demonstrate superiority of 
safety of MitraClip balanced against reduced effectiveness when compared to mitral valve 
repair or replacement surgery (mitral valve replacement in the Control arm was not 
considered a failure).  Both primary safety and effectiveness endpoints were met.  Significant 
and meaningful clinical benefits were observed as follows: 
• Superiority of safety compared to mitral valve surgery 
• Reduction of MR to 2+ or less was achieved in a majority of patients in both arms, 
and was durable through 2 years  
• Degree of MR reduction was lower in the MitraClip arm than surgery arm 
• Reduction in left ventricular (LV) size was demonstrated in both MitraClip and 
surgery groups, despite a smaller degree of acute MR reduction with the MitraClip as 
compared with mitral valve surgery 
• Similar improvements in NYHA Functional Class compared to mitral valve surgery   
• Similar improvements in SF-36 Quality of Life compared to mitral valve surgery 
• Shorter ICU time, hospital length of stay and requirement for nursing or rehabilitation 
care post hospitalization compared to mitral valve surgery 
Additionally, the clinical benefits observed in patients with functional MR etiology were 
consistent with those observed in patients with degenerative MR etiology. 
The results of the EVEREST II RCT through 2 years have recently been published in The 
New England Journal of Medicine.2  On an intention to treat basis, the MitraClip approach 
has an early safety advantage, and 78% of patients in the device arm were free from surgery 
at two years with similar clinical benefit compared to surgery.  There was no incidence of 
mitral stenosis, device embolization or device migration in the EVEREST II RCT.  Sustained 
reduction in mitral regurgitation was observed, although not quite to the extent of surgery as 
measured by a core laboratory with established echocardiographic techniques.  Continued 
reduction in left ventricular (LV) volumes and dimensions were observed in both MitraClip 
and surgery groups, although diastolic volumes were reduced to a greater degree post-
surgery.  Symptomatic benefit, as evidenced by improvements in NYHA Functional Class 
and Quality of Life measures for patients in the MitraClip device arm, was at least as good as 
surgery.  The authors concluded that although percutaneous repair was less effective at 
reducing MR than conventional surgery, the procedure was associated with superior safety 
and similar improvements in clinical outcomes.  The authors also concluded the data 
                                                 
2 Feldman T, Foster E, Glower DG, Kar S, Rinaldi MJ, Fail PS, Smalling, RW, Siegel R, Rose GA, Engeron E, 
Loghin C, Trento A, Skipper ER, Fudge T, Letsou GV, Massaro JM, and Mauri L, for the EVEREST II 
Investigators. Percutaneous Repair or Surgery for Mitral Regurgitation, New Engl J Med. 2011;364:1395-1406. 

 
 
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demonstrate a place for the MitraClip device as a therapeutic option for selected patients with 
mitral regurgitation. 
2.2.3 EVEREST II High Risk Registry (HRR) Study 
Patients enrolled in the EVEREST II HRR Study were considered high surgical risk if the 
cardiothoracic surgeon at the investigational site assessed a predicted surgical mortality for 
mitral valve surgery of ≥ 12% based on either: 
I) 
STS (Society of Thoracic Surgeons) mortality risk ≥ 12%, or  
II) 
The presence of at least one of the following: 
1) Porcelain aorta or mobile ascending aortic atheroma 
2) Post-radiation mediastinum  
3) Previous mediastinitis 
4) Functional MR with EF < 40% 
5) Over 75 years old with EF < 40% 
6) Prior re-operation with patent grafts 
7) Two or more prior chest surgeries 
8) Hepatic cirrhosis 
9) Three or more of the following STS high risk factors: 
i. Creatinine > 2.5 mg/dL 
ii. Prior chest surgery 
iii. Age over 75 
iv. EF < 35% 
The trial enrolled both degenerative and functional MR etiologies (41% DMR, 59% FMR). 
The primary safety endpoint of the EVEREST II HRR Study was procedural mortality at 30 
days or prior to discharge, whichever was longer.  The observed procedural mortality was 
statistically significantly lower than the predicted surgical mortality, thus the trial met the 
primary endpoint of lower procedural mortality than predicted for surgery. 
For this high surgical risk population with limited options, safe reduction of MR is clinically 
meaningful, as observed in the following endpoints:  

 
 
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• Reduction of MR to 2+ or less can be achieved in a majority of patients and is durable 
through 2 years  
• Improvements in NYHA Functional Class and SF-36 Quality of Life  
• Reduction in left ventricular size  
• Significant decrease in the rate of hospitalization for heart failure after treatment with 
the device  
• Reduced mortality for high surgical risk patients compared to predicted mortality 
from the STS database and publications 
• Shorter ICU time, hospital length of stay and requirement for nursing or rehabilitation 
care post hospitalization compared to mitral valve surgery in non-high risk surgical 
patients 
• Mortality at 12 months was within the range expected based on medical therapy and 
surgical literature 
2.2.4 EVEREST II REALISM Continued Access Study 
There are two groups (High Risk and Non-High Risk) in the REALISM Continued Access 
Study.  The REALISM study began enrollment in 2009. As of August 30, 2013, 272 and 594 
patients have been respectively enrolled in the Non-High Risk and High Risk arms of 
REALISM.  Enrollment of the Non-High Risk arm of the REALISM study is complete with 
a total enrollment of 272 patients and follow-up through 5 years is ongoing. The High Risk 
arm of the REALISM study is currently enrolling. An additional 66 patients have been 
treated as Compassionate Use or Emergency Use cases to date.  The results reported in the 
Non-High Risk and High Risk arms of the ongoing REALISM Study are consistent with the 
results reported for the RCT and HRR Study, respectively.   
2.2.5 ACCESS-EU Study  
The purpose of the ACCESS-EU Study was to gain information regarding the use of the 
MitraClip System in Europe with respect to health economics and clinical care, and to 
provide further evidence of the safety and effectiveness of the MitraClip System in a post-
market setting.  The results observed in this study are consistent with those observed in the 

 
 
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US clinical trials.  The following results were observed in a 12-month publication on a cohort 
of 567 ACCESS-EU Phase-13 patients: 
• A majority (78.9%) of patients were free from MR > 2+ at 12 months compared to 
3.1% at baseline 
• A majority (71.4%) of patients had NYHA Class I/II at 12 months compared to 
17.8% at baseline 
• Clinically and statistically significant improvement (59.5 meters) in 6 Minute Walk 
Distance (6MWD) at 12 months compared to baseline 
• Clinically and statistically significant improvement in quality of life (13.5 points ) as 
measured by the Minnesota Living with Heart Failure (MLWHF) questionnaire at 12 
months as compared to baseline 
The ACCESS-EU Phase II Study started enrolling in September 2011, and includes an 
Echocardiography Core Laboratory assessment of study echocardiograms. A total of 286 
patients were enrolled in this study. The ACCESS-EU Phase II Study has been recently 
closed by the Sponsor. No data have yet been reported. 
2.2.6  Results in High Surgical Risk Patients 
In December 2011, data from the EVEREST II HR Study (N = 78 patients with 2 years of 
follow-up) and the EVEREST II REALISM Continued Access High Risk arm (133 patients 
with 1 year of follow-up) were pooled as described in the REALISM protocol and reported to 
FDA in support of a high surgical risk indication (hereafter referred to as EVEREST High 
Risk Cohort, N = 211).  These patients had a large range of co-morbidities that elevated their 
risk of surgical mortality.  Approximately 2/3 of patients in this cohort had functional MR 
etiology. 
Procedural results in high surgical risk patients who underwent the MitraClip procedure are 
very favorable even when compared to results in non-high risk patients who underwent 
mitral valve surgery.  Procedural mortality was significantly lower than the predicted surgical 
mortality.  EVEREST High Risk Cohort patients undergoing the MitraClip procedure had 
shorter anesthesia durations, post-procedure ICU/CCU/PACU duration and post-procedure 
hospital stay, and were discharged home without home healthcare more often than the non-
high risk Control patients who underwent mitral valve surgery in the EVEREST II RCT.   
                                                 
3 Maisano F, Franzen O, Baldus S, Schäfer U, Hausleiter J, Butter C, Ussia GP, Sievert H, Richardt G, Widder 
JD, Moccetti T, Schillinger W, Percutaneous Mitral Valve Interventions in the Real World: Early and One Year 
Results From the ACCESS-EU, a Prospective, Multicenter, Non-Randomized Post-Approval Study of the 
MitraClip® Therapy in Europe, J Am Coll Cardiol. 2013;62:1052-61. 
 

 
 
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To provide perspective on the procedural mortality results on this cohort of patients, AV 
compared data collected from the high surgical risk patients to the following: 
• medical therapy and surgical literature for patients with MR  
• retrospectively gathered Concurrent Control4 consisting of patients who were 
screened for the EVEREST II HR Study, but did not enroll 
• a single center analysis of mortality for high risk patients with a diagnosis of any 
grade of MR (mild to severe) who underwent non-surgical management (Ohio State 
University (OSU) Cardiac Database) 
• a single center analysis of mortality for a propensity matched cohort of high risk 
patients with a diagnosis of moderate-to-severe or severe MR (Duke University 
Medical Center) who underwent non-surgical management  
Procedural (30 day) mortality in EVEREST High Risk Cohort patients was: 
• lower than in-hospital mortality reported in the literature in elderly patients 
undergoing mitral valve surgery 
• statistically significantly lower than the predicted surgical mortality, and comparable 
with that observed in high surgical risk patients in the Concurrent Control (no 
MitraClip) 
• consistent with 30-day mortality observed in high surgical risk patients post-diagnosis 
of any MR who underwent non-surgical management from the Ohio State University 
Cardiac database  
• comparable to 30-day mortality observed in high surgical risk patients post-diagnosis 
of moderate-to-severe or severe MR who underwent non-surgical management from 
the Duke University Medical Center 
A low rate of major adverse events (MAE)5 was also noted at 30 days.  The MAE rate in the 
EVEREST High Risk Cohort was much lower than that in the non-high risk Control patients 
who underwent mitral valve surgery in the EVEREST II RCT.  These results support the 
                                                 
4 The Concurrent Control consists of patients who were screened for the EVEREST II HR Study and met the 
high surgical risk and MR severity criteria, but did not enroll.  Abbott Vascular retrospectively gathered data on 
this Concurrent Control (N = 36) to assess 30 day and 12 month mortality.  A majority of these patients (31 of 
36) remained on medical therapy through 12 months. 
5 MAE is defined as a combined clinical endpoint of death (all cause), myocardial infarction, re-operation for 
failed surgical repair or replacement, non-elective cardiovascular surgery for adverse events, stroke, renal 
failure, deep wound infection, ventilation for greater than 48 hours, GI complication requiring surgery, new 
onset of permanent atrial fibrillation, septicemia, and transfusion of 2 or more units of blood. 

 
 
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MitraClip as a safe procedure in these high surgical risk patients with extensive baseline co-
morbidities. 
High surgical risk patients with untreated clinically significant MR are highly symptomatic, 
have a high rate of heart failure hospitalizations, poor quality of life and impaired functional 
capacity.  EVEREST High Risk Cohort patients treated with the MitraClip experienced 
immediate (post-procedure) clinically and statistically significant improvements in quality of 
life, heart failure symptoms, functional capacity and left ventricular volumes and dimensions, 
which were sustained through 12 months.  These patients also experienced substantially 
lower rate of heart failure hospitalizations in the 12 months post-MitraClip procedure than in 
the preceding 12 months. 
The consistent improvement across the multiple measures observed post-treatment with the 
MitraClip device are expected benefits of mechanical reduction of MR.  Similar clinical 
benefits have been observed in non-high risk patients treated surgically for MR.  
Although there is expectation for only a modest reduction in long-term mortality from the 
MitraClip, any clinical benefit with the MitraClip device must be balanced with the long-
term safety of the device, i.e., no elevated risk for long-term mortality.  It is therefore 
important to assess 12-month mortality in symptomatic patients treated with the MitraClip 
that are extremely high risk for mitral valve surgery.  Since no parallel control was included 
in the EVEREST II high risk studies, long-term mortality outcomes in the EVEREST High 
Risk Cohort were assessed against the same comparators as those described for 30-day 
mortality. 
The 12-month mortality rate in the EVEREST High Risk patients (N = 211) was 24%.  
Figure 2 places the 12-month mortality rate in EVEREST High Risk patients in context with 
the comparators assessed.  
This figure shows a high rate of mortality at 12 months with either mitral valve surgery or 
medical therapy, as expected in an elderly population with multiple co-morbidities in 
addition to MR.  The 12-month mortality post-MitraClip implant in the EVEREST High Risk 
Cohort is not excessive in comparison with that reported in the literature, the Concurrent 
Control, and the Ohio State University Cardiac database, and is accompanied by substantial 
clinical benefits.  In a propensity matched cohort of 127 of 211 EVEREST High Risk 
patients, mortality was reduced by 30% in comparison with high surgical risk patients with 
moderate-to-severe or severe MR in the Duke University database who underwent non-
surgical management. 

 
 
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Figure 2 12-Month Mortality in EVEREST High Risk Patients and Comparators 
 
(Reproduced from Integrated High Surgical Risk Report submitted in PMA 
P100009/A016) 
2.3 
Rationale to Conduct the COAPT Trial 
Multiple clinical trials in a large number of patients provide scientific data on the safety and 
effectiveness of the MitraClip System.  The results of these trials provide evidence for 
significant clinical benefit with relatively low risk of excessive peri-procedural or long-term 
mortality.  A large volume of data has been collected on the MitraClip device (1,270 patients 
treated in US clinical trials, of which 705 were high surgical risk).   
In July 2013, Abbott Vascular submitted an amendment (P100009/A022) reporting safety 
and effectiveness results in 127 patients from the EVEREST II HRR and REALISM High 
Risk studies who had degenerative mitral regurgitation and were at prohibitive risk for mitral 
valve surgery.  These data were the basis of FDA approval of the MitraClip System on 
October 24, 2013.  In the United States, the MitraClip System is indicated for the 
percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥ 3+) due to 
primary abnormality of the mitral apparatus [degenerative MR] in patients who have been 
determined to be at prohibitive risk for mitral valve surgery by a heart team, which includes a 
cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral 
0%
10
20
30
40
50
12-Month Mortality
Severe MR
Moderate MR
COMPANION
OSU Historical
Cohort
Chikwe
Acorn Trial
Bolling
Series
Cioffi
et al
Koelling
et al
Mirabel
et al
Patel et al
Trichon
et al
Bursi et al
Grigioni
et al
Duke Historical
Cohort*
Concurrent
Control
EVEREST
High Risk
MR Status Unknown
MR Present –
Severity Unknown
Moderate to Severe MR
Moderate to
Severe of
Severe MR
Core Lab
Confirmed
●
MV Surgery
♦
Medical Mgmt.
■
MitraClip
♦
Concurrent Control
Age ≥80
Adv. CHF
EROA ≥0.2
All Patients
MitraClip
Age ≥80

 
 
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valve disease, and in whom existing comorbidities would not preclude the expected benefit 
from reduction of the mitral regurgitation. 
An additional trial with a parallel control in heart failure patients with moderate-to-severe or 
severe symptomatic functional MR is in order.   
Non-surgical treatment of symptomatic HF patients with functional MR is consistent with the 
most recent 2013 ACCF/AHA Heart Failure guidelines, in which mitral valve surgery is 
considered a class IIb recommendation6. Therefore, the Sponsor (Abbott Vascular) proposes 
to initiate a randomized controlled trial of moderate sample size in symptomatic heart failure 
subjects who are treated per standard of care and who have been determined by the site’s 
local heart team as not appropriate for mitral valve surgery.  This randomized controlled trial 
will provide opportunity to strengthen or add labeling claims regarding safety and clinical 
benefits in symptomatic heart failure subjects who are treated per standard of care and who 
have been determined by the site’s local heart team as not appropriate for mitral valve 
surgery.  Eligible subjects will be randomized in a 1:1 ratio to the MitraClip device (Device 
group) or to no MitraClip device (Control group).   
2.3.1 Intended Indication  
The MitraClip System is intended to treat heart failure patients with symptomatic ischemic or 
non-ischemic functional MR (≥3+) despite optimal standard of care therapy, who have been 
determined by the local heart team as not appropriate for mitral valve surgery. 
2.4 
Summary of Investigational Device and Control Therapy 
2.4.1 Name of the Investigational Device 
The investigational device to be used in this trial is the MitraClip System. In this Clinical 
Investigational Plan, the investigational device is referred to as the “MitraClip System” or the 
“MitraClip device”.  
2.4.2 Description of the Investigational Device (MitraClip System) 
The MitraClip System consists of two parts: 1) the Clip Delivery System and 2) the Steerable 
Guide Catheter.   
 
The Clip Delivery System consists of three major components: 1) the Delivery Catheter 2) 
the Steerable Sleeve and 3) the MitraClip Device.  The Clip Delivery System is introduced 
                                                 
62013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of 
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Yancy CW, Jessup M, 
Bozkurt B et al.; ACCF/AHA Task Force Members. J Am Coll Cardiol. 2013 62:e147-239. 

 
 
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into the body through a Steerable Guide Catheter and is used to advance and manipulate the 
implantable MitraClip Device for proper positioning and placement on the mitral valve 
leaflets. The Clip Delivery System is designed to deploy the implant in a way that requires 
multiple steps to ensure safe delivery of the device.   
 
The MitraClip Device is a percutaneously implanted mechanical Clip.  The MitraClip Device 
grasps and coapts the mitral valve leaflets resulting in fixed approximation of the mitral 
leaflets throughout the cardiac cycle.  The MitraClip Device is placed without the need for 
arresting the heart or cardiopulmonary bypass.  The implantable MitraClip Device is 
manufactured with metal alloys and polyester fabric (Clip cover) that are commonly used in 
cardiovascular implants.  The MitraClip Device arms can be adjusted to any position from 
fully opened, fully inverted and fully closed.  These positions are designed to allow the 
MitraClip Device to grasp and approximate the leaflets of the mitral valve using controls on 
the Delivery Catheter Handle.  The MitraClip Device can be locked, unlocked and repeatedly 
opened and closed.  The Grippers can be raised or lowered repeatedly.  
 
The 510(k) cleared Steerable Guide Catheter (K112239), which includes a Dilator, is used to 
introduce the Clip Delivery System into the left side of the heart through the interatrial 
septum.  The Steerable Guide Catheter is also used to position and orient the Clip Delivery 
System to the appropriate location above the mitral valve.  The Dilator is used for the 
introduction of the Steerable Guide Catheter into the femoral vein and left atrium.   
 
Several Class I accessories are used in conjunction with the MitraClip System including: 1) a 
Stabilizer, 2) a Lift 3) a Support Plate, 4) a Silicone Pad and 5) Fasteners to support and 
position the System during the procedure. 
The MitraClip System is manufactured by Abbott Vascular Inc. 
In addition to undergoing the MitraClip procedure, subjects randomized to the Device group 
will continue to be treated per standard of care consistent with the subject’s condition during 
follow-up. 
2.4.3 Description of the Control Group Therapy  
All subjects must have been adequately treated per applicable standards, such as for coronary 
artery disease, left ventricular dysfunction, mitral regurgitation or heart failure (e.g., cardiac 
resynchronization therapy, revascularization, and/or GDMT for heart failure; see 
APPENDIX A: Definitions) and must have been determined by the site’s local heart team as 
not appropriate for mitral valve surgery.  Subjects randomized to the Control group will 
continue to be treated per standard of care consistent with the subject’s condition during 
follow-up, just as the Device group, but will not undergo the MitraClip procedure for at least 
24 months.   

 
 
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2.4.4 Procedures Involved in the Use of the Device 
The procedures outlined in the approved MitraClip System Instruction for Use (IFU) must be 
followed in the use of this device under this Clinical Investigational Plan. 
2.4.5 Training Required for the Use of the Device 
Investigators will be trained in accordance with the approved MitraClip System Instruction 
for Use (IFU) and established MitraClip Therapy Training.  Investigator training will include, 
but will not be limited to, the use of a heart model and demonstration unit to ensure that 
investigators understand the mechanics and characteristics of the MitraClip System.  Sponsor 
staff will conduct this training and a training log will be used to document the training.  Only 
physicians who receive all required device training and complete a training log can perform 
the MitraClip procedure under this Clinical Investigational Plan.  
2.4.6 Investigational Device Accountability 
Abbott Vascular, the Sponsor, is responsible for the availability and traceability of all 
investigational products.  The Sponsor will ship devices (the MitraClip System) only to the 
Principal Investigator or his/her legal designee at each site.  Documentation at each step of 
the process via a device disposition log is required.  Use and final disposition of the 
investigational product will be reconciled on a regular basis. 
The Investigator will maintain adequate records of the receipt and disposition of the 
investigational device, including part number and serial number, date of use, subject number 
and implanting physician.  An Inventory/Device Accountability Log supplied by the Sponsor 
will be used.  Upon completion of trial registration, investigators will be notified in writing.  
All unused investigational devices must be returned to the Sponsor when trial registration is 
complete (completed Inventory/Device Accountability Report will be generated for the site) 
or as otherwise deemed necessary (e.g., expired devices). 
3 Trial Objectives 
The objective of the COAPT Trial is to evaluate the safety and effectiveness of the MitraClip 
System for the treatment of moderate-to-severe (3+) or severe (4+) functional mitral 
regurgitation (FMR) in symptomatic heart failure subjects treated per standard of care and 
who have been determined by the site’s local heart team as not appropriate for mitral valve 
surgery.  Eligible subjects will be randomized in a 1:1 ratio to the MitraClip device (Device 
group) or to no MitraClip device (Control group). As these patients typically do not undergo 
surgery, the appropriate control group is non-surgical treatment for management of 
symptoms from MR. 

 
 
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The trial has two co-primary objectives, including one primary safety objective and one 
primary effectiveness objective.  The trial also has two secondary safety objectives and 
several secondary effectiveness objectives. 
3.1 
Primary Objectives 
The primary safety objective is to demonstrate that freedom from a composite of device-
related complications in the Device group at 12 months is greater than a performance goal of 
88%.  The safety composite includes Single Leaflet Device Attachment (SLDA), device 
embolizations, endocarditis requiring surgery, Echocardiography Core Laboratory confirmed 
mitral stenosis requiring surgery, LVAD implant, heart transplant, and any device related 
complications requiring non-elective cardiovascular surgery (See APPENDIX A: 
Definitions). 
The primary effectiveness objective is to demonstrate that subjects in the Device group 
experience a lower rate of recurrent heart failure (HF) hospitalization than subjects in the 
Control group.  See APPENDIX A: Definitions for definition of HF hospitalization.   
3.2 
Secondary Objectives 
There are two secondary safety objectives: 
• To demonstrate that freedom from death (all-cause), stroke, myocardial infarction 
(MI), and non-elective (i.e. urgent or emergent) cardiovascular surgery for device 
related complications in the Device group at 30 days post-procedure is greater than 
80%  
• To demonstrate that the relative risk of all-cause mortality at 12 months between the 
Device and Control groups is less than 1.5 
The secondary effectiveness objectives are to demonstrate that subjects in the Device group: 
• Achieve MR reduction at 12 months to a greater extent than subjects in the Control 
group 
• Have greater improvement in distance walked on the 6 Minute Walk Test (6MWT) at 
12 months over baseline than subjects in the Control group 
• Experience greater improvement in quality of life (QoL) at 12 months over baseline, 
as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) than 
subjects in the Control group  
• Have larger reductions in Left Ventricular End Diastolic Volume (LVEDV) at 12 
months over baseline than subjects in the Control group 

 
 
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• Achieve New York Heart Association (NYHA) Functional Class I/II more often at 12 
months than the Control group 
• Experience a lower rate of death or recurrent HF  hospitalization than subjects in the 
Control group (hierarchical composite of death and recurrent HF hospitalization) 
• Experience a lower rate of recurrent all-cause hospitalization than subjects in the 
Control group 
4 Trial Endpoints 
4.1 
Primary Safety Endpoint 
The primary safety endpoint is a composite of Single Leaflet Device Attachment (SLDA), 
device embolizations, endocarditis requiring surgery, Echocardiography Core Laboratory 
confirmed mitral stenosis requiring surgery, LVAD implant, heart transplant, and any device 
related complications requiring non-elective cardiovascular surgery at 12 months.   
4.2 
Primary Effectiveness Endpoint 
The primary effectiveness endpoint is recurrent heart failure (HF) hospitalizations through 24 
months (analyzed when the last subject completes 12 months of follow-up). 
4.3 
Secondary Safety Endpoints 
• A composite of all-cause death, stroke, MI, or non-elective cardiovascular surgery for 
device related complications in the Device group at 30 days 
• All-cause mortality at 12 months 
4.4 
Secondary Effectiveness Endpoints 
• MR severity at 12 months  
• Change in distance walked on the 6 Minute Walk Test (6MWT distance or 6MWD) at 
12 months over baseline  
• Change in quality of life (QoL) at 12 months from baseline, as measured by the 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 

 
 
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• Change in Left Ventricular End Diastolic Volume (LVEDV) at 12 months over 
baseline  
• New York Heart Association (NYHA) Functional Class I/II at 12 months 
• Hierarchical composite of death and recurrent HF hospitalization (analyzed when the 
last subject completes 12 months of follow-up) 
• Recurrent hospitalizations - all-cause (analyzed when the last subject completes 12 
months of follow-up) 
4.5 
Additional Endpoints 
Labeling claims for the MitraClip device will be based on primary and secondary endpoints.  
Additional descriptive endpoints will also be reported as described below.  
4.5.1 Device or Procedure-Related Adverse Events 
Device or procedure-related adverse events are defined as adverse events that are adjudicated 
by the Clinical Events Committee as possibly, probably or definitely device and/or 
procedure-related, regardless of the temporal relationship to the MitraClip procedure.  Device 
or procedure-related adverse events will be broken down into those that occur within 30 days 
of the procedure and those that occur after 30 days of the procedure.  Examples of device-
related adverse events are: 
• myocardial perforation 
• Single Leaflet Device Attachment  
• embolization of the MitraClip device or MitraClip System components 
• iatrogenic atrial septal defect 
• mitral valve stenosis 
• need for mitral valve replacement instead of repair due at least in part to the 
MitraClip procedure or the presence of the MitraClip device 
4.5.2 Device and Procedure-Related Endpoints 
The following device and procedure-related acute endpoints will be reported for the Device 
group: 

 
 
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• Implant Rate: defined as the rate of successful delivery and deployment of the 
MitraClip device(s) with echocardiographic evidence of leaflet approximation and 
retrieval of the delivery catheter 
• Device Procedure Time: defined as the time elapsed from the start of the transseptal 
procedure to the time the Steerable Guide Catheter is removed 
• Total Procedure Time: defined as the time elapsed from the first of any of the 
following: intravascular catheter placement, anesthesia or sedation, or 
transesophageal echocardiogram (TEE), to the removal of the last catheter and TEE 
• Device Time: defined as the time the Steerable Guide Catheter is placed in the intra-
atrial septum until the time the MitraClip Delivery System (CDS) is retracted into the 
Steerable Guide Catheter 
• Fluoroscopy duration: defined as the duration of exposure to fluoroscopy during the 
MitraClip procedure 
4.5.3 Echocardiographic Endpoints  
The following echocardiographic endpoints will be reported for the Device and Control 
groups at baseline, discharge (or 30 days if discharge echocardiogram is not available), 6 
months, 12 months, 24 months and then yearly through 5 years.  For continuous variables, 
change from baseline to each follow-up will also be reported:  
• MR Severity Grade 
• Effective Regurgitant Orifice Area 
• Regurgitant Volume 
• Regurgitant Fraction 
• Left Ventricle End Diastolic Volume (LVEDV) 
• Left Ventricular End Systolic Volume (LVESV) 
• Left Ventricular End Diastolic Dimension (LVEDD) 
• Left Ventricular End Systolic Dimension (LVESD) 
• Left Ventricular Ejection Fraction (LVEF) 
• Right Ventricular Systolic Pressure (RVSP) 

 
 
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• Mitral Valve Area  
• Mean Mitral Valve Gradient 
• Systolic Anterior Motion of the mitral valve (present or absent) 
• Cardiac Output  
• Forward Stroke Volume 
4.5.4 Clinical Endpoints 
The following clinical endpoints will be reported for the Device and Control groups: 
• Kaplan-Meier freedom from the components of the primary safety composite at 12 
months, 24 months and yearly through 5 years (Device group only) 
• Kaplan-Meier freedom from the primary safety composite at 24 months and yearly 
through 5 years (Device group only) 
• Kaplan-Meier freedom from all-cause mortality at 12 months, 24 months and yearly 
through 5 years 
• Kaplan-Meier freedom from: (1) cardiovascular mortality (2) the first HF related 
hospitalization (3) the first cardiovascular hospitalization (4) the first HF related 
hospitalization or all-cause mortality at 12 months and 24 months and then yearly 
through 5 years  
• NYHA Functional Class at baseline, 30 days, 6 months, 12 months, 24 months and 
then yearly through 5 years 
• 6MWD at baseline, 30 days, 6 months, 12 months and 24 months (and change from 
baseline to follow-up) 
• KCCQ QoL scores at baseline, 30 days, 6 months, 12 months and 24 months (and 
change from baseline to follow-up) 
• SF-36 QoL scores at baseline, 30 days, 6 months, 12 months and 24 months (and 
change from baseline to follow-up) 
• Mitral valve surgery (including type of surgery), new use of CRT, new use of single 
or dual chamber pacemaker, permanent LVAD implant, heart transplant, additional 
MitraClip device intervention in Device group or de novo MitraClip device 
intervention in Control group, including reason for intervention through 5 years 

 
 
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• Responder analysis for 6MWD, where responder is defined as alive and experiencing 
an improvement of 24 meters and 50 meters at 12 months (difference in proportion of 
responders between Device and Control groups) at 12 months and 24 months  
• Responder analysis for LVEDV Index, where responder is defined as alive and 
experiencing an improvement of 12 ml/m2 (difference in proportion of responders 
between Device and Control groups) at 12 months, 24 months and then yearly 
through 5 years 
• Responder analysis for QoL (KCCQ), where responder is defined as alive and 
experiencing an improvement of 5 points (difference in proportion of responders 
between Device and Control groups) at 12 months and 24 months 
• Each subscale for QoL (KCCQ) (difference in means between Device and Control 
groups) at 12 months and 24 months 
• Length of index hospitalization for MitraClip procedure (Device group) 
• Number of hospitalizations and reason for hospitalization (i.e. heart failure, 
cardiovascular, non-cardiovascular) at 12 months and 24 months in each of the 
Device and Control groups   
• Number of days alive and out of hospital from the time of randomization (difference 
in medians between Device and Control groups) to 12 months, 24 months and then 
yearly through 5 years 
• Number of days hospitalized from the “Treatment” visit (difference in medians 
between Device and Control groups) at 12 months, 24 months and then yearly 
through 5 years 
• Proportion of alive time in hospital will be summarized and compared between 
Device and Control groups at 12 months, 24 months and then yearly through 5 years 
• Proportion of subjects living in the baseline location at 12 months, 24 months and 
then yearly through 5 years 
• Mitral valve replacement rates will be summarized and compared between Device 
and Control groups at 12 months, 24 months and then yearly through 5 years 
• New onset of permanent atrial fibrillation at 12 months, 24 months and then yearly 
through 5 years 
• Mitral stenosis at 12 months, 24 months and then yearly through 5 years 
• Clinically significant atrial septal defect (ASD) that requires intervention at 12 
months, 24 months and then yearly through 5 years 

 
 
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• Device-related complications in Device group subjects and Control group subjects 
who undergo the MitraClip procedure through 5 years 
• BNP or NT-proBNP levels at baseline, 30 days and 12 months  
• Modified Rankin Scale Score at baseline, 30 days, 6 months, 12 months 
• Major bleeding at 30 days 
• Prolonged ventilation at 30 days  
• Average dosages of GDMT at baseline, 30 days, 6 months, 12 months, 24 months, 
and then yearly through 5 years 
• The number and reasons for (1) any changes in GDMT and GDMT dosage from 
baseline at 30 days, 6 months, 12 months, 24 months, and then yearly through 5 years 
and  (2) any changes in GDMT from baseline that result in a greater than 100% 
increase or greater than 50% decrease in dose at 30 days, 6 months, 12 months, 24 
months, and then yearly through 5 years 
4.5.5 CPX Sub-Study Endpoint 
A sub-study endpoint will be added utilizing peak VO2 as a parameter for cardiopulmonary 
exercise testing (CPX).  CPX testing will be conducted at baseline and 12 months on a total 
of at least 50 and up to 100 subjects at qualified sites.  Mean changes in peak VO2 
(ml/kg/min) will be summarized at 12 months from baseline for the subset of patients who 
complete a CPX test at baseline and 12 months.  A comparison of change from baseline 
between Device and Control groups will be presented.  Formal hypothesis testing and 
multiplicity adjustments will not be performed.  A p-value for the peak VO2 endpoint will be 
generated for descriptive purposes. 
Peak VO2 may be assessed in conjunction with electrocardiography, hemodynamics, subject 
symptomatology, and other CPX testing parameters.  Abnormal responses in several of these 
variables may serve as exercise test termination criteria and should therefore be diligently 
monitored in patients.7 
Abbott Vascular will qualify relevant sites for CPX testing through an experienced core 
laboratory, and all patients randomized in qualified sites will be required to undergo CPX 
testing.  A separate Cardiopulmonary Exercise Test protocol will provide details on 
qualification of sites for CPX testing and the conduct of the CPX test. 
                                                 
7 Gibbons RJ, Balady GJ, Timothy BJ, et al. ACC/AHA 2002 guideline update for exercise testing: summary 
article. A report of the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40:1531-40. 

 
 
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4.5.6 Health Economic Data 
During the course of the trial, Abbott Vascular (or third party designee) will collect health 
economic data.  This includes gathering information regarding hospitalizations for the 
MitraClip procedure (index or otherwise).  The data required may include billing information 
(provided as a UB-04 form or equivalent and itemized hospital bills) for items such as 
hospital care, physician services, laboratory tests and diagnostic procedures.  The Institution 
shall submit a UB-04 form or equivalent to Sponsor in connection with the 30-day eCRFs 
completed following a MitraClip procedure. 
As in previous MitraClip clinical studies, it is anticipated that a majority of patients enrolled 
in the COAPT trial will be elderly U.S. Medicare beneficiaries8,9.  Therefore, the results from 
COAPT are expected to be generalizable to the Medicare population. 
5 Trial Design, Scope and Duration 
5.1 
Trial Design 
The COAPT Trial is a prospective, randomized, parallel-controlled, multicenter clinical 
evaluation of the MitraClip device for the treatment of clinically significant functional mitral 
regurgitation in symptomatic heart failure subjects who are treated per standard of care and 
who have been determined by the site’s local heart team as not appropriate for mitral valve 
surgery.  Eligible subjects will be randomized in a 1:1 ratio to the MitraClip device (Device 
group) or to no MitraClip device (Control group).  Randomization will be stratified by study 
site and cardiomyopathy etiology (i.e. ischemic or non-ischemic). 
5.2 
Number of Subjects to be Registered 
Investigational sites will attempt to recruit consecutive subjects who meet trial eligibility 
criteria.  Subjects who provide written informed consent are considered registered for the 
COAPT Trial upon MitraClip procedure attempt (such subjects are referred to as “roll-in” 
subjects) or upon randomization (such subjects are referred to as randomized subjects).  
Approximately six hundred and ten (610) subjects will be randomized at up to 100 
investigational sites.  Up to an additional 150 roll-in subjects may be treated by operators 
without recent or prior experience with the MitraClip device to gain hands-on experience 
                                                 
8 Glower DD, Kar S, Trento A, Lim DS, Bajwa T, Quesada R, Whitlow PL, Rinaldi MJ, Grayburn P, Mack MJ, 
Mauri L, McCarthy PM, Feldman T.  Percutaneous Mitral Valve Repair for Mitral Regurgitation in High-Risk 
Patients: Results of the EVEREST II Study.  J Am Coll Cardiol 2014;2:172-81. 
9 Lim DS, Reynolds MR, Feldman T, Kar S, Herrmann HC, Wang A, Whitlow PL, Gray WA, Grayburn P, 
Mack MJ, Glower DD.  Improved Functional Status and Quality of Life in Prohibitive Surgical Risk Patients 
With Degenerative Mitral Regurgitation After Transcatheter Mitral Valve Repair.  J Am Coll Cardiol 
2014;2:182-91. 

 
 
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before randomizing subjects in the trial.  See Section 6.5.1: Roll-in Subjects for further 
detail on roll-in subjects.  Once the site completes the roll-in phase, the randomization phase 
will begin.  Once the randomization phase has begun, all subsequent subjects must be 
randomized in the trial.  Roll-in subjects will not count toward the approximately 610 subject 
cap for randomized subjects. 
5.3 
Trial Duration 
The trial registration period is estimated to last approximately 24 months.  Investigators at 
any site may not register more than 15% of the total of the approximately 610 randomized 
subjects. There is no minimum number of subjects to be registered at any site.  Subjects will 
have required follow-up evaluations at 1-week, 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter through 5 years.  Control group subjects will be allowed to 
undergo the MitraClip procedure only after completion of the 24-month follow-up visit. 
When all registered subjects have been followed for 5 years, or have exited the trial, the trial 
will be closed. 
5.4 
Participation of Women in COAPT 
Historically, women have been under-represented in or excluded from many clinical trials.  It 
is important to assess the burden of disease and the safety and effectiveness of the device in 
both sexes.  The sections below describe the prevalence of valvular heart disease, in 
particular, mitral regurgitation, and the measures that will be taken to ensure participation of 
women in the COAPT trial. 
5.4.1 Sex-Specific Prevalence of Valvular Heart Disease, Diagnosis and Treatment 
Patterns 
Population-based studies demonstrated no difference in the prevalence of valvular heart 
disease in men and women (Nkomo et al.10).  Nkomo et al. report that in the community 
setting, women are diagnosed with valvular heart disease less often than men.  However, the 
Society of Thoracic Surgeons (STS) database, which reports on mitral valve surgeries 
between the years 2002 and 2006, had an equal representation of women and men, although 
women underwent mitral valve replacement at a higher rate than men (57% women; 43% 
men) and mitral valve repair at a lower rate than men (41% women; 59% men).   
                                                 
10 Nkomo VT, Gardin JM, Skelton TN, et al. Burden of valvular heart diseases: a population-based study. 
Lancet 2006; 368: 1005–1011. 

 
 
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5.4.2 Proportion of Women Included in Past Studies for Target Indication 
In prior US clinical trials of the MitraClip System in high surgical risk patients (EVEREST 
High Risk Cohort), women constituted almost 40% of patients enrolled.  This representation 
of women is reflective of the prevalence and diagnosis of valvular heart disease in women.  
This high representation of women is likely due to the following factors:  
• Enrollment criteria in the US clinical trials of the MitraClip System did not 
differentially select men or women  
• Barriers to enrollment of women (e.g., fear of fetal consequences, family 
responsibilities which limit ability for time commitment to study follow-up, lack of 
understanding about differences in disease etiology and pathophysiology leading to 
under-diagnosis and under-referral of women, etc.) were not significant variables.  
The typical subject was elderly (average age = 75 years) and enrollment was likely 
not impacted by issues that tend to select men preferentially over women (e.g., child 
care or elder care needs). 
• Sites in prior clinical trials were selected to have a high rate of compliance to the 
Clinical Investigational Plan; therefore, subjects of either sex who met the eligibility 
criteria of the trial were enrolled.  
5.4.3 Safety and Effectiveness Outcomes by Sex 
Data from previous US clinical trials of the MitraClip System in both surgical patients and 
high surgical risk patients indicate no difference in either safety or effectiveness outcomes 
between women and men, with the exception of a higher rate of transfusions ≥ 2 units in 
women than men.   
5.4.4 Representation of Women in the COAPT Trial 
It is expected that the COAPT Trial will enroll a high proportion of women consistent with 
the rate registered in prior US clinical trials of the MitraClip System for the following 
reasons: 
• As with prior clinical trials, enrollment criteria for the COAPT trial do not 
differentially select men or women 
• Barriers to enrollment of women (e.g., fear of fetal consequences, family 
responsibilities which limit ability for time commitment to study follow-up, lack of 
understanding about differences in disease etiology and pathophysiology leading to 
under-diagnosis and under-referral of women, etc.) are not significant variables.  The 
typical subject is expected to be elderly (average age = 75 years) and enrollment is 

 
 
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not likely to be impacted by issues that tend to select men preferentially over women 
(e.g., child care or elder care needs) 
• Sites in the COAPT Trial will be selected to have a high rate of compliance to the 
Clinical Investigational Plan, therefore, subjects of either sex who met the eligibility 
criteria of the trial will be enrolled.  
5.4.5 Subgroup Analysis for Sex 
Although differences in safety and effectiveness between the Device and Control groups are 
not expected to be impacted by sex, the statistical analysis plan specifies a subgroup analysis 
by sex to evaluate treatment differences in primary safety and effectiveness endpoints. 
6 Clinical Trial Procedure 
6.1 
Site Selection 
Sites will be selected after review of a recent site assessment and the qualifications of the 
Principal Investigator at the site. 
Each site will be required to have a multidisciplinary team.  The multidisciplinary team will 
consist of a minimum of the following representatives: 
• One (1) Interventional Cardiologist 
• One (1) Cardiothoracic (CT) Surgeon 
• One (1) Echocardiographer 
• One (1) Heart Failure specialist  
The requirements for the experience of the investigators on the multidisciplinary team are 
detailed in Section 6.2.1 Investigator Experience Requirements.  Sites will use best 
practice guidelines such as those defined in the 2013 ACCF/AHA Heart Failure guidelines to 
guide the management of heart failure.   
Upon Sponsor’s request, Institution shall provide Sponsor with a copy of Institution’s STS 
data for Sponsor to use in connection with the Trial in order to verify the Institution’s and 
Investigator’s surgery volumes and outcomes.  The Sponsor will not use the STS database for 
any other purpose or disclose it to any third party other than to regulatory agencies in 
connection with the Trial, without Institution’s prior written consent. 

 
 
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Sites must have adequate volume of potential subjects who meet the eligibility criteria (at 
least 1 subject per site per month). 
Sites must have appropriate facilities (including surgical back-up facilities), resources, and 
equipment to perform the MitraClip procedure. 
6.2 
Site Personnel Selection 
Site investigators selected to participate in this trial will be responsible for fulfilling the 
clinical trial requirements specified in this Clinical Investigational Plan. 
The Sponsor will select investigators who are qualified by training and experience to perform 
clinical research and to participate in the investigation.  The following criteria will be used to 
select investigators for participation in this clinical trial: 
• The Principal Investigator is qualified by training and expertise as a Heart Failure 
specialist, Interventional Cardiologist, CT Surgeon, or Echocardiographer.  
• Each site must have an investigator from each of the following specialties: Heart 
Failure, Interventional Cardiology, CT Surgery, and Echocardiography. 
• Each site must have research staff trained to administer the modified Rankin Scale. 
• Investigator and clinical research staff must have experience conducting 
Investigational Device Exemption (IDE) studies and have the resources to conduct 
the trial in accordance with this Clinical Investigational Plan. 
• Investigators must agree to comply with this Clinical Investigational Plan, appropriate 
trial-related agreements (Investigator Agreement) and regulatory requirements. 
All investigators will sign the appropriate trial-related agreements (Investigator Agreement) 
before they are added to the clinical trial. 
The Local Site Heart Team, responsible for subject selection for the COAPT Trial, must 
consist of, at a minimum, the CT Surgeon and Heart Failure specialist investigators.  
6.2.1 Investigator Experience Requirements 
The CT surgeon investigator must be board certified (or equivalent) and have performed at 
least 25 mitral valve surgeries in the prior year or at least 40 mitral valve surgeries in the 
prior 2 years.   
Investigators who serve as operators implanting the MitraClip device must be experienced in 
the transseptal technique.  

 
 
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Each site must have a HF specialist investigator that will meet with each potential subject to 
determine if the subject has been adequately treated per applicable standards, including for 
coronary artery disease, left ventricular dysfunction, mitral regurgitation and heart failure 
(e.g., with cardiac resynchronization therapy, revascularization, and/or GDMT as 
appropriate; see APPENDIX A: Definitions).  The Heart Failure specialist investigator must 
meet at least one of the following criteria:   
• Certified by ABIM (American Board of Internal Medicine) Board in Advanced Heart 
Failure and Transplant Cardiology or must meet the eligibility to sit for the board 
• UNOS (United Network for Organ Sharing) certification 
• Director of Heart Failure/Transplant Cardiology at their institution 
• Experience conducting advanced heart failure clinical trials as a principal 
investigator, and approved by HF specialist on the Central Eligibility Committee  
• Recognition for heart failure skills in local/regional area, and approved by HF 
specialist on the Central Eligibility Committee 
• Significant portion (at least 50%) of practice involves treating patients with heart 
failure, and approved by heart failure specialist on the Central Eligibility Committee 
• Provides care within the context of a heart failure clinic and approved by HF 
specialist on the Central Eligibility Committee 
See Section 10.2 Central Eligibility Committee for description of the role of the Central 
Eligibility Committee.  
The responsibilities of the various roles/specialties on the multidisciplinary team at the site 
are summarized below: 
Role / Specialty 
Responsibility 
Interventional 
Cardiologist 
• Evaluates potential subjects (optional) 
• Performs MitraClip procedure* 
Heart Failure Specialist 
• Local Site Heart Team member 
• Evaluates all potential subjects in-person 
• Verifies and ensures stable GDMT at screening; examines 
subjects at all follow-up visits, including assessment of 
continued GDMT 
• Presents potential subjects to Central Eligibility Committee 
CT Surgeon 
• Local Site Heart Team member 
• Evaluates all potential subjects in-person 
• May present potential subjects to Central Eligibility 
Committee 

 
 
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Echocardiographer 
• Evaluates potential subjects for echocardiographic eligibility 
criteria 
• Participates in the MitraClip procedure 
* Any of the Interventional Cardiologist, HF Specialist, CT Surgeon or Echocardiographer can be a MitraClip 
implanter as long as they have undergone the MitraClip Therapy Training and are authorized by the Sponsor to 
perform the procedure 
6.3 
Subject Selection 
Subjects in this trial must have heart failure with moderate-to-severe (3+) or severe (4+) 
symptomatic functional mitral regurgitation who are treated per standard of care and who 
have been determined by the site’s local heart team as not appropriate for mitral valve 
surgery.  Several mechanisms will be employed in this trial to ensure appropriate subjects are 
registered in the trial. 
Subjects will be selected for inclusion in the COAPT Trial by a multidisciplinary team at 
each investigational site involving heart failure, interventional cardiology, echocardiography 
and cardiac surgery.  Additionally, the transthoracic echocardiogram (TTE) will be assessed 
by the Echocardiography Core Laboratory. The independent Central Eligibility Committee 
will confirm that surgery will not be offered to the subject and that subject is receiving 
optimal therapy, including GDMT, (see Section 10.2 Central Eligibility Committee for 
more details). 
6.3.1 Defining Heart Failure Patients with Functional Mitral Regurgitation 
In order to be eligible for the trial, the Local Site Heart Team (at a minimum CT surgeon and 
the HF specialist investigators) must determine that the subject has been treated per standard 
of care and is not appropriate for mitral valve surgery either before or after randomization.  
The HF specialist investigator must confirm that the subject is on optimal therapy i.e., subject 
has been adequately treated per applicable standards, such as for coronary artery disease, left 
ventricular dysfunction, mitral regurgitation and heart failure (e.g., with cardiac 
resynchronization therapy, revascularization and/or GDMT as appropriate; see APPENDIX 
A: Definitions).   
Once the Local Site Heart Team has determined that the subject has been optimally treated 
and is not appropriate for mitral valve surgery, and the Echocardiography Core Laboratory 
has confirmed that subject meets eligibility based on transthoracic echocardiogram (TTE), 
the site will submit subject data to the Eligibility Committee for review.  In order to qualify 
for the trial, the Eligibility Committee must confirm that the subject is on optimal therapy, 
including GDMT and that mitral valve surgery will not be offered to the subject even if the 
subject is randomized to the control group, consistent with his/her medical condition (see 
Section 10.2 Central Eligibility Committee for responsibilities of the Eligibility 
Committee).  See Figure 3 for a flow chart detailing the screening process.   

 
 
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6.3.2 Eligibility Criteria 
Assessment of eligibility is based on medical records and interview with the candidate 
subject.  Clinical and laboratory tests of eligibility assessments shall be per site standard.  If a 
specific test required to determine subject’s eligibility is not included in site’s standard tests, 
the test must be performed after written informed consent has been obtained from subject (or 
subject’s legally authorized representative, if applicable).  If any of the required screening 
assessments are conducted as part of standard of care prior to obtaining written informed 
consent, it is acceptable to provide the results of these previously performed tests for 
purposes of screening after the subject (or subject’s legally authorized representative) has 
consented to participate in the study. See Section 6.4 Subject Screening and Informed 
Consent for additional details on subject screening and informed consent process. 
6.3.2.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to participate in the trial: 
1. Symptomatic functional MR (≥3+) due to cardiomyopathy of either ischemic or non-
ischemic etiology determined by assessment of a qualifying transthoracic 
echocardiogram (TTE) obtained within 90 days and transesophageal echocardiogram 
(TEE) obtained within 180 days prior to subject registration, with MR severity based 
principally on the TTE study, confirmed by the Echocardiography Core Lab (ECL).  
The ECL may request a transesophageal echocardiogram (TEE) to confirm MR 
etiology. 
Note: Functional MR requires the presence of global or regional left ventricular wall 
motion abnormalities, which are believed to be the primary cause of the MR.  If a flail 
leaflet or other evidence of degenerative MR is present, the subject is not eligible 
even if global or regional left ventricular systolic dysfunction is present. 
Note: Qualifying TTE must be obtained after the subject has been stabilized on 
optimal therapy including GDMT and at least 30 days after:  
a) a greater than 100% increase or greater than 50% decrease in dose of GDMT  
b) revascularization and/or implant of Cardiac Resynchronization Therapy device 
(CRT or CRT-D) or reprogramming of an implanted CRT or CRT-D that results 
in increased biventricular pacing (from <92% to ≥92%)   
2. In the judgment of the HF specialist investigator at the site, the subject has been 
adequately treated per applicable standards, including for coronary artery disease, left 
ventricular dysfunction, mitral regurgitation and heart failure (e.g., with cardiac 
resynchronization therapy, revascularization, and/or GDMT; see APPENDIX A: 
Definitions for definition of GDMT).  The Eligibility Committee must concur that 
the subject has been adequately treated. 

 
 
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3. The subject has had at least one hospitalization for heart failure in the 12 months prior 
to subject registration and/or a corrected BNP ≥300 pg/ml or corrected NT-proBNP 
≥1500 pg/ml measured within 90 days prior to subject registration (“corrected” refers 
to a 4% reduction in the BNP or NT-proBNP cutoff for every increase of 1 kg/m2 in 
BMI above a reference BMI of 20 kg/m2).  
Note: BNP or NT-proBNP must be obtained after the subject has been stabilized on 
GDMT and at least 30 days after:  
a) a greater than 100% increase or greater than 50% decrease in dose of GDMT  
b) revascularization and/or implant of Cardiac Resynchronization Therapy device 
(CRT or CRT-D) or reprogramming of an implanted CRT or CRT-D that results 
in increased biventricular pacing (from <92% to ≥92%)  
4. New York Heart Association (NYHA) Functional Class II, III or ambulatory IV. 
5. The Local Site Heart Team (CT surgeon and HF specialist investigators) and the 
Central Eligibility Committee concur that surgery will not be offered as a treatment 
option and that medical therapy is the intended therapy for the subject, even if the 
subject is randomized to the Control group.  
6. Left Ventricular Ejection Fraction (LVEF) is ≥20% and ≤50% within 90 days prior to 
subject registration, assessed by the site using any one of the following methods: 
echocardiography, contrast left ventriculography, gated blood pool scan or cardiac 
magnetic resonance imaging (MRI).   
Note: The method must provide a quantitative readout (not a visual assessment).   
7. Left Ventricular End Systolic Dimension (LVESD) is ≤70 mm assessed by site based 
on a transthoracic echocardiographic (TTE) obtained within 90 days prior to subject 
registration. 
8. The primary regurgitant jet is non-commissural, and in the opinion of the MitraClip 
implanting investigator can be successfully be treated by the MitraClip.  If a 
secondary jet exists, it must be considered clinically insignificant.   
9. Creatine Kinase-MB (CK-MB)  obtained within prior 14 days < local laboratory ULN  
(Upper Limit of Normal) 
10. Transseptal catheterization and femoral vein access is determined to be feasible by 
the MitraClip implanting investigator. 
11. Age 18 years or older.  

 
 
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12. The subject or the subject’s legal representative understands and agrees that should 
he/she be assigned to the Control group, he/she will be treated with medical therapy 
and conservative management without surgery and without the MitraClip, either 
domestically or abroad.  If the subject would actively contemplate surgery and/or 
MitraClip if randomized to Control, he/she should not be registered in this trial. 
13. The subject or the subject’s legal representative has been informed of the nature of 
the trial and agrees to its provisions, including the possibility of randomization to the 
Control group and returning for all required post-procedure follow-up visits, and has 
provided written informed consent. 
6.3.2.2 
Exclusion Criteria 
Subjects must NOT meet any of the following exclusion criteria to participate in the trial: 
1. Chronic Obstructive Pulmonary Disease (COPD) requiring continuous home oxygen 
therapy or chronic outpatient oral steroid use. 
2. Untreated clinically significant coronary artery disease requiring revascularization. 
3. Coronary artery bypass grafting (CABG) within 30 days prior to subject registration. 
4. Percutaneous coronary intervention within 30 days prior to subject registration. 
5. Transcatheter aortic valve replacement (TAVR) within 30 days prior to subject 
registration. 
6. Tricuspid valve disease requiring surgery. 
7. Aortic valve disease requiring surgery or transcatheter intervention. 
8. Cerebrovascular accident within 30 days prior to subject registration. 
9. Severe symptomatic carotid stenosis (> 70% by ultrasound). 
10. Carotid surgery or stenting within 30 days prior to subject registration. 
11. ACC/AHA Stage D heart failure.  
12. Presence of any of the following: 
• Estimated pulmonary artery systolic pressure (PASP) > 70 mm Hg assessed by 
site based on echocardiography or right heart catheterization, unless active 
vasodilator therapy in the cath lab is able to reduce the pulmonary vascular 
resistance (PVR) to < 3 Wood Units or between 3 and 4.5 Wood Units with v 
wave less than twice the mean of the pulmonary capillary wedge pressure 

 
 
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• Hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive 
pericarditis, or any other structural heart disease causing heart failure other than 
dilated cardiomyopathy of either ischemic or non-ischemic etiology 
• Infiltrative cardiomyopathies (e.g., amyloidosis, hemochromatosis, sarcoidosis) 
• Hemodynamic instability requiring inotropic support or mechanical heart 
assistance 
13. Physical evidence of right-sided congestive heart failure with echocardiographic 
evidence of moderate or severe right ventricular dysfunction, as assessed by site.   
14. Implant of any Cardiac Resynchronization Therapy (CRT) or Cardiac 
Resynchronization Therapy with cardioverter-defibrillator (CRT-D) within the last 30 
days prior to subject registration. 
15. Mitral valve orifice area < 4.0 cm2 assessed by site based on a transthoracic 
echocardiogram (TTE) within 90 days prior to subject registration. 
16. Leaflet anatomy which may preclude MitraClip implantation, proper MitraClip 
positioning on the leaflets or sufficient reduction in MR by the MitraClip.  This 
evaluation is based on transesophageal echocardiogram (TEE) evaluation of the 
mitral valve within 180 days prior to subject registration and includes: 
• Insufficient mobile leaflet available for grasping with the MitraClip device 
• Evidence of calcification in the grasping area  
• Presence of a significant cleft in the grasping area 
• Lack of both primary and secondary chordal support in the grasping area 
• Leaflet mobility length < 1 cm 
17. Hemodynamic instability defined as systolic pressure < 90 mmHg with or without 
afterload reduction, cardiogenic shock or the need for inotropic support or intra-aortic 
balloon pump or other hemodynamic support device.  
18. Need for emergent or urgent surgery for any reason or any planned cardiac surgery 
within the next 12 months. 
19. Life expectancy < 12 months due to non-cardiac conditions. 
20. Modified Rankin Scale ≥ 4 disability. 
21. Status 1 heart transplant or prior orthotopic heart transplantation. 

 
 
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22. Prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve, 
or any prior transcatheter mitral valve procedure.  
23. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. 
24. Active endocarditis or active rheumatic heart disease or leaflets degenerated from 
rheumatic disease (i.e., noncompliant, perforated). 
25. Active infections requiring current antibiotic therapy.  
26. Subjects in whom transesophageal echocardiography (TEE) is contraindicated or high 
risk.   
27. Known hypersensitivity or contraindication to procedural medications which cannot 
be adequately managed medically. 
28. Pregnant or planning pregnancy within next 12 months.  
Note:  Female patients of childbearing age should be instructed to use safe 
contraception (e.g. intrauterine devices, hormonal contraceptives: contraceptive pills, 
implants, transdermal patches hormonal vaginal devices, injections with prolonged 
release.   
29. Currently participating in an investigational drug or another device study that has not 
reached its primary endpoint.  Note: Trials requiring extended follow-up for products 
that were investigational, but have since become commercially available, are not 
considered investigational trials. 
30. Subject belongs to a vulnerable population (see APPENDIX A: Definitions for 
definition of vulnerable population) per investigator’s judgment or subject has any 
kind of disorder that compromises his/her ability to give written informed consent 
and/or to comply with study procedures. 
6.3.3 Justification for Inclusion and Exclusion Criteria 
The COAPT Trial is designed to study heart failure subjects with moderate-to-severe (3+) or 
severe (4+) symptomatic functional mitral regurgitation who are not appropriate for mitral 
valve surgery.  
Several eligibility criteria are defined to include symptomatic heart failure subjects who are 
not appropriate for mitral valve surgery.  Additionally, the HF specialist investigator at the 
investigational site is required to examine the subject to assess the subject for appropriateness 
and optimization of medical and device therapy.  All subjects must be evaluated by the Local 
Site Heart Team to confirm that the subject is on optimal therapy including GDMT and that 
mitral valve surgery will not be offered to the patient either at baseline or after randomization 

 
 
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even if the patient deteriorates, consistent with local standards of practice.  Finally, to ensure 
consistency of criteria applied across sites to determine subject eligibility, an Eligibility 
Committee will review pertinent medical history to make the final determination regarding 
eligibility of prospective subjects (see Section 10.2 Central Eligibility Committee for more 
details). An upper limit for LV ejection fraction (LVEF) has been set at 50% to ensure 
inclusion of subjects with functional MR etiology.  A lower limit of 20% for LVEF and an 
upper limit of 70mm on LV end systolic dimension have been set to exclude subjects whose 
LV dysfunction is so advanced that their symptoms and prognosis will be dominated by LV 
dysfunction rather than MR (and to exclude ventricles so large that 3 or more MitraClips may 
be required).  To isolate the effect of the MitraClip device, eligible subjects must have been 
adequately treated per applicable standards, including for coronary artery disease, left 
ventricular dysfunction, mitral regurgitation and heart failure prior to registration.  Subjects 
must also have received appropriate revascularization therapy for their coronary artery 
disease, and/or cardiac resynchronization therapy, if appropriate, at least 90 days prior to 
randomization. 
Subjects must also have had a heart failure hospitalization or elevated BNP (corrected BNP 
≥300 pg/ml or corrected NT-proBNP ≥1500 pg/ml) in the last 90 days so as to ensure a 
population at high likelihood of future heart failure hospitalizations is registered in the 
trial11,12,13,14.  A corrected BNP or NT-proBNP is implemented to account for obese subjects. 
Subjects who are unlikely to benefit from the MitraClip intervention, have a life expectancy 
of less than 12 months due to non-cardiac conditions, or who have refractory heart failure 
requiring specialized interventions, such as implantation of a LVAD or listing for heart 
transplant, are excluded from the trial.  As such, ACC/AHA Stage D heart failure subjects, 
non-ambulatory NYHA Functional Class IV subjects, subjects dependent on inotropic 
support, subjects with baseline modified Rankin Scale grade ≥ 4 disability and subjects with 
concomitant severe right heart dysfunction, tricuspid disease, or aortic valve disease are 
specifically excluded from the trial.  Finally, subjects presenting with hypertrophic and 
restrictive cardiomyopathies are also excluded on the grounds that their left ventricle is less 
likely to reverse remodel. 
                                                 
11 Pfister R, Diedrichs H, Schiedermair A. Prognostic impact of NT‐proBNP and renal function in comparison 
to contemporary multi-marker risk scores in heart failure patients. Eur J Heart Fail 2008; 10:315-320. 
12 Berger R, Shankar A, Fruhwald F. et al. Relationships between cardiac resynchronization therapy and N-
terminal pro-brain natriuretic peptide in patients with heart failure and markers of cardiac dyssynchrony: an 
analysis from the Cardiac Resynchronization in Heart Failure (CARE-HF) study. Eur Heart J 2009; 30:2109-
2016. 
13 Olsson LG, Swedberg K, Cleland JGF. Prognostic importance of plasma NT‐pro BNP in chronic heart failure 
in patients treated with a β‐blocker: Results from the Carvedilol Or Metoprolol European Trial (COMET) trial. 
Euro J Heart Fail 2007; 9:795–801. 
14 Pocock SJ, Wand D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart 
failure. Eur Heart J 2006; 27:65-75. 

 
 
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Additionally, appropriate mitral valve anatomic criteria ensure subjects are candidates for the 
MitraClip procedure. 
6.4 
Subject Screening and Informed Consent 
All subjects must be screened by the site’s investigator and clinical research staff, who have 
been trained to the Clinical Investigational Plan, to determine if the potential subject is 
eligible for trial registration.  Potential subjects may be assigned up to two screening 
numbers; (assigned sequentially/chronologically) – the initial screening number on the 
Screening Log (Excel spreadsheet) and then the screening number through the electronic 
Case Report Form (eCRF) database.  An accurate and up-to-date screening log of all subjects 
considered for the trial must be maintained and submitted to the Sponsor on a weekly basis 
during the trial registration period.  The result of the subject screening process should be 
documented in the screening log to include clinical presentation route, whether the subject 
met eligibility criteria (and if not, which eligibility criteria were not met), whether the subject 
was subsequently registered, and the reason for not enrolling if the subject was not registered.   
During the informed consent process, the investigator or designee, who has been trained on 
the Clinical Investigational Plan, will explain the nature and scope of the trial, potential risks 
and benefits of participation, and answer questions from potential subjects.  All subjects (or 
subjects’ legally authorized representatives, if applicable) must sign and date the Institutional 
Review Board (IRB)/ Ethics Committee (EC) approved informed consent form prior to any 
clinical trial-specific procedures.  No subjects belonging to a vulnerable population (see 
APPENDIX A: Definitions for definition of vulnerable population) will be registered. 
Obtaining the consent, provision of copy to the subject, along with date and time must be 
documented in the subject’s medical records. The informed consent form must be signed by 
the investigator or designate. In addition, the signed informed consent must be kept in the 
subjects medical records. Sites may use a screening informed consent initially, followed by a 
full informed consent once the subject is deemed eligible for subject registration in the trial.  
The investigator or designee is responsible for advising the subject of any new information 
about the study or the MitraClip device that may become known during the study.   
If a specific test required to determine subject’s eligibility is not site standard of care, the test 
must be performed after written informed consent has been obtained.  If any of the required 
screening assessments are conducted as part of standard of care prior to obtaining written 
informed consent, it is acceptable to provide the results of these previously performed tests 
for purposes of screening after subject (or subject’s legally authorized representative) has 
provided informed consent.  
An authorization for use and disclosure of the subjects’ protected health information, in 
accordance with the Health Insurance Portability and Accountability Act (HIPAA), must be 
obtained from the subject or the subject’s legally authorized representative. 

 
 
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For live cases at congresses the patients need to sign a specific Live Case ICF, approved by 
the IRB/EC and by AV, as well as by the competent authorities (e.g., FDA), as applicable.  
The investigator must request AV approval prior to performing a Live Case. 
The Sponsor will provide echocardiographic training to all sites and may assist in the review 
of screening echocardiograms to ensure conformance to echocardiographic eligibility 
requirements.  Transthoracic echocardiograms will be submitted to the ECL for confirmation 
of eligibility prior to subject registration.  
6.5 
Pre-Randomization  
6.5.1 Roll-in Subjects 
The decision to identify a subject as a roll-in will depend on the level of experience of the 
Investigator with the device.  Roll-in subjects will be designated by the Sponsor as such prior 
to treatment and will not undergo randomization.  Sites may perform up to 3 roll-in 
procedures prior to beginning the randomization phase of the trial based on the following 
criteria: 
• Investigators that do not have prior experience with the MitraClip device OR that have 
not performed a MitraClip procedure in the prior 12 months may perform up to 3 roll-in 
procedures upon approval from the Sponsor 
The site must receive authorization from the Sponsor to enroll each roll-in case.  
6.5.2 Screening and Baseline Assessments  
Screening of a subject for possible inclusion in the trial may commence once a subject has 
been identified as symptomatic, potentially having clinically significant functional mitral 
regurgitation (MR ≥ 3+).  Subject’s general medical eligibility must be assessed by the sites 
through subject’s interview and subject’s medical record review prior to subject registration 
and within the windows stipulated (see Table 1 for more details).  Standard of care tests that 
are performed prior to obtaining informed consents can be used to determine eligibility if 
those tests meet the requirements of this trial and are within the screening window.  
Outlined below is the schedule of tests and assessments that need to be completed prior to 
registration: 
Screening assessments within 180 days prior to registration: 
• Transesophageal echocardiographic (TEE) images to be obtained and submitted to the 
Sponsor. Site must review the TEE images and confirm that subject has functional 
MR and suitable mitral valve anatomic criteria, without intracardiac mass, thrombus 

 
 
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or vegetation.  Trained AV personnel may provide support to sites in reviewing TEE 
images. 
- 
If the TEE is not standard of care at the site, the subject (or subject’s legally 
authorized representative) must provide informed consent prior to the 
echocardiographic study. 
Screening assessments within 90 days prior to registration: 
• Medical history must be obtained, including review of subject’s medical records.  
• Subject is examined by the HF specialist investigator to assess the subject for 
appropriateness and optimization of medical and device therapy. 
• STS Risk Score for mitral valve replacement and repair must be calculated. 
• Subject has in-person consult with CT surgeon investigator.  CT surgeon investigator 
must document in the subject’s medical record that medical therapy is the intended 
therapy for the patient per their site’s practice, even if the subject is randomized to the 
Control group and even if the subject deteriorates and/or the severity of MR 
increases. 
• Subject is evaluated by the Local Site Heart Team to confirm that they are adequately 
treated per applicable standards, including for coronary artery disease, left ventricular 
dysfunction, mitral regurgitation and heart failure.  Subjects with current or prior 
symptoms of heart failure and reduced LVEF must be on stable GDMT recommended 
according to current guidelines6 as standard of care for heart failure therapy in the 
United States.  See APPENDIX A: Definitions for definition of GDMT therapy.  
Additionally, the Local Site Heart Team must confirm that the subject is not 
appropriate for mitral valve surgery. 
• NYHA Functional Class assessment. 
• If subject has not had a heart failure hospitalization within the prior year, measure 
BNP or NT-proBNP. 
• Transthoracic echocardiographic (TTE) images to be obtained and submitted to the 
Sponsor.  
• Medical history must be obtained, including review of subject’s medical records. 
• A 12-lead ECG must be performed. 
• After the ECL has confirmed subject eligibility, sites will be notified by Sponsor to 
compile and submit subject’s pertinent medical history to the Eligibility Committee. 

 
 
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Screening and Baseline assessments within 14 days prior to randomization (may occur 
on the day of, but prior to, randomization) or registration (for roll-in subjects): 
• Medical history must be obtained, including review of subject’s medical records. 
• A physical exam including an assessment of subject’s cardiac status and vital signs 
measures (such as height, weight, heart rate, blood pressure and temperature) must be 
completed. 
• Blood tests performed. 
• Concomitant cardiovascular medications must be documented. 
• Modified Rankin Scale must be assessed. 
• A 12-lead ECG must be performed. 
• Katz activities of daily living, grip strength, 15 feet walk test components of Frailty 
Index15 must be assessed but will not be used for screening subjects for the trial or 
submitted to the Eligibility Committee. Note: These assessments must be completed 
after the 6MWT and QoL questionnaires are completed.  
• Site must reassess subject eligibility and reconfirm that the subject meets eligibility 
criteria.  If there has been significant change in subject’s overall condition (i.e. due to 
recent MI, stroke, etc.), it may be necessary to update assessments completed during 
the screening process, such as TTE, STS risk calculation, etc. 
• If site is participating in the CPX sub-study, subject must undergo a CPX test. 
• The following tests must be performed by a coordinator who will not be involved in 
day-to-day activities of the COAPT trial and will not have access to the eCRFs.  This 
coordinator will be designated as “blinded” study personnel, and will not have 
knowledge of the subject’s treatment assignment.  A standardized script will be used 
when administering these assessments: 
o KCCQ and SF-36 QoL questionnaires must be completed by the subject; 
Note: To minimize bias and undue influence, the QoL questionnaires will be 
completed by the subject, unless the subject is unable to complete the 
questionnaire on their own (in such cases a note to file must be completed to 
document the inability of subject to complete the questionnaire). 
                                                 
15 Fried LP, Tangen CM, Waltson J et al. Frailty in older adults: Evidence for a phenotype.  J Gerontol A Biol 
Sci Med Sci. 2001 56:M146-M156. 

 
 
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o The 6-Minute Walk Test (6MWT) must be administered according to the ATS 
Statement: Guidelines for the Six-Minute Walk Test, Official Statement of the 
American Thoracic Society, approved March 2002  (See APPENDIX E: 6 
Minute Walk Test Guidelines). 
o An assessment of NYHA Functional Class must be completed.   
The following screening and baseline information must be captured on the appropriate 
electronic Case Report Forms (eCRFs): 
• Inclusion and Exclusion criteria 
• Demographics (e.g., date of birth, gender, race/ethnicity)  
• Informed Consent date 
6.6 
Subject Registration 
Subjects are enrolled upon providing written informed consent.  Subjects will be assigned a 
subject number upon MitraClip procedure attempt (see APPENDIX A: Definitions for 
definition of MitraClip procedure attempt) for roll-in subjects and upon randomization for 
those subjects who are randomized.   Such subjects are registered in the trial.   
6.7 
Randomization 
Before randomization: 
• Echocardiography Core Lab must confirm MR severity 
• Eligibility Committee must  confirm that the subject is on optimal therapy including 
GDMT and is not appropriate for mitral valve surgery according to local site 
standards either at baseline or if the subject deteriorates and/or MR increases in 
severity during follow-up 
• Site must reconfirm that subject meets eligibility criteria after Eligibility Committee 
approval and all baseline tests and assessments must be completed (within 14 prior to 
randomization) 
If screening TEE shows intracardiac mass, thrombus or vegetation, or the Eligibility 
Committee determines subject requires additional treatment before consideration for the trial, 
the subject may be deferred and reconsidered for the trial, at which time the TEE must be 
repeated.   

 
 
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Subjects will be randomized or assigned as a roll-in through the eCRF database.  The 
following baseline information must be captured for registered subjects on the appropriate 
eCRFs: 
• Subject medical history and risk factors  
• Current cardiovascular medications 
• Physical measurements and vital signs (e.g. weight, height, heart rate, blood pressure 
and temperature) 
6.8 
“Treatment” Visit (Device Group or Roll-in Subjects) 
For Device group or roll-in subjects, the MitraClip procedure will be performed during the 
“Treatment” visit.  For randomized subjects, the MitraClip procedure must be completed 
between 1 and 14 days after randomization. 
6.8.1 Anticoagulation and Antibiotic Therapy 
6.8.1.1 
Anticoagulation Therapy 
Discontinue the use of warfarin for at least three (3) days prior to the scheduled MitraClip 
procedure and ensure that the international normalized ratio (INR) is ≤1.7 prior to the 
MitraClip procedure.  Similarly, discontinue dabigatran or factor Xa inhibitors for a 
sufficient duration to ensure restoration of normal coagulation.  Subjects may be treated with 
heparin during this period at the treating physician’s discretion.  If heparin is used, it should 
be discontinued ≥8 hours prior to the MitraClip procedure for subcutaneous low molecular 
weight heparin (LMWH) and ≥4 hours prior to the MitraClip procedure for intravenous 
unfractionated heparin (UFH).  
6.8.1.2 
Clopidogrel 
A loading dose of clopidogrel (≥300 mg) is recommended within 24 hours prior to the 
procedure (6-24 hours prior if possible) or immediately following the procedure.   
Note: A loading dose of clopidogrel may be considered even if the patient is taking 
clopidogrel on a daily basis either at home or in the hospital, as long as no other clopidogrel 
loading dose has been given within 24 hours.  However, clopidogrel use is optional and its 
use is left to the discretion of the investigator.   
Aspirin may also be used at operator discretion. If aspirin is to be used, a loading dose of 325 
mg acetylsalicylic acid (ASA) may be administered either pre- or immediately post-
MitraClip procedure. 

 
 
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6.8.1.3 
Antibiotic Therapy 
Administer a single dose of intravenous broad spectrum antibiotics approximately one hour 
prior to initiation of the procedure. The type of antibiotic is at the Investigator’s discretion. 
6.8.2 MitraClip Procedure  
6.8.2.1 
Pre-Procedural TEE 
Prior to the MitraClip procedure, Device group (after randomization) and roll-in subjects 
must be assessed to ensure there is no significant change in subject’s overall condition (e.g., 
stroke, MI, active infection, endocarditis, hemodynamic instability, etc. post-randomization) 
that would preclude treatment.  If the subject has experienced any significant change that 
would preclude treatment, the subject must be treated and rescheduled for the MitraClip 
procedure as soon as possible.  Subjects are required to complete an additional 
transesophageal (TEE) echocardiogram study within 3 days prior to the procedure to rule out 
the presence of intracardiac mass, thrombus or vegetation.  This echocardiogram may be 
performed immediately preceding initiation of the MitraClip procedure.  This 
echocardiogram will not be submitted to the ECL.  If an intracardiac mass, thrombus or 
vegetation or other change in echocardiographic eligibility is identified in the TEE performed 
immediately preceding the procedure, the subject will be considered registered even if no 
device implant is attempted.  If a thrombus is identified, the subject should be 
pharmacologically treated to resolve the thrombus and, if successful, the subject should be 
reassessed as soon as possible to undergo the MitraClip procedure.  Such subjects will be 
considered registered even if they do not undergo the MitraClip procedure. 
6.8.2.2 
Pre-Procedural ECG and Physical Exam 
A 12-lead ECG and physical exam should be performed within 24 hours prior to the 
procedure. 
6.8.2.3 
Baseline Activated Clotting Time 
Prior to the MitraClip procedure, baseline activated clotting time (ACT) will be determined 
following transseptal puncture for the MitraClip procedure.  ACT and heparin administration 
(or alternative anticoagulation therapy, e.g., bivalirudin) should be recorded. 
6.8.3 Personnel 
The use of transesophageal echocardiography (TEE) requires conscious sedation or general 
anesthesia, depending on hospital standard practice. 

 
 
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If complications arise during the procedure, it may be necessary to convert to an open 
surgical procedure.  Emergency surgical back-up should be available as per the institution’s 
standard procedures. 
The Sponsor will be available to provide technical support to answer questions regarding the 
function and operation of the MitraClip System. 
6.8.4 Subject Preparation 
Subjects will be prepared for the procedure as per the institution’s standard practice for a 
percutaneous procedure and TEE. 
Note:  
Prior to performing the procedure, all Investigators must also undergo 
documented training by the Sponsor on the MitraClip System and the Clinical 
Investigation Plan.  In addition, all Investigators must read and understand the 
Instructions for Use (IFU) that accompanies the Device.   
Femoral vein transseptal catheterization will be completed in accordance with the IFU. 
6.8.5 Anticoagulation Therapy 
Following transseptal crossing, administer intravenous heparin (or alternative anticoagulation 
therapy, e.g., bivalirudin) in accordance with standard hospital practice.  Maintain an ACT 
(activated clotting time) of > 250 seconds throughout the procedure. Low molecular weight 
heparin and fondaparinux may not be used for procedural anticoagulation. 
6.8.6 MitraClip Device Placement Procedure 
The Steerable Guide Catheter (Guide) is inserted into the femoral vein and advanced across 
the transseptal puncture.  Fluoroscopic and echocardiographic guidance will be used during 
the procedure to visualize the devices and the vasculature and cardiac anatomy.  See 
APPENDIX C: Monitoring Exposure to Ionizing for requirements for training and data 
gathering on ionizing radiation required per this Clinical Investigational Plan.  For subjects 
with renal dysfunction, intravenous contrast should not be used during the procedure unless 
absolutely necessary. 
The Guide is positioned over the mitral valve and the MitraClip Delivery System is inserted 
into the Guide and properly positioned over the mitral valve.  The MitraClip Delivery 
Catheter is advanced until the MitraClip device emerges from the tip of the Guide into the 
left atrium.  Manipulations of the catheter tip (via the control knobs on the handles) will 
continue in the left atrium until the MitraClip device is properly oriented perpendicular to the 
line of coaptation of the mitral valve.  The MitraClip device is opened and advanced across 
the mitral valve into the ventricle then pulled back to grasp the leaflets.  Two-dimensional 

 
 
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and/or 3-dimensional echocardiography and color flow Doppler are used to evaluate the 
presence of a double orifice, leaflet insertion, MitraClip device position and residual MR.  If 
the MitraClip device is not positioned properly or MR has not been adequately reduced, 
additional grasping may be attempted and the MitraClip device may be inverted in the left 
atrium as required for additional grasping attempts.  When placement is successful, the 
MitraClip device is closed and deployed from the Delivery Catheter.  The catheters are then 
removed from the subject. 
If placement of one MitraClip device does not result in reduction in MR to a level deemed 
acceptable by the operator, then a second MitraClip device may be placed to further reduce 
MR.  The Investigator should determine if there is adequate mitral valve orifice area to 
accommodate the second MitraClip device without creating mitral stenosis.  In most cases a 
maximum of two (2) MitraClip devices will be allowed to be implanted in subjects registered 
in this trial.  However, a third MitraClip may be used in the special circumstance when one 
or both of the two previous MitraClip devices have detached from one leaflet or when there 
is evidence of inadequate MR reduction with two MitraClip devices during either the 
treatment visit or follow-up.   
6.9 
Post-MitraClip Procedure (Device Group or Roll-in Subjects) 
6.9.1 Subject Management Guidelines 
Immediately following the MitraClip procedure, heparin (or alternative anticoagulation 
therapy, e.g., bivalirudin) should be discontinued and the ACT should be monitored in 
accordance with hospital protocols.  Vascular sheaths should be removed according to usual 
hospital practice. 
Subjects will receive standard post-cardiac catheterization procedure care as judged 
appropriate by the Investigator.  Subjects should be advised to limit strenuous physical 
activity for the first month following the MitraClip procedure or longer, as deemed 
appropriate by the Investigator. 
6.9.2 Antibiotic Therapy 
Administer additional intravenous doses of antibiotics at approximately 6 and 12 hours (or 
per institutional guidelines) after the completion of the procedure. 
The Investigator should instruct all subjects who receive the MitraClip device of the need for 
endocarditis prophylaxis, as recommended in the ACC/AHA 2008 Guideline Update on 

 
 
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Valvular Heart Disease: Focused Update on Infective Endocarditis16.  Subjects should be 
instructed to notify the Investigator or the subject’s primary care physician in the event that a 
procedure recommended by this Guideline is planned, so that prophylactic antibiotics can be 
prescribed.  A prescription for endocarditis prophylaxis may be provided to the subject at 
discharge. 
6.9.3 Antiplatelet/Anticoagulation Regimen 
Following placement of the MitraClip device, anticoagulation therapy is prescribed.  If a 
loading dose of clopidogrel was not given prior to the MitraClip procedure, it may be 
administered after the procedure at investigator discretion.  Post-MitraClip procedure 
anticoagulation is as follows: 
1. Reinitiate warfarin, dabigatran or factor Xa inhibitor (if discontinued for the 
MitraClip procedure) at pre-procedure levels or as appropriate.  If chronic oral 
anticoagulation is used, aspirin and clopidogrel use are not recommended, but are 
allowed if otherwise indicated for other conditions. 
2. If chronic oral anticoagulation is not used, it is strongly recommended that either 
daily clopidogrel (75 mg) and/or aspirin (81 mg) is administered for 6 months or 
longer. If aspirin is to be used, a loading dose of 325 mg acetylsalicylic acid (ASA) 
may be administered either pre- or immediately post-MitraClip procedure followed 
by 81 mg per day for 6 months or longer at the Investigator’s discretion. 
6.9.4 Management of Hypertension 
Subjects should have their blood pressure checked prior to discharge.  Subjects should be 
prescribed medication as necessary following current standard of care to maintain 
normotensive blood pressure. 
6.9.5 Vital Signs 
Vital signs (i.e., weight, blood pressure, heart rate, temperature) will be obtained prior to 
subject discharge from the hospital. 
                                                 
16 Nishimura, et al.  ACC/AHA 2008 Guideline Update on Valvular Heart Disease: Focused Update on 
Infective Endocarditas: A Report of the American College of Cardiology/American Heart Association Task 
Force on Practice Guidelines: Endorsed by the Society of Cardiovascular Anesthesiologists, Society for 
Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.  Circulation 2008; 
118(8):887-894. 

 
 
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6.9.6 Implant Identification Card 
At discharge, each subject implanted with a MitraClip device(s) must be provided an Implant 
Identification Card.  An Implant Identification Card is included in the package with each 
MitraClip System.  The subject should be instructed to keep this Implant Identification Card 
on their person at all times.  The serial number of all implanted MitraClip device(s) should be 
recorded on the Implant Identification Card. 
6.9.7 Procedural and Discharge Data 
The following MitraClip procedural information should be recorded on the appropriate 
eCRF(s) after implant or attempted implant of the MitraClip device: 
• General procedure information  
• MitraClip implant information 
• Laboratory and clinical tests 
• Antiplatelet/Anticoagulation medications  
• Concomitant cardiovascular medications  
• Fluoroscopy duration 
• Adverse events  
• Protocol deviations  
• Device deficiency 
At the Discharge visit (Discharge occurs when subject leaves the implanting hospital), the 
following required tests and procedures should be completed (> 16 hours post MitraClip 
procedure and no later than day of discharge) as outlined below, and the information should 
be captured on the appropriate eCRFs: 
• 12-lead ECG 
• Blood draw 
• Brief physical exam including vital signs (weight, heart rate, blood pressure and 
temperature) 
• Echocardiogram (TTE) - discharge TTE must be performed at least 16 hours post 
MitraClip procedure and no later than 24 hours post-discharge 

 
 
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• Modified Rankin Scale 
• Adverse events  
• Protocol deviations  
• Device deficiency 
Instructions for the TTE are provided in this investigational plan and are located in 
APPENDIX B: Echocardiography Protocol. 
6.10 
“Treatment” Visit (Control Group) 
The “Treatment” visit in the Control group must occur between 1 and 14 days after 
randomization.  At the “Treatment” visit, Control group subjects will be seen by the HF 
specialist investigator, and will undergo a physical exam, including vital signs, cardiac health 
status and evaluation of heart failure medications.   
6.11 
Clinical Follow-up (All registered subjects) 
Follow-up visits are required at 1 week (phone contact), 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter through 5 years.  For all randomized subjects, 
follow-up visits will be calculated from the date of the “Treatment” visit and for roll-in 
subjects, follow-up visits will be calculated from the date of the index procedure.  Follow-up 
assessments can be performed at any point in the window, and should be conducted, 
whenever possible, by the same individual who performed the baseline tests.  The subject 
should be followed at the investigational site where the subject was registered, and may be 
followed at another investigational site only with prior agreement from that site’s 
Investigator and from the Sponsor. 
Subjects should have their blood pressure checked at each scheduled in-clinic visit.  Subjects 
should be prescribed medication as necessary following current standard of care to maintain 
normotensive blood pressure. 
All subjects, regardless of randomization assignment or roll-in designation, should continue 
to be monitored and treated per applicable standards of care consistent with the subject’s 
condition.  All subjects must be followed by the heart failure specialist investigator at all 
scheduled follow-up visits.  Subjects implanted with the MitraClip device must also be 
evaluated for device integrity.  The site Principal Investigator should collaborate with the 
other site investigators as applicable in determining the treatment strategy for all subjects 
registered at their site.  The electronic case report forms will document changes in treatment 
strategy (i.e. new use of CRT, PCI, and mitral valve surgery) and who was involved with 
determining changes in treatment strategy.   

 
 
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Study personnel administering the 6MWT and QoL questionnaires from baseline through 24 
months excluding the 18-month visit and assessing NYHA Functional Class from baseline 
through the 5 year visit will be blinded, i.e., will not have access to the eCRF and will not 
have knowledge of the subject’s treatment assignment.  Additionally, a standardized script 
will be used when administering the assessments and the subject will be reminded to not 
reveal their treatment history to the administrator (See Section 10.14 Measures Taken to 
Avoid and Minimize Bias During Study Conduct for additional information).   
To support the primary effectiveness endpoint analysis, clinical sites and all randomized 
subjects (or their identified contacts) will be contacted to determine each subject’s survival 
status and date(s) of last known heart failure hospitalizations.  This data sweep of death and 
heart failure hospitalizations will be conducted when the last randomized subject has passed 
the upper limit of the window for the 12-month follow-up period (i.e., 395 days after 
enrollment).  The sweep contact is not needed for subjects who had a follow-up visit within 
30 days of the sweep date, or for subjects who already completed their 24-month follow-up 
visit.  
6.11.1 1-Week Phone Contact 
All subjects will be contacted by telephone at the 1-week visit.  Sites will follow a 
standardized script for all subjects to minimize bias.  Additionally, for Device group or roll-
in subjects who underwent the MitraClip procedure, the script will include a query about 
adverse events, including suspected skin injury.   
6.11.2 30-Day, 6-Month, 12-Month, 18-Month and 24-Month Visits 
During the physical examination at the 30-day follow-up clinic visit, the implanting or 
treating investigator shall examine the integrity of the Device group or roll-in subject’s skin 
at or near the beam entrance site for subjects that have undergone a MitraClip procedure.  At 
the 30-day, 6-month, 12-month, 18-month and 24-month follow-up visits, all subjects must 
be examined by the heart failure specialist investigator.  Subjects must continue to take 
baseline medications without change during follow-up, unless clinically (medically) 
necessary.  If there are any cardiovascular medication changes (including dosage changes), 
these changes, and the reason for change must be documented on the electronic case report 
form.  In general, neurohormonal antagonists should not be changed. Subjects implanted with 
the MitraClip device must also be evaluated for device integrity.  Required tests and 
procedures outlined below must be completed. All visits and tests must be completed even if 
the subject is in hospital.   
• 12-lead ECG 
• Blood draw 

 
 
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• Brief physical exam including vital signs (weight, heart rate, blood pressure and 
temperature) 
• Echocardiogram (TTE) 
• Modified Rankin Scale (Assessment of mRS should additionally be done at 90 days 
after onset of stroke) (not required after 12 months) 
• 6-Minute Walk Test (6MWT) (not required at 18 months) – See APPENDIX E: ATS 
6 Minute Walk Test Guidelines – must be administered by “blinded” study 
personnel 
• Concomitant cardiovascular medications assessment 
• NYHA Functional Class assessment – must be administered by “blinded” study 
personnel 
• QoL questionnaires to be completed by the subject (not required at 18 months) – must 
be administered by “blinded” study personnel; Note: To minimize bias and undue 
influence, the QoL questionnaires will be completed by the subject, unless the subject 
is unable to complete the questionnaire on their own (in such cases, a note to file must 
be completed to document the inability of subject to complete the questionnaire) 
• Assess and record adverse events  
• Assess and record protocol deviations  
Instructions for the TTE are provided in APPENDIX B: Echocardiography Protocol. 
6.11.3 3, 4 and 5 Year Visits 
Medications should be recorded and required tests and procedures outlined below should be 
completed.  All subjects must be examined by the heart failure specialist investigator.  
Subjects must continue to take baseline medications without change during follow-up, unless 
clinically (medically) necessary.  If there are any cardiovascular medication changes 
(including dosage changes), these changes, and the reason for change must be documented 
on the electronic case report form.  In general, neurohormonal antagonists should not be 
changed.  Subjects implanted with the MitraClip device must also be evaluated for device 
integrity.  Required tests and procedures outlined below must be completed.  All visits and 
tests must be completed even if the subject is in hospital. 
• 12-lead ECG 
• Brief physical exam including vital signs (weight, heart rate, blood pressure and 
temperature) 

 
 
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• Concomitant cardiovascular medications assessment 
• Echocardiogram (TTE) 
• NYHA Functional Class assessment 
• Assess and record adverse events  
• Assess and record protocol deviations  
Instructions for the TTE are provided in APPENDIX B: Echocardiography Protocol. 

 
 
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Figure 3: Trial Flowchart 
Subject 
meets I/E 
Subject Selection 
Site investigator/coordinator identifies potential subject 
Screening informed consent* obtained and eligibility assessed by site investigator/coordinator 
Subject has in-person visit with HF specialist investigator to confirm subject is on optimal therapy including GDMT 
Subject has in-person visit with CT Surgeon investigator 
Subject evaluated by Local Site Heart Team to confirm that mitral valve surgery is not appropriate  
Echocardiographic image (TTE) obtained and submitted to Echocardiography Core Lab 
Subject’s pertinent medical history compiled for submission to Eligibility Committee 
*Or per site standard practice for informed consent. 
Echocardiography 
 Core Lab 
Subject approved? 
Subject is a screen failure 
Eligibility Committee 
Subject approved? 
Site reconfirms subject meets all 
eligibility criteria? 
Full Informed Consent Obtained* 
*Or per site standard practice for 
informed consent 
Baseline Visit 
Medical history, physical exam, blood tests, 6MWT, QoL questionnaires, NYHA Functional Class, 
Concomitant heart failure medications, 12-lead ECG, Frailty Index, TTE, BNP/NT-pro BNP level, modified 
Rankin Scale 
Clinical Follow-up with HF specialist and Echo Follow-up at 1 week (phone only), 30 Days, 6, 12, 18 
and 24 Months, 3, 4, 5 Yrs post-“Treatment” visit  
See Table 2 for required tests and procedures at each visit 
“Treatment” Visit: Device 
procedure and Discharge 
“Treatment” Visit: Clinical follow-
up with HF specialist 
MitraClip Device 
(Device Group) 
Randomization 1:1 
Device or Control (Subject Enrolled) 
No MitraClip Device 
(Control Group) 
Yes 
No 
No 
Yes 
Yes 
Yes 
Yes 
No 
No 
No 

 
 
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After the “Treatment” visit, the investigational sites will be provided the target date and 
required follow-up window time-frames for each subject in the electronic data capture 
system.  Follow-up windows are summarized in Table 1: Follow-up Schedule* and 
Windows for Registered Subjects.  All data required for follow-up must be collected within 
the window for that scheduled visit, and not necessarily on the same day. 
Table 1: Follow-up Schedule* and Windows for Registered Subjects 
Follow-Up Visit 
Window Start 
Day 
Target Day 
Window Close 
Day 
Follow up 
Method 
Discharge 
(Device group 
only) 
NA 
Discharge date 
NA 
In hospital or 
Site visit 
1 Week  
(-1 /+3 days) 
6  
7  
10  
Phone contact 
30 Days 
(-3 /+14 days) 
27 
30 
44 
Site visit 
6 Months 
(±30 days) 
152 
182 
212 
Site visit 
12 Months 
(-14/+30 days) 
351 
365 
395 
Site visit 
18 Months 
(±30 days) 
518 
548 
578 
Site visit 
24 Months 
(±30 days) 
701 
731 
761 
Site visit 
3 Years 
(±45 days) 
1051 
1096 
1141 
Site visit 
4 Years 
(±45 days) 
1416 
1461 
1506 
Site visit 
5 Years 
(±45 days) 
1781 
1826 
1871 
Site visit 
* Follow-up visit dates are calculated from the “Treatment visit” for randomized subjects and from the index 
procedure for roll-in subjects 
Echocardiography images (TTE) obtained at each follow-up visit should be submitted to the 
Sponsor in a timely manner.  The ECL will provide feedback to sites regarding quality of 
images obtained. 
During the follow-up period, if a subject requires a cardiac procedure (i.e. MV surgery, 
permanent LVAD, heart transplant, additional MitraClip procedure, etc.) which may or may 
not result in explant of the MitraClip device, the subject will remain in the trial and continue 
to be followed. 
Subjects who do not have a scheduled follow-up visit will be documented as having a missed 
visit and a Protocol Deviation will be completed.  The investigator will keep a record of 

 
 
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documented follow-up attempts in the subject’s study file.  Refer to Section 10.10 Protocol 
Deviations for additional information. 
Table 2 provides a complete listing of required tests and procedures for all subjects through 
the trial follow-up period. 

 
 
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Table 2: Clinical Evaluation Schedule for Registered Subjects 
Items 
Screening/ 
Baseline 
Randomization 
Assignment 
(For randomized 
Subjects only) 
Treatment 
Visit (Control 
Group 
Treatment 
Visit (Device 
Group or 
Roll-in) 
Discharge 
(Device 
Group or 
Roll-in) 
1-Week 
Phone 
Contact 
30-Daysd, 
6, 12, 18, 24 
Months 
3, 4, 5 
Years 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
within 90 days 
pre-registration 
 
 
 
 
 
 
 
Evaluation by Local Heart 
Team including HF 
Specialist Investigator and 
CT Surgeon Investigator 
(in-person consult with HF 
specialist and CT Surgeon 
investigators is required). 
X 
within 90 days 
pre-registration 
 
X 
 
 
 
X 
X 
Components of Frailty 
Index 
X 
within 14 days 
pre-registration 
 
 
 
 
 
 
 
STS Risk Score 
X 
within 90 days 
pre-registration 
 
 
 
 
 
 
 
Modified Rankin Scalea 
X 
within 14 days 
pre-registration 
 
 
 
X 
 
X 
not required after 
12-month visit 
 
Physical Examination & 
Vital Signs:  
 
 
 
 
 
 
 
 
(height (at Baseline only), 
weight, heart rate, blood 
pressure and temperature) 
X 
within 14 days 
pre-registration 
 
X 
X 
within 24 hours pre-
procedure 
X 
 
X 
X 
Concomitant 
Cardiovascular 
Medications 
X 
 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
within 90 days 
and 14 days pre-
registration  
 
 
X 
within 24 hours pre-
procedure 
X 
 
X 
X 
Transthoracic 
Echocardiogramb 
X 
within 90 days 
pre-registration 
 
 
 
X 
 
X 
X 

 
 
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Items 
Screening/ 
Baseline 
Randomization 
Assignment 
(For randomized 
Subjects only) 
Treatment 
Visit (Control 
Group 
Treatment 
Visit (Device 
Group or 
Roll-in) 
Discharge 
(Device 
Group or 
Roll-in) 
1-Week 
Phone 
Contact 
30-Daysd, 
6, 12, 18, 24 
Months 
3, 4, 5 
Years 
Transesophageal 
Echocardiogram 
X 
within 180 days 
pre-registration 
 
 
X 
within 3 days pre-
procedure 
 
 
 
 
Albumin  
X 
within 14 days 
pre-registration 
 
 
 
 
 
 
 
CBC with differentials and 
platelet count 
Serum Creatinine 
PTT or PT or INR 
CK, CK-MB 
X 
within 14 days 
pre-registration 
 
 
 
X 
 
X 
 
BNP or NT-proBNPc 
X 
within 90 days 
pre-registration 
 
 
 
 
 
X  
 
6 Minute Walk Test 
Quality of Life 
Questionnaires (KCCQ 
and SF-36) 
X 
within 14 days 
pre-registration 
(by blinded 
study personnel) 
 
 
 
 
 
X 
(by blinded study 
personnel) 
not required at 
18-month visit 
 
NYHA Functional Class 
X 
within 90 days 
and 14 days pre-
registration  
(by blinded 
study personnel) 
 
 
 
 
 
X  
(by blinded study 
personnel) 
X 
(by blinded study 
personnel) 
Inquiry of Subject Status 
 
 
 
 
 
X 
 
 
Adverse Events 
 
Xe 
X 
X 
X 
X 
X 
X 
a     Assessment of mRS should also be done 90 days after onset of stroke 
b TTE for the purpose of determining eligibility must be obtained after the subject has been stabilized on optimal therapy including GDMT and undergone 
revascularization and/or CRT, as appropriate (see APPENDIX A: Definitions for definition of optimal therapy and GDMT), and submitted to the ECL. A TTE must 
also be performed within 90 days prior to any additional MitraClip procedure or mitral valve surgery.      
c     BNP or NT-proBNP must be measured after the subject has been stabilized on GDMT and undergone revascularization and/or CRT, as appropriate (see APPENDIX 
A: Definitions for definition of GDMT) 
d    A 30-day visit should be performed 30 days after mitral valve surgery or MitraClip procedure in the Control group and after mitral valve surgery or additional 
MitraClip procedure in Device group or roll-in subjects per the requirements specified in Section 6.13.1 30-Day Post-MitraClip Follow-up and Section 6.14.1 30-
Day Post-Mitral Valve Surgery Follow-up. 
e     Adverse events must be collected upon trial registration for roll-in and randomized subjects 
NOTE:  When the last randomized subject has passed the upper limit of the window for the 12-month follow-up, subjects (or their identified contacts) will be contacted to 
determine survival status and date(s) of last known heart failure hospitalizations.  See Section 6.11 Clinical Follow-up (All registered subjects) for details.  

 
 
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6.12 
Heart-Related Office Visits  
A Heart-Related Office Visit eCRF should be completed if a subject is seen for a heart-
related reason at the investigational site or at any other facility.  Information pertaining to 
adverse events, heart failure medication changes or hospitalizations, as appropriate, should 
also be collected.   
If an echocardiographic imaging study is performed at any visit, whether or not it is a study 
related visit, echocardiography images should be submitted to the ECL in a timely manner.  
6.13 
MitraClip Intervention in Control Group Subjects or Additional MitraClip 
Intervention in Device Group or Roll-in Subjects 
Control group subjects will not be allowed to undergo the MitraClip procedure prior to 
completion of the 24-month visit.  MitraClip intervention in the Control group prior to the 
24-month visit will be considered a major protocol deviation.  Prior to MitraClip procedure 
attempt in a Control group subject upon completion of 24-month visit, the following must be 
verified:  
• The primary regurgitant jet must be non-commissural, and in the opinion of the 
MitraClip implanting investigator can be successfully be treated by the MitraClip.  If 
a secondary jet exists, it must be considered clinically insignificant 
• Mitral valve orifice area must be ≥4.0 cm2  
• Leaflet anatomy must not preclude MitraClip implantation, proper MitraClip 
positioning on the leaflets or sufficient reduction in MR by the MitraClip 
• No echocardiographic evidence of intracardiac mass, thrombus or vegetation 
It may be necessary for a Device group or roll-in subject to undergo additional MitraClip 
procedures.  A TTE must be performed within 90 days prior to a MitraClip procedure in 
either group.  A 30-Day Post-MitraClip Follow-up visit must be completed 30 days (-3 /+14 
days) after the additional MitraClip procedure.  This visit should still be completed even if 
the subject is in hospital. Requirements for this visit are described in Section 6.13.1 30-Day 
Post-MitraClip Follow-up.   
6.13.1 30-Day Post-MitraClip Follow-up 
Requirements for the 30-day Post-MitraClip Follow-up visit are described below. 
• 12-lead ECG 
• Blood draw 

 
 
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• Brief physical exam including vital signs (weight, heart rate, blood pressure and 
temperature) 
• Echocardiogram (TTE) 
• Modified Rankin Scale (Assessment of mRS should additionally be performed at 90 
days after onset of stroke) 
• Concomitant cardiovascular medications assessment 
• NYHA Functional Class assessment 
• Assess and record adverse events  
• Assess and record protocol deviations 
Instructions for the TTE are provided in APPENDIX B: Echocardiography Protocol. 
6.14 
Mitral Valve Surgery 
For inclusion into this trial, all subjects prior to registration are deemed not appropriate for 
mitral valve surgery.  Mitral valve surgery in either group is not allowed at any time during 
follow-up.  Mitral valve surgery in either group will be considered a protocol deviation, 
unless the subject experiences a complication (e.g., endocarditis, clip detachment, or leaflet 
injury from the MitraClip procedure).  Subjects who undergo mitral valve surgery will 
continue to be followed per this Clinical Investigational Plan.  A TTE must be performed 
within 90 days prior to mitral valve surgery.     
A 30-Day Post-Mitral Valve Surgery Follow-up visit must be completed 30 days (-3 /+14 
days) after the mitral valve surgery.  This visit should still be completed even if the subject is 
in hospital. Requirements for this visit are described in Section 6.14.1 30-Day Post-Mitral 
Valve Surgery Follow-up. 
6.14.1 30-Day Post-Mitral Valve Surgery Follow-up 
Requirements for the 30-day Post-Mitral Valve Surgery Follow-up visit are described below. 
• 12-lead ECG 
• Blood draw 
• Brief physical exam including vital signs (weight, heart rate, blood pressure and 
temperature) 
• Echocardiogram (TTE) 

 
 
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• Modified Rankin Scale (Assessment of mRS should additionally be performed at 90 
days after onset of stroke) 
• Concomitant cardiovascular medications assessment 
• NYHA Functional Class assessment 
• Assess and record adverse events  
• Assess and record protocol deviations 
Instructions for the TTE are provided in APPENDIX B: Echocardiography Protocol. 
6.15 
Explanted MitraClip Device  
The MitraClip device may be explanted during mitral valve surgery or an autopsy.  If 
possible, fluoroscopic images with side views of the device should be obtained prior to 
explant.  Following explant of the MitraClip device(s) during surgery, the subject will 
continue to be followed as defined in Table 1: 
Follow-up Schedule* and Windows 
for Registered Subjects.  Explant information will be captured on the Mitral Valve Surgery 
Form or Death Form.   
6.16 
Subject Discontinuation 
Each registered subject shall remain in the trial until the 5-year follow-up visit; however, a 
subject’s participation in any clinical trial is voluntary and the subject has the right to 
withdraw at any time without penalty or loss of benefit.  Conceivable reasons for 
discontinuation may include, but not be limited to, the following: 
• Subject death 
• Subject voluntary withdrawal  
• Subject’s follow-up is terminated according to Section 6.17 Early Termination of 
the Clinical Trial. 
Investigators should meet with the subject if there is any consideration of withdrawal.  The 
Sponsor must be notified of subject discontinuation and the reason for discontinuation on the 
electronic Case Report Form (eCRF).  Investigators must also report the withdrawal to their 
IRB/EC as defined by their institution’s procedure.  Discontinued subjects will not be 
replaced.  However, if a subject withdraws from the study due to problems related to the 
investigational device safety or performance, the investigator shall ask for the subject’s 
permission to follow his/her status/condition outside of the clinical evaluation. 

 
 
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6.16.1 Lost-to-Follow-up 
If the subject misses two consecutive scheduled follow-up visits, and attempts at contacting 
the subject detailed below are unsuccessful, then the subject is considered lost to follow-up.  
Site personnel shall make all reasonable efforts to locate and communicate with the subject 
(and document these efforts in the source documents), including the following, at each 
follow-up visit: 
A minimum of 3 telephone calls on different days over the specified follow-up windows to 
contact the subject should be recorded in the source documentation, including date and 
initials of site personnel trying to make contact. 
If these attempts are unsuccessful, a certified or registered letter with confirmed receipt 
should be sent to the subject. 
If a subject misses one or more non-consecutive follow-up visits, these will be considered 
missed visits.  The subject may then return for subsequent visits.  If the subject misses two 
consecutive follow-up visits and the above-mentioned attempts at communicating with the 
subject are unsuccessful, the subject will be considered lost-to-follow-up. 
Note:  
Telephone contact with General Practitioner, non-study cardiologist or relative 
without presence of subject, or indirect documentation obtained via discharge 
letters will not be considered as subject contact. 
Until trial completion, sites shall continue to obtain vital status for lost-to-follow subjects 
from death registries or social security index, as applicable, and document in the eCRF. 
6.17 
Early Termination of the Clinical Trial 
The Sponsor reserves the right to discontinue this clinical investigation at any stage or reduce 
the follow-up period with suitable written notice to the investigator.  Possible reason(s) 
include: 
• Unanticipated adverse device effect (UADE) occurs and it presents an unreasonable 
risk to subjects. 
• The Steering Committee makes a decision for the early termination of the clinical 
trial per Data Monitoring Committee (DMC) recommendation (such as high 
frequency of anticipated adverse device effects). 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor 
or company representative will attempt to secure compliance by one or more of the following 
(and not limited to): 
• Visiting the investigator  

 
 
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• Telephoning the investigator  
• Corresponding with the investigator  
Repeated non-compliance with the Clinical Investigational Plan or any other conditions of 
the study may result in further escalation in accordance with the Sponsor’s written 
procedures including securing compliance or, at its sole discretion, Sponsor may terminate 
the investigator's participation in the study. 
6.18 
Trial Completion  
The trial will be completed when all subjects have either completed a 5-year follow-up visit 
or withdrawn from the trial.  A subject is considered to have completed participation in the 
trial: 
• if the subject is considered lost to follow-up per the above definition or  
• if the subject withdraws from the clinical trial or 
• if the subject has died prior to completion of 5-year follow-up or 
• upon completion of 5-year follow-up  
6.19 
Trial Closure 
Upon trial completion, the Sponsor and/or its designees will notify the sites.  Trial closeout 
visits will be performed.  All unused devices and any unused trial materials and equipment 
will be collected and returned to the Sponsor and/or its designees.  The monitors will ensure 
that the investigator’s regulatory files are up to date and complete, that database queries are 
resolved, and that any outstanding issues from previous visits have been resolved.  Other 
issues that will be reviewed at this visit include: discussing record retention requirements 
(refer to Section 11.3 Site Record Retention), device accountability, possibility of site 
audits, publication policy, and notifying the IRB/EC of study closure, etc. 
7 Statistical Methods 
There are two co-primary safety and effectiveness endpoints in this trial and several 
secondary safety and effectiveness endpoints.     
 

 
 
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7.1 
Analysis Populations  
7.1.1 Intention to Treat (ITT) Population  
The Intention to Treat population will consist of all subjects randomized in the trial.  All 
subjects will be analyzed in the group randomized regardless of the treatment actually 
received.  
7.1.2 Per Protocol Population  
The Per Protocol (PP) cohort will consist of subjects who meet all inclusion and none of the 
exclusion criteria for the trial, and receive the treatment as randomized.  Subjects who are 
randomized to Device group but refuse to receive the treatment, or subjects in the Device or 
Control group who fail to return for the “Treatment” visit within the pre-specified window 
will be excluded from the Per Protocol cohort.  For subjects in either group who undergo 
other interventions for heart failure (e.g. mitral valve surgery, LVAD/CRT implant, heart 
transplant), follow-up data after the date of the intervention will be excluded from analysis.  
Similarly, for subjects in the Control group who receive the MitraClip device, follow-up data 
after the date of the procedure will be excluded from analysis. 
7.1.3 As Treated Population  
The As Treated cohort is defined to consist of randomized subjects who receive treatment as 
randomized. Subjects who are randomized to the Device group but have an unsuccessful 
implant will be analyzed in the Device group of the As Treated cohort. Subjects who are 
randomized to the Device group but refuse to receive the treatment will be excluded from 
analyses of the As Treated cohort. For subjects who undergo other interventions for heart 
failure (e.g. mitral valve surgery, LVAD/CRT implant, heart transplant) in either group, 
follow-up data after the date of the intervention will be excluded from analysis.  Similarly, 
for subjects in the Control group who receive the MitraClip device, follow-up data after the 
date of the procedure will be excluded from analysis. 
7.2 
Primary Endpoints 
7.2.1 Primary Safety Endpoint 
A composite of Single Leaflet Device Attachment (SLDA), device embolizations, 
endocarditis requiring surgery, Echocardiography Core Laboratory confirmed mitral stenosis 
requiring surgery, LVAD implant, heart transplant, and any device related complications 
requiring non-elective cardiovascular surgery will be the primary measure of safety.  The 
analysis of the primary safety endpoint is a comparison of the freedom from the composite of 
Device related safety events in the Device group at 12 months to a pre-specified performance 
goal of 88%. 

 
 
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Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: PD(12) ≤ 88% vs. 
H1: PD(12) > 88% 
where PD(12) is freedom from the primary safety composite in the Device group at 12 
months.  A one-sided Z-test will be performed to test the null hypothesis against the 
alternative hypothesis.  Kaplan-Meier survival estimate at 12 months, together with the 
variance estimated using the Greenwood formula, will be used to calculate the Z-statistic.  
The null hypothesis will be rejected at the 5% significance level if the Z-statistic is greater 
than 1.645. 
Analysis: 
Since the primary safety endpoint will be evaluated at 12 months, all data will be truncated at 
12 months for the analysis.  The Kaplan Meier survival estimate, together with variance 
estimated by the Greenwood method17 will be used to set up the test of the null hypothesis as 
a Z-test.  The null hypothesis will be rejected at the 5% level of significance if the test 
statistic is greater than 1.645. 
The primary analysis will be performed in all Device group subjects in whom a MitraClip 
procedure is attempted.  Additional analyses, including sensitivity analyses, are detailed in 
the Statistical Analysis Plan. 
7.2.2 Primary Effectiveness Endpoint  
Treatment with the MitraClip device is expected to reduce the risk of recurrent HF 
hospitalization.  Recurrent HF hospitalization is the primary effectiveness endpoint for the 
trial. 
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: RRR ≤ 0 vs.  
H1: RRR > 0 
where RRR is the relative risk reduction in the rate of recurrent HF hospitalization due to 
treatment with the MitraClip device.  Hospitalizations that are adjudicated by the CEC as 
                                                 
17 Lee, Elisa T. (2003) Statistical Methods for Survival Data Analysis – 3rd Edition (Wiley Series in Probability 
and Statistics). 

 
 
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related to heart failure using the pre-specified Clinical Investigational Plan definition will be 
included as events in the analysis. 
Analysis: 
The primary analysis will be an ITT analysis.  The Joint Frailty Model method will be used 
to model the recurrent heart failure hospitalization data and estimate the RRR.   
The primary effectiveness endpoint will be analyzed when the last subject completes 12 
months of follow-up.  All available follow-up through 24 months at the time of data cut-off 
will be included in the analysis.  Subjects who do not experience any HF hospitalizations will 
be censored on their data cut-off date.  Subjects who die will be censored on the date of 
death.  Subjects who withdraw from the trial will be censored on the date of withdrawal. 
The null hypothesis is rejected if the regression coefficient for the Device group is significant 
at the 5% level of significance.  Beneficial treatment effect is established if the lower one-
sided 95% confidence limit of the relative risk reduction is greater than zero. 
A sensitivity analysis will be performed, in which this endpoint will be analyzed to include 
Unplanned Heart Failure visits in addition to heart failure hospitalizations (see definition of 
Unplanned Heart Failure visits in APPENDIX A: Definitions).  Additional sensitivity 
analyses are detailed in the Statistical Analysis Plan. 
7.3 
Secondary Safety Endpoints   
The following two secondary endpoints will be used as secondary measures of safety. Power 
analysis of the secondary safety endpoints are detailed in the Statistical Analysis Plan.  
7.3.1 
Composite 30-Day Secondary Safety Endpoint  
A composite of all-cause death, stroke, MI, or non-elective cardiovascular surgery for device 
related complications in the Device group at 30 days will be used as a secondary measure of 
safety.  The analysis of this secondary safety endpoint is a one-group test against an objective 
performance goal for the proportion of subjects in the Device group free from the composite 
of secondary safety events at 30 days. 
Hypothesis: 
The null and alternative hypotheses may be stated as: 
H0: PD(30) ≤ 0.80 vs.  
H1: PD(30) > 0.80 
where PD(30) is the proportion of subjects in the Device group free from the composite of 
secondary safety events at 30 days post procedure.  A performance goal of 80% is set under a 

 
 
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conservative assumption that the event rate of the composite is obtained additively from the 
individual components. 
Analysis: 
The primary analysis will be performed in all Device group subjects who undergo the 
MitraClip procedure.  An exact test for a single proportion will be performed at the 5% level 
of significance. 
7.3.2 
All-Cause Mortality at 12 Months 
The relative risk of all-cause mortality at 12 months between the Device and Control groups 
is a secondary measure of safety. 
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: RR ≥ 1.5 vs. 
H1: RR < 1.5 
where RR is the relative risk of all-cause mortality at 12 months between the Device and 
Control groups. 
Analysis: 
The primary analysis will be an ITT analysis.  Follow-up will be truncated at 12 months.  A 
Cox regression model will be used to estimate RR using the hazard ratio.  The null 
hypothesis will be rejected at the 5% significance level if the 95% upper confidence bound 
for RR is less than 1.5. 
7.4 
Secondary Effectiveness Endpoints 
The following secondary endpoints will be used as secondary measures of effectiveness 
between the Device group and the Control group. Details of the analyses for the secondary 
effectiveness endpoints can be found in the Statistical Analysis Plan. 
7.4.1 MR Severity at 12 Months 
Subjects in the Device group are expected to experience greater reduction in MR severity 
than subjects in the Control group. 

 
 
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Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: Categorization of MR severity at 12 months is independent of treatment vs.  
H1: Categorization of MR severity at 12 months is not independent of treatment  
7.4.2 Change in Six-Minute Walk Test Distance (6MWD) at 12 Months over Baseline 
Improvement in the 6MWD at 12 months from baseline is an important secondary 
effectiveness endpoint in the comparison of the Device group to the Control group.  See 
Section 10.14 Measures Taken to Avoid and Minimize Bias During Study Conduct for 
measures taken to minimize bias in assessment of the 6MWD.  If a subject does not complete 
a 6MWT, the reason for not completing the test will be documented. 
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: µT, Δ6MWD - µC, Δ6MWD ≤ 0 vs.  
H1: µT, Δ6MWD - µC, Δ6MWD > 0 
where µT, Δ6MWD and µC, Δ6MWD represent the mean change in distance walked between 12 
months and baseline in the Device and Control groups respectively.  This endpoint will be 
evaluated at the 5% level of significance.  In addition to a significant p-value for this 
analysis, the point estimate of the difference in mean improvement between the two groups 
(Device – Control) should be at least 24 meters to meet this endpoint. 
7.4.3 Change in Quality of Life (Kansas City Cardiomyopathy Questionnaire, KCCQ) 
at 12 Months over Baseline 
Improvement in quality of life as measured by the KCCQ Test at 12 months from baseline 
will be a secondary effectiveness endpoint in the comparison of the Device group to the 
Control group.  See Section 10.14 Measures Taken to Avoid and Minimize Bias During 
Study Conduct for measures taken to minimize bias in assessment of quality of life.  If a 
subject does not complete the KCCQ, the reason for not completing the test will be 
documented. 
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: µD, ΔKCCQ - µC, ΔKCCQ ≤ 0 vs.  

 
 
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H1: µD, ΔKCCQ - µC, ΔKCCQ > 0 
where µD, ΔKCCQ and µC, ΔKCCQ represent the mean change in quality of life score between 12 
months and baseline in the Device and Control groups respectively.  This endpoint will be 
evaluated at the 5% level of significance.  In addition to a significant p-value for this 
analysis, the point estimate of the difference in mean improvement between the two groups 
(Device – Control) should be at least 5 units to meet this endpoint. 
7.4.4 Change in LVEDV at 12 Months over Baseline 
Reduction in MR severity with the MitraClip device is expected to be associated with 
reduction in LVEDV. 
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: µD, ΔLVEDV - µC, ΔLVEDV ≥ 0 vs.  
H1: µD, ΔLVEDV - µC, ΔLVEDV < 0 
where µD, ΔLVEDV and µC, ΔLVEDV represent the mean change in left ventricular end diastolic 
volumes at 12 months over baseline in the Device and Control groups, respectively. 
7.4.5 NYHA Functional Class at 12 Months 
Reduction in MR severity with the MitraClip device is expected to be associated with 
improvement in NYHA Functional Class.  NYHA Functional Class at 12 months will be 
compared between the Device and Control groups. 
Hypothesis: 
The null and alternative hypotheses may be stated as: 
H0: PD, NYHA I/II - PC, NYHA I/II ≤ 0 vs. 
H1: PD, NYHA I/II - PC, NYHA I/II > 0 
where PD, NYHA I/II and PC, NYHA I/II represent the proportion of alive subjects with NYHA Class 
I/II at 12 months in the Device and Control groups, respectively. 

 
 
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7.4.6 Finkelstein-Schoenfeld Analysis of All-Cause Death and Recurrent HF 
Hospitalization 
A hierarchical composite of all-cause death and recurrent HF hospitalization will be analyzed 
using the Finkelstein-Schoenfeld18 method. 
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: λD,Death = λC,Death AND λD,Hosp = λC,Hosp 
H1: λD,Death ≠ λC,Death OR λD,Hosp ≠ λC,Hosp 
Where λD,Death and λC,Death represent the rate of all-cause mortality in the Device group and 
Control group, respectively.  λD,Hosp and λC,Hosp represent the rate of recurrent HF 
hospitalizations in the Device group and Control group, respectively. 
This endpoint will be analyzed when the last subject completes 12 months of follow-up.  All 
available follow-up through 24 months at the time of data cut-off will be included in the 
analysis.  The composite endpoint will be analyzed at the 5% level of significance using the 
method of Finkelstein and Schoenfeld with death higher in the hierarchy than recurrent HF 
hospitalizations.   
7.4.7 Recurrent Hospitalization - All-Cause 
Treatment with the MitraClip device may reduce the risk of recurrent all-cause 
hospitalization.   
Hypothesis: 
The null and alternative hypotheses are stated as: 
H0: RRR ≤ 0 vs.  
H1: RRR > 0 
where RRR is the relative risk reduction in the rate of recurrent hospitalization due to 
treatment with the MitraClip device.  All hospitalizations will be included as events in the 
analysis. 
                                                 
18 D. M. Finkelstein and D. A. Schoenfeld, Combining Mortality and Longitudinal Measures in Clinical Trials, 
Statistics in Medicine 1999;18:1341-54.. 

 
 
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Analysis: 
This endpoint will be analyzed when the last subject completes 12 months of follow-up.  All 
available follow-up through 24 months at the time of data cut-off will be included in the 
analysis.  Subjects who do not experience any hospitalizations will be censored on their data 
cut-off date.  Subjects who die will be censored on the date of death.  Subjects who withdraw 
from the trial will be censored on the date of withdrawal. 
7.5 
Adjustment for Multiple Testing 
Both the primary safety and primary effectiveness endpoints must be met for study success.  
The secondary endpoints will be evaluated for labeling claims if both primary endpoints are 
met.  Secondary endpoints will be tested sequentially as detailed in the Statistical Analysis 
Plan.  Secondary endpoints include the following: 
• Composite 30-Day Secondary Safety Endpoint  
• All-Cause Mortality at 12 Months 
• MR Severity 
• Change in 6MWD 
• Change in KCCQ QoL score 
• Change in Left Ventricular End Diastolic Volume 
• NYHA Functional Class 
• Hierarchical composite of mortality and recurrent HF hospitalization  
• Recurrent hospitalizations, all-cause  
7.6 
Additional Endpoints 
Additional descriptive endpoints will also be reported as described below.    
7.6.1 Device or Procedure-Related Adverse Events 
Device or procedure-related adverse events are defined as adverse events that are adjudicated 
by the Clinical Events Committee as possibly, probably or definitely device and/or 
procedure-related, regardless of the temporal relationship to the MitraClip procedure.  Device 
or procedure-related adverse events will be broken down into those that occur within 30 days 
of the procedure and those that occur after 30 days of the procedure.  Examples of device-
related adverse events are: 

 
 
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• myocardial perforation 
• Single Leaflet Device Attachment  
• embolization of the MitraClip device or MitraClip System components 
• iatrogenic atrial septal defect 
• mitral valve stenosis 
• need for mitral valve replacement instead of repair due at least in part to the 
MitraClip procedure or the presence of the MitraClip device 
7.6.2 Device and Procedure-Related Endpoints 
The following device and procedure-related acute endpoints will be reported for the Device 
group: 
• Implant Rate: defined as the rate of successful delivery and deployment of the 
MitraClip device with echocardiographic evidence of leaflet approximation and 
retrieval of the delivery catheter 
• Device Procedure Time: defined as the time elapsed from the start of the transseptal 
procedure to the time the Steerable Guide Catheter is removed 
• Total Procedure Time: defined as the time elapsed from the first of any of the 
following: intravascular catheter placement, anesthesia or sedation, or TEE, to the 
removal of the last catheter and TEE. 
• Device Time: defined as the time the Steerable Guide Catheter is placed in the intra-
atrial septum until the time the MitraClip Delivery System (CDS) is retracted into the 
Steerable Guide Catheter. 
• Fluoroscopy duration: defined as the duration of exposure to fluoroscopy during the 
MitraClip procedure.   
7.6.3 Echocardiographic Endpoints  
The following echocardiographic endpoints will be reported for the Device and Control 
groups at baseline, discharge (or 30 days if discharge echocardiogram is not available), 6 
months, 12 months, 24 months and then yearly through 5 years.  For continuous variables, 
change from baseline to each follow-up will also be reported:  
• MR Severity Grade 

 
 
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• Effective Regurgitant Orifice Area 
• Regurgitant Volume 
• Regurgitant Fraction 
• Left Ventricle End Diastolic Volume (LVEDV) 
• Left Ventricular End Systolic Volume (LVESV) 
• Left Ventricular End Diastolic Dimension (LVEDD) 
• Left Ventricular End Systolic Dimension (LVESD) 
• Left Ventricular Ejection Fraction (LVEF) 
• Right Ventricular Systolic Pressure (RVSP) 
• Mitral Valve Area  
• Mean Mitral Valve Gradient 
• Systolic Anterior Motion of the mitral valve (present or absent) 
• Cardiac Output  
• Forward Stroke Volume 
7.6.4 Clinical Endpoints 
The following clinical endpoints will be reported for the Device and Control groups: 
• Kaplan-Meier freedom from the components of the primary safety composite at 12 
months, and yearly through 5 years (Device group only) 
• Kaplan-Meier freedom from the primary safety composite at 24 months and yearly 
through 5 years (Device group only) 
• Kaplan-Meier freedom from all-cause mortality at 12 months, 24 months and yearly 
through 5 years 
• Kaplan-Meier freedom from: (1) cardiovascular mortality (2) the first HF related 
hospitalization (3) the first cardiovascular hospitalization (4) the first HF related 
hospitalization or all-cause mortality at 12 months and 24 months and then yearly 
through 5 years  

 
 
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• NYHA Functional Class at baseline, 30 days, 6 months, 12 months, 24 months and 
then yearly through 5 years 
• 6MWD at baseline, 30 days, 6 months, 12 months and 24 months (and change from 
baseline to follow-up) 
• KCCQ QoL scores at baseline, 30 days, 6 months, 12 months and 24 months (and 
change from baseline to follow-up) 
• SF-36 QoL scores at baseline, 30 days, 6 months, 12 months and 24 months (and 
change from baseline to follow-up) 
• Mitral valve surgery (including type of surgery), new use of CRT, new use of single 
or dual chamber pacemaker, permanent LVAD implant, heart transplant, additional 
MitraClip device intervention in Device group or de novo MitraClip device 
intervention in Control group, including reason for intervention through 5 years 
• Responder analysis for 6MWD, where responder is defined as alive and experiencing 
an improvement of 24 meters and 50 meters at 12 months (difference in proportion of 
responders between Device and Control groups) at 12 months and 24 months  
• Responder analysis for LVEDV Index, where responder is defined as alive and 
experiencing an improvement of 12 ml/m2 (difference in proportion of responders 
between Device and Control groups) at 12 months, 24 months and then yearly 
through 5 years 
• Responder analysis for QoL (KCCQ), where responder is defined as alive and 
experiencing an improvement of 5 points (difference in proportion of responders 
between Device and Control groups) at 12 months and 24 months 
• Each subscale for QoL (KCCQ) (difference in means between Device and Control 
groups) at 12 months and 24 months 
• Length of index hospitalization for MitraClip procedure (Device group) 
• Number of hospitalizations and reason for hospitalization (i.e. heart failure, 
cardiovascular, non-cardiovascular) at 12 months and 24 months in each of the 
Device and Control groups   
• Number of days alive and out of hospital from the time of randomization (difference 
in medians between Device and Control groups) to 12 months, 24 months and then 
yearly through 5 years 
• Number of days hospitalized from the “Treatment” visit (difference in medians 
between Device and Control groups) at 12 months, 24 months and then yearly 
through 5 years 

 
 
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• Proportion of alive time in hospital will be summarized and compared between 
Device and Control groups at 12 months, 24 months and then yearly through 5 years 
• Proportion of subjects living in the baseline location at 12 months, 24 months and 
then yearly through 5 years 
• Mitral valve replacement rates will be summarized and compared between Device 
and Control groups at 12 months, 24 months and then yearly through 5 years 
• New onset of permanent atrial fibrillation at 12 months, 24 months and then yearly 
through 5 years 
• Mitral stenosis at 12 months, 24 months and then yearly through 5 years 
• Clinically significant atrial septal defect (ASD) that requires intervention at 12 
months, 24 months and then yearly through 5 years 
• Device-related complications in Device group subjects and Control group subjects 
who the undergo MitraClip procedure through 5 years 
• BNP or NT-proBNP levels at baseline, 30 days and 12 months  
• Modified Rankin Scale Score at baseline, 30 days, 6 months, 12 months 
• Major bleeding at 30 days 
• Prolonged ventilation at 30 days 
• Average dosages of GDMT at baseline, 30 days, 6 months, 12 months, 24 months, 
and then yearly through 5 years 
• The number and reasons for (1) any changes in GDMT and GDMT dosage from 
baseline at 30 days, 6 months, 12 months, 24 months, and then yearly through 5 years 
and  (2) any changes in GDMT from baseline that result in a larger than 100% 
increase or 50% decrease in dose at 30 days, 6 months, 12 months, 24 months, and 
then yearly through 5 years 
• Peak VO2 from cardiopulmonary exercise testing (CPX) in the subset of patients 
participating in the CPX sub-study at baseline and 12 months 
7.7 
Power and Sample Size 
A total sample size of approximately 610 randomized subjects is planned.  The power for the 
primary safety endpoint when approximately 305 Device group subjects complete 12 months 
of follow-up is >95%.  The power for the primary effectiveness endpoint with follow-up 
through 24 months in approximately 610 subjects when the last subject completes 12 months 

 
 
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of follow-up is ~80%.  The overall power for the study for the primary endpoints with the 
planned randomization of approximately 610 subjects is ~80%.  Details of sample size and 
power calculations are included in the Statistical Analysis Plan. 
7.8 
Trial Success 
The trial will be considered successful if the primary safety and primary effectiveness 
endpoints are met.  Additional labeling claims may be made based on the secondary 
endpoints. 
8 Adverse Events 
8.1 
Definition of Adverse Event and Serious Adverse Event 
8.1.1 Adverse Event (AE) 
An adverse event is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users, or other 
persons, whether or not related to the investigational medical device.   
This definition includes events related to the investigational medical device or comparator 
and/or the procedures involved.  For users or other persons, this definition is restricted to 
events related to the investigational medical device. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
Device failure may constitute an adverse event if an undesirable experience occurs 
Adverse events information will be collected throughout the trial.  Adverse events will be 
recorded on the electronic case report forms by the Investigator or designee.  Event 
description, date of onset, severity, duration, and relationship to device will be recorded on 
the appropriate electronic case report form.  Adverse events will be monitored through the 
course of the trial.  A list of adverse events, which may result from this procedure, is located 
below in Table 3. 
Note:  
Unchanged, chronic conditions are not adverse events and should not be recorded 
on the eCRF Adverse Event form.  Pre-existing conditions that have not worsened 
are not considered AEs.  

 
 
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8.1.2 Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as serious adverse event (SAE).  
a) Led to a death, 
b) Led to a serious deterioration in health that either: 
1) Resulted in a life-threatening illness or injury, or 
2) Resulted in a permanent impairment of a body structure or a body function, or 
3) Required in-patient hospitalization or prolongation of existing hospitalization, or 
4) Resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function. 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
d) An important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical 
judgment, may jeopardize the subject and/or may require intervention to prevent one of the 
outcomes listed in this definition 
Note 1: 
This includes device deficiencies that might have led to a serious adverse event if 
a) suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate. These are handled under the SAE reporting 
system. 
 
Note 2:  
A planned hospitalization for pre-existing condition, or a procedure required by 
the Clinical Investigation Plan, without a serious deterioration in health, is not 
considered to be a serious adverse event. 
8.1.3 Anticipated Adverse Events 
Table 3 lists the following anticipated events that have been identified as possible 
complications from the MitraClip procedure expected in this trial.  Please also refer to the list 
of anticipated events in the MitraClip System Instructions for Use (IFU) and package insert 
for other (drug or device) therapies required per protocol. 

 
 
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Table 3: Anticipated Adverse Events (MitraClip Procedure) 
Allergic reaction (anesthetic, contrast, 
Heparin, nickel alloy, latex) 
Hypotension/hypertension 
Aneurysm or pseudo-aneurysm 
Infection  
Arrhythmias 
Injury to mitral valve complicating or 
preventing later surgical repair 
Atrial fibrillation 
Lymphatic complications 
Atrial septal defect requiring intervention 
Mesenteric ischemia 
Arterio-venous fistula 
MitraClip erosion, migration or malposition 
Bleeding 
MitraClip Device thrombosis 
Cardiac arrest 
MitraClip System component(s) 
embolization 
Cardiac perforation 
Mitral stenosis 
Cardiac tamponade/Pericardial Effusion 
Mitral valve injury 
Chordal entanglement/rupture 
Multi-system organ failure 
Coagulopathy 
Myocardial infarction 
Conversion to standard valve surgery 
Nausea/vomiting 
Death 
Pain 
Deep venous thrombus (DVT) 
Peripheral ischemia 
Dislodgement of previously implanted 
devices 
Prolonged angina 
Dizziness 
Prolonged ventilation 
Drug reaction to anti-platelet/anticoagulation 
agents/contrast media 
Pulmonary congestion 
Dyskinesia 
Pulmonary thrombo-embolism 
Dyspnea 
Renal insufficiency or failure 
Edema 
Respiratory failure/atelectasis/pneumonia 
Emboli (air, thrombus, MitraClip Device) 
Septicemia 
 
Shock, Anaphylactic or Cardiogenic 
Emergency cardiac surgery 
Single leaflet device attachment (SLDA) 
Endocarditis 
Skin injury or tissue changes due to exposure 
to ionizing radiation  
Esophageal irritation 
Stroke* or transient ischemic attack (TIA) 
Esophageal perforation or stricture 
Urinary tract infection 
Failure to deliver MitraClip to the intended 
site 
Vascular trauma, dissection or occlusion 
Failure to retrieve MitraClip System 
components 
Vessel spasm 
Fever or hyperthermia 
Vessel perforation or laceration 
Gastrointestinal bleeding or infarct 
Worsening heart failure 
Hematoma 
Worsening mitral regurgitation 
Hemolysis 
Wound dehiscence 
Hemorrhage requiring transfusion 
 
*Subjects must have a visit with a neurologist and mRS assessment 90 days after onset of stroke  

 
 
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8.1.4 Unanticipated Adverse Device Effect  
Unanticipated adverse device effect (UADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, the MitraClip 
system, if that effect, problem, or death was not previously identified in nature, severity, 
or degree of incidence in the Clinical Investigational Plan, including the Device Instructions 
for Use, or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
8.2 
Device Deficiency/Product Experience 
Device deficiency (DD) is defined as an inadequacy of a medical device related to its 
identity, quality, durability, reliability, safety or performance, such as malfunction, misuse or 
use error and inadequate labeling. This includes the failure of the device to meet its 
performance specifications or otherwise perform as intended.  Note: performance 
specifications include all claims made in the labeling of the device 
Product Experience (PE) is defined as any expression of customer concern or dissatisfaction, 
including adverse events and patient issues that occurred during or after the use of a 
commercially available medical device.  
8.3 
Device or Procedure-Relationship 
Determination of whether there is a reasonable possibility that the MitraClip device or 
MitraClip procedure caused or contributed to an AE is to be assessed by the Investigator and 
recorded on the appropriate eCRF form as not related, possibly related, probably related, 
definitely related or unknown.  Determination should be based on assessment of temporal 
relationships, biologic plausibility, association (or lack of association) with underlying 
disease and/or presence (or absence) of a more-likely cause.   
Definitions for determination of MitraClip device relationship include: 
Not Related:  
Exposure to the MitraClip device has not occurred (no temporal 
relationship), or the occurrence of the adverse event is not reasonably 
related in time, or there is a definite alternative etiology, or it is 
biologically implausible for the adverse event to be related to the use of 
the device.  
Possibly Related:   Exposure to the MitraClip device has occurred; and it cannot be ruled 
out that the device is not responsible for the adverse event. 
Probably Related:  Exposure to the MitraClip device has occurred or the adverse event is 
reasonably related in time; and the device is more likely than other 
alternative causes to be responsible for the adverse event.  

 
 
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Definitely Related: Exposure to the MitraClip device has occurred or the adverse event is 
related in time; and the device is definitely responsible for the adverse 
event. 
Unknown 
Exposure to the device and the occurrence of adverse event cannot be 
reasonably determined to be unrelated to the device. If the relationship is 
identified as unknown it will be treated as related to the device. 
Determination of MitraClip procedure relationship includes assessment of AEs for 
relationship to any of the following: discontinuation of medications for the MitraClip 
procedure, administration of local or general anesthesia, or the MitraClip procedure.  
Relationship of MitraClip procedure will be assessed regardless of the temporal relationship 
to the MitraClip procedure. 
8.4 
Adverse Event/Device Deficiency/Product Experience Reporting 
8.4.1 Adverse Event Monitoring 
The Investigator will monitor the occurrence of adverse events for each subject during the 
course of the trial.  All adverse events (AEs) reported by the subject, observed by the 
Investigator, or documented in medical records will be documented on the eCRF Adverse 
Event form  A fax form will be made available to allow the investigator to report SAEs and 
device deficiencies in the event the eCRF is not available.  
For all registered subjects, AEs (any new event/experience that was not present at baseline or 
worsening of an event present at baseline) will be collected.  Adverse events will be 
monitored through the course of the trial.  Additional information related to a previously 
reported adverse event should be updated within the appropriate electronic case report form. 
The SAE and device deficiency should be entered in the eCRF as soon as the system is 
available. 
Unchanged, chronic non-worsening or pre-existing conditions are not adverse events and 
should not be recorded in the eCRF.  
8.4.2 Serious Adverse Event Reporting to Sponsor and IRB/EC 
The Investigator will monitor the occurrence of AEs for each subject during the course of the 
clinical trial/investigation and report as required by this protocol in section 8 per AE and 
SAE definitions.  AEs need to be collected from the time of randomization for randomized 
subjects and from the initiation of the MitraClip procedure for roll-in subjects on the 
appropriate AE eCRF form. Additional information with regards to an AE should be updated 
within the AE eCRF. 

 
 
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A fax form will be made available to allow the investigator to report SAEs in the event the 
entry cannot be made in the eCRF system.  This does not replace the eCRF reporting system. 
All information must still be entered in the eCRF system as soon as feasible.  
The investigator should report all SAEs to the Sponsor as soon as possible but no later than 3 
calendar days from the day study personnel became aware of the event or as per the 
investigative site’s local requirements if the requirement is more stringent than those 
outlined. The date the site staff became aware that the event met the criteria of a serious 
adverse event must be recorded in the source document. 
Serious adverse events that occurred in the user or persons other than the study subject 
should not be entered in the eCRF system, however need to be reported on the SAE 
Notification Form provided by Sponsor.   
The Investigator will further report the SAE to the local IRB/EC according to the institution’s 
IRB/EC reporting requirements. 
8.4.3 Unanticipated Adverse Device Effect (UADE) Reporting to Sponsor and IRB/EC 
The Investigator should report any UADE to the sponsor and the IRB/EC within 3 calendar 
days following the investigator’s knowledge of the event.  The sponsor is required to report 
the findings of the investigation of any UADE to the FDA, other appropriate regulatory 
agency and the IRB/EC as soon as possible, but in no event later than 10 working days after 
knowledge of the event. 
8.4.4 Unanticipated Serious Adverse Device Effect (USADE) Reporting to Sponsor 
and IRB/EC 
Abbott Vascular requires the Investigator to report any unanticipated serious adverse device 
effect (USADE) to the sponsor within 3 calendar days of the investigator’s knowledge of the 
event, unless local requirements are more stringent, and to the IRB/EC per IRB/EC 
requirements. The sponsor is required to report the findings of the investigation of any 
USADE to regulatory agencies and the IRB/EC per local requirements. 
8.4.5 Device Deficiency/Product Experience Reporting 
The investigator should report all Device Deficiencies/Product Experiences to the Sponsor as 
soon as possible but no later 3 calendar days from the day the study personnel becoming 
aware of the event or as per the investigative site’s local requirements if the requirement is 
more stringent than those outlined. 
The device, if not implanted or not remained in the subject, should be returned to Abbott 
Vascular.   

 
 
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Device deficiencies should be reported to the IRB/EC per the investigative site’s local 
requirements. 
8.4.6 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor 
The Sponsor will report the SAEs and DDs/PEs to the country regulatory authority, per local 
requirements. 
8.5 
Anticipated Adverse Event Rates 
To comply with ISO 14155:2011 requirement to provide the likely incidence of foreseeable 
adverse events, APPENDIX F:  Rates of Foreseeable Adverse Events has been included. 
8.6 
Adjudication of Events 
The Sponsor will review all adverse events.  Adverse events requiring adjudication will be 
submitted to the Clinical Events Committee (CEC).  Refer to Section 10.4 Clinical Events 
Committee for the CEC’s role and responsibility. 
9 Direct Access to Source Data/Documents 
The Investigator/institution will permit and assure direct access to source data/documents 
(e.g., hospital/clinic/office charts, catheterization reports, laboratory results, etc.) for trial-
related monitoring, audits, IRB/EC review, and regulatory inspections. 
Subjects providing informed consent agree to allow the Sponsor representatives or designee 
access and copying rights to pertinent information in their medical records relevant to trial 
participation. 
The Investigator will obtain, as part of the informed consent, permission for Sponsor 
monitors and designees, including auditors, or regulatory authorities to review, in confidence, 
any records identifying the subjects in this clinical trial/investigation.  This information may 
be shared with regulatory agencies; however, per relevant confidentiality and privacy rules 
(HIPAA), the Sponsor and its designees will not otherwise release the subject's personal, 
private and protected health information. 
10 Quality Control and Quality Assurance 
To ensure uniformity of subject assessment across all study sites, regulatory compliance by 
both Sponsor and investigational sites, and that the trial is conducted in accordance with the 
Clinical Investigational Plan, proper quality control and assurance procedures will be 

 
 
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followed in this trial. These controls include establishment of study committees, training, 
monitoring and support of quality audits.  
10.1 
Steering Committee 
The Steering Committee is an expert advisory leadership group that provides scientific and 
medical input on trial design, data collection, data analyses and interpretation of results.  It is 
intended that the Steering Committee leverage the experiences, expertise, and insights of key 
individuals at organizations committed to cardiovascular excellence, and provide an 
organizational structure within which to ensure scientific objectives of the trial are 
adequately addressed.  The Steering Committee is charged with driving commitment to the 
trial, motivating investigational sites, encouraging patient recruitment, and producing high 
quality data. 
10.2 
Central Eligibility Committee 
An independent Eligibility Committee will confirm that each subject is on optimal therapy 
including GDMT prior to being considered for the trial.  The committee will also confirm 
through discussion with the site investigators (including the site surgeon) that the patient is 
not appropriate for mitral valve surgery, even if randomized to the Control group.  The 
committee will also categorize whether or not the subject is extremely high surgical risk, as 
defined in APPENDIX A: Definitions). 
The Eligibility Committee will be comprised of, at a minimum, representatives from the 
following specialties:  CT surgery (with expertise in mitral valve surgery) and cardiology 
(with expertise in heart failure).  The composition, guiding policies, and operating procedures 
governing the Eligibility Committee are described in a separate Eligibility Committee 
Manual of Operations. 
10.3 
Central Echocardiography Core Laboratory (ECL) 
The ECL will be responsible for reviewing subject’s screening echocardiography images to 
determine if the subject meets the MR severity eligibility criterion prior to the subject being 
considered eligible for the trial.   
MR severity and left ventricular measurements, along with other measures, will be assessed 
by the ECL at baseline and follow-up.   
The ECL will operate according to a separate ECL Manual of Operations. 
10.4 
Clinical Events Committee 
The Clinical Events Committee (CEC) is a multi-disciplinary team comprised of qualified 
physicians who are not investigators in the trial. The composition, guiding policies, and 

 
 
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operating procedures governing the CEC are described in a separate CEC Manual of 
Operations.  The CEC will review and adjudicate pre-specified events reported by trial 
investigators or identified by the Safety & Surveillance personnel/designate for the trial as 
documented in CEC Manual of Operations (MOPs).  Every effort will be made to blind the 
CEC to the subject’s treatment assignment. 
10.5 
Data Monitoring Committee 
The Data Monitoring Committee (DMC) will monitor the safety of subjects throughout trial 
registration on an on-going basis.  The composition, guiding policies, and operating 
procedures governing the DMC are described in a separate DMC charter.   
The Data Monitoring Committee (DMC) will serve in an advisory role to Abbott Vascular to 
ensure safety by reviewing cumulative data from the clinical trial at pre-scribed intervals for 
the purpose of safeguarding the interests of trial participants. The DMC will meet 
periodically at a frequency set out in the DMC charter to monitor the safety of subjects 
registered in the study.  The DMC may consider a recommendation for modifications or 
termination of the study based on safety concerns.  The recommendations of the DMC are 
not binding, and all final decisions regarding the clinical investigation, however, rest with 
Abbott Vascular and the Steering Committee.   
10.6 
Publication Committee 
The Publication Committee will oversee and guide the ongoing scientific presentation and 
publication activities for the COAPT Trial. The Publication Committee will determine 
policies and strategies regarding presentations and/or publications arising from study 
generated data.  The committee will also review and approve all external requests for 
accessing study-related data and strategies for presentation and publication. The Committee 
will follow Abbott Vascular applicable policies and standard operating procedures.  The 
Steering Committee Chairs will chair the COAPT Publication Committee.  The composition, 
guiding policies, and operating procedures governing the Publication Committee are 
described in detail in a separate Publication Committee Charter. 
10.7 
Training 
10.7.1 Site Training 
All Investigators and site clinical trial personnel are required to attend Sponsor training 
sessions, which may be conducted at an Investigator's meeting, a site initiation visit or other 
appropriate training sessions.  Training of Investigators or clinical trial personnel will 
include, but is not limited to, device training, the Clinical Investigational Plan requirements, 
investigational device usage, electronic case report form completion, trial personnel 
responsibilities and regulatory requirements. 

 
 
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All Investigators or clinical trial personnel that are trained must sign a training log upon 
completion of the training.  Investigator or clinical trial personnel must not perform any trial-
related activities prior to signing the training log unless these activities are standard of care at 
the site.  Prior to the start of the clinical trial, the trial monitor or designee will visit each site 
where the clinical trial will be conducted.  The clinical trial monitor will ensure that sites’ 
clinical trial personnel are informed about and understand the clinical trial requirements. 

 
 
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The following matrix describes the training requirements for study personnel at each site. Training will be provided by Abbott 
Vascular:   
MITRACLIP PROCEDURE ROLE 
Procedural Role 
Implanter 
Curricula  
Echo         
Curricula 
System Prep     
Curricula 
Implanter 
 
  
  
Echo 
 
 
  
System preparation  
  
  
 
  = required  
 
STUDY ROLE 
Clinical Investigational Plan Elements 
Study 
Design 
Informed 
Consent  
Process 
 
Eligibility 
Criteria 
6-Minute    
Walk Test 
QOL  
NYHA 
Functional 
Class 
eCRFs 
AE / SAE 
Reporting 
modified 
Rankin Scale 
Certification a 
Site Principal/Primary Investigator 
 
 
 
 
 
 
 
 
 
Site Sub-Investigator  
 
 
 
  
  
 
  
 
  
Study Coordinator #1 (non-blinded) 
 
 
 
 
 
 
 
 
 
Study Coordinator #2 (blinded) 
 
 
 
 
 
 
  
 
 
  = required  
a = certification to be verified by Abbott Vascular 
 
 
 
 
 
 

 
 
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10.7.2 Training of Sponsor’s Monitors 
Sponsor’s designated monitors will be trained to the Clinical Investigational Plan, case report 
forms and investigational device usage (as appropriate), according to the Sponsor’s written 
procedures. 
10.7.3 Training of Sponsor’s Designees or Vendors 
All Sponsor partners and/or designated vendors (e.g., Echocardiography Core Laboratory) 
responsible for any function in the conduct of the clinical trial will be trained to the Clinical 
Investigational Plan and other trial documents (as appropriate).   
10.8 
Monitoring 
Sponsor and/or designee will monitor the study over its duration according to the pre-
specified monitoring plan and relevant standard operating procedures which will include the 
planned extent of source data verification.  
10.8.1 Designated Monitors 
Study monitors are individuals who are designated to oversee the progress of a study.  These 
individuals are appropriately trained and qualified to monitor the progress of a clinical trial. 
The study Sponsor may designate additional monitors at any time during the study.  The 
Sponsor should be contacted for information on the person(s) responsible for monitoring 
activities at the following address: 
Abbott Vascular Inc. 
3200 Lakeside Drive 
Santa Clara, CA 95054 
10.8.2 Monitoring Visits  
Scheduled visits to the clinical investigational site may occur at the following times: prior to 
the start of the clinical study (pre-study qualification visit), at initiation of the study (at first 
implant or shortly thereafter), interim visits throughout the clinical study as required, 
annually, and upon completion of the clinical study. 

 
 
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10.8.2.1 
Pre-study Qualification Visit 
A pre-study visit may be conducted by Sponsor personnel (or designees) to review the 
Clinical Investigational Plan and regulatory requirements with the investigator and the trial 
personnel to assure that they: 
• Understand the requirements for an adequate and well-controlled clinical trial. 
• Understand and accept the obligation to conduct the clinical investigation in 
accordance with the local, state and national (federal) regulations. 
• Understand the investigational status of the device and the requirements for its use 
and accountability. 
• Understand and accept the obligation to obtain informed consent in accordance with 
the local, state and national (federal) regulations. 
• Understand and accept the obligation to obtain IRB/EC approval before the clinical 
study is initiated, ensure continuing review of the study by the IRB/EC, and keep the 
Sponsor informed of IRB/EC approval and actions concerning the clinical trial. 
• Have access to an adequate number of eligible subjects to participate in the trial (at 
least 1 per month). 
• Have adequate facilities and resources to conduct the trial.  This includes resources 
appropriate for use of electronic data capture (EDC) systems. 
• Have sufficient time from other obligations to carry out the responsibilities of the 
clinical trial. 
10.8.2.2 
Initiation Visit 
Sponsor clinical personnel (or designees) may provide assistance for both scientific concerns 
and study management issues during the initiation visit.  Any observations will be 
documented and issues requiring follow-up will be identified on a monitoring report.   
10.8.2.3 
On-Site Interim Monitoring Visits 
On-site monitoring visits will occur on an as-required basis (and at least annually) to assess 
adherence to the clinical investigation plan, IRB/EC review of study progress, maintenance 
of records and reports, and selected review of source documents for accuracy, completeness, 
legibility, and omissions.  The monitors will acquire information to assess the progress of the 
study (toward meeting study objectives) and identify any concerns that stem from 
observation of device performance and/or review of the investigator's subject records, study 

 
 
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management documents, and subject informed consent documents.  Source documentation 
must be available to substantiate proper informed consent procedures, adherence to protocol 
procedures, adequate reporting and follow-up of adverse events, accuracy of data collected 
on eCRFs and device information. Monitoring reports will be generated along with 
communications to the investigator, which document the result of the monitoring visits and 
any recommended actions.  Resolution of concerns and completion of assigned tasks will be 
documented. 
The Institution must provide documentation of Echo machine calibration and/or maintenance 
records to the Sponsor on a routine basis.  Abbott Vascular and/or designee will periodically 
monitor the calibration documentation, to ensure the machine is properly functioning for the 
duration of the study. 
10.8.2.4 
Final Monitoring Review 
Depending upon the status of the study at each center, a close-out or final visit may be 
conducted.  Any ongoing responsibilities will be discussed with the investigator and the 
study center coordinator.  A final monitoring report, which includes, at a minimum, 
disposition of any unused devices, will be completed. 
10.9 
Quality Assurance Audit 
The Sponsor may conduct periodic Quality Assurance audits (on-site audits) at various 
clinical trial sites.  A sponsor representative or designee may request access to all trial 
records, including source documentation, for inspection and duplication during a Quality 
Assurance audit.  The Investigator and research coordinator must be available to respond to 
reasonable requests and queries made during the audit process.  
10.10 
Protocol Deviations 
It is the Investigator's responsibility to ensure that there are no deviations from the Clinical 
Investigational Plan, except in cases of medical emergencies, when the deviation is necessary 
to protect the life or physical well-being of the subject or eliminate an apparent immediate 
hazard to the subject.  All deviations must be reported to the Sponsor.  The occurrence of 
protocol deviations will be monitored by the Sponsor for evaluation of investigator 
compliance to the Clinical Investigational Plan and regulatory requirements and dealt with 
according to written procedures.  
10.10.1  Deviations with Expedited Reporting Requirements  
For the following types of protocol deviations (per 21 CRF 812.150), an investigator is 
required to notify the Sponsor and the IRB/EC within 5 business days of the deviation. 

 
 
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• Emergency Deviation from the Clinical Investigational Plan (a deviation to protect 
the life or physical well-being of a subject in an emergency). 
• Failure to obtain Informed Consent.  
Notification to the Sponsor and/or the IRB/EC should be documented and maintained in the 
clinical study file at the site and at Abbott Vascular.   
10.10.2  Non-Critical Deviations   
Protocol deviations which do not have the urgency associated with expedited notification or 
prior Abbott Vascular/ IRB/EC approval (as discussed in the above paragraphs) will be 
reported upon discovery, such as during completion of eCRFs or a monitoring visit. 
10.11 
Device Malfunction 
Device malfunction is the failure of the MitraClip device to meet its performance 
specifications or otherwise perform as intended.  Performance specifications include all 
claims made in the labeling of the device.  The intended performance of the MitraClip device 
refers to the intended use for which the device is labeled or marketed.  An occurrence of any 
device malfunction during the MitraClip placement procedure should be reported to the 
Sponsor as soon as possible.  The device, if not implanted in the subject, should be returned 
to Abbott Vascular.  If a device malfunction is observed during the follow-up period via 
echocardiography images, such failure should be reported to the sponsor as soon as possible.  
A device malfunction may or may not be related to an adverse event in a subject.  If adverse 
events occurred as a result of the device malfunction, then the adverse events must be 
reported as well. 
10.12 
Device Misuse 
A misused device (one that is used by the Investigator in a manner that is contradictory to the 
Instructions for Use) will not be considered a malfunction. 
10.13 
Sponsor Support to Clinical Trial/Investigation Site for Regulatory Body 
Inspection 
In the event that an Investigator is contacted by a Regulatory Agency regarding this clinical 
trial/investigation, the Investigator will notify the Sponsor immediately.  The Investigator 
and research coordinator must be available to respond to reasonable requests and inspection 
queries made during the inspection process.  The Investigator must provide the Sponsor with 
copies of all correspondence that may affect the review of the current clinical 
trial/investigation (e.g., Form FDA 483, Inspectional Observations, and warning letters).  As 
necessary, the Sponsor may provide any assistance in responding to regulatory inspections. 

 
 
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10.14 
Measures Taken to Avoid and Minimize Bias During Study Conduct 
Due to the nature of the treatment in the two randomized groups, the subject, some site 
personnel and some Sponsor personnel will be aware of treatment assignment.  The 
following steps will be taken to minimize bias in the conduct of the trial and analyses of 
clinical data. 
10.14.1  Subject Recruitment and Randomization 
Investigational sites will attempt to recruit consecutive subjects who meet trial eligibility 
criteria (see Section 5 Trial Design, Scope and Duration for more information on the 
participation of women in the trial). 
• Candidates will be considered for the trial after they have been informed of trial 
requirements and have signed the informed consent form.  See Section 6.4 Subject 
Screening and Informed Consent for additional details on subject screening and 
informed consent process.  
• Transthoracic echocardiographic criteria for trial eligibility will be confirmed by an 
independent Echocardiography Core Laboratory 
• All baseline tests and assessments must be completed prior to randomization 
• Subjects will be randomized only after the sites’ clinical personnel have confirmed 
and documented that the subject has met all eligibility criteria, the ECL has confirmed 
the MR severity eligibility criterion, and the Eligibility Committee has confirmed that 
the subject is on optimal  therapy including GDMT and is not appropriate for mitral 
valve surgery.   
• Randomization within each site will be stratified by site and cardiomyopathy etiology 
(i.e. ischemic or non-ischemic), assigned in permuted block sizes, and block sizes will 
not be disclosed to the sites.  
• A centralized randomization service will be used.   
10.14.2  Maintaining Similar Levels of Follow-up 
In order to maintain similar levels of contact between the investigational site and subjects, all 
subjects will have a “Treatment” visit.  During the “Treatment” visit for the Control group, 
subjects will be seen by a HF specialist, and will undergo a physical exam, including vital 
signs, cardiac health status and evaluation of heart failure medications.  Subjects in the 
Device group will undergo the MitraClip procedure during the “Treatment” visit.  The 
follow-up schedule post-“Treatment” visit is identical for both groups and both groups will 
be followed by the HF specialist. 

 
 
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10.14.3  Administration of Assessments 
Site personnel assessing NYHA Functional Class and administering the 6MWT and QoL 
questionnaires will not have knowledge of the subject’s treatment assignment and will not be 
involved in day-to-day activities of the COAPT trial.  Additionally, personnel performing 
these assessments will not have access to the eCRFs.  A standardized script will be used 
when administering the assessments and the subject will be reminded to not reveal their 
treatment history to the administrator.  To minimize bias and undue influence, the QoL 
questionnaires will be completed by the subject, unless the subject is unable to complete the 
questionnaire on their own (in such cases, a note to file must be completed to document the 
inability of subject to complete the questionnaire).  
10.14.4  Review of Echocardiography Images  
MR severity and left ventricular measurements, along with other measures, will be assessed 
by an Echocardiography Core Lab (ECL) at baseline and follow-up.  For follow-up echoes, 
the ECL will not have knowledge of the follow-up visit. 
10.14.5  Safety and Effectiveness Monitoring  
• All adverse events will be reviewed by Abbott Vascular. 
• Adverse events requiring adjudication will be submitted to an independent Clinical 
Events Committee (CEC).  Every effort will be made to keep the CEC blinded to the 
subject’s treatment assignment. 
• A Data Monitoring Committee (DMC) will review accumulating safety and 
effectiveness data as described in Section 10.5.  
10.14.6  Follow-Up Compliance 
The Sponsor will work with investigational sites to maintain high follow-up compliance. The 
following are strategies for increasing compliance: 
1. During site initiation and training, the Sponsor will emphasize to the site the 
importance of subject follow-up, and that the site should communicate this 
importance to each subject. 
2. Sites will be informed to promptly reschedule any missed subject visits, and to 
reinforce the necessity of a follow-up visit. 
3. If a scheduled visit is missed due to subject illness, transportation issues, or travel, the 
site will be advised to: 

 
 
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a. Reinforce the necessity of follow-up visits; 
b. Identify alternate transportation sources, and involve the Sponsor if necessary. 
4. Sites will be instructed to ask subjects who withdraw during the trial to provide the 
reason for withdrawal and ask them if the investigator may contact them once more at 
the end of the trial follow-up.   
5. Follow-up rates will be monitored closely so follow-up problems may be identified 
and addressed as soon as possible.   
6. For subjects lost-to-follow-up, sites may be requested to examine the Social Security 
Death Index to determine subject status (only the status will be sent to Sponsor, not 
any subject identifying information). 
In addition to aforementioned steps, investigational sites will be educated on the importance 
of maintaining low rates of withdrawals in both Device and Control groups, and will be 
expected to make all effort to maintain low withdrawals during trial conduct.  Withdrawals 
from the trial will require discussion between investigator and the Sponsor.  
10.14.7  Analysis 
The primary analysis for the effectiveness endpoint will be performed on an intention to treat 
basis. The primary analysis for the safety endpoint will be performed in Device group 
subjects who undergo the MitraClip procedure.  
10.15 
Subject Confidentiality 
Subject confidentiality will be maintained throughout the clinical study to the extent required 
by law.  Every attempt will be made to remove patient identifiers from clinical study 
documents and eCRFs.  For this purpose, a unique subject identification code will be 
assigned and used to allow identification of all data reported for each subject.  This will also 
ensure that the information can be traced back to the source data.  
Study data may be made available to third parties, e.g., in the case of an audit performed by 
regulatory authorities, provided the data are treated confidentially and that the subject’s 
privacy is guaranteed, to the extent permitted by law.  The identity of a subject will never be 
disclosed in the event that study data are published. 
The Sponsor requires that the study sites comply with the subject confidentiality provisions 
of the Health Insurance Portability and Accountability Act (HIPAA) issued by the U.S. 
Department of Health and Human Services (HHS).  Sites should maintain patient privacy in 
accordance to federal regulations (45 CFR Parts 160 and 164), local regulations, and 
institutional requirements. 

 
 
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11 Data Handling and Record Keeping 
Clinical data will be collected pre-randomization during the screening period to establish 
subject eligibility at baseline, during the MitraClip device placement procedure and 
throughout the MitraClip placement hospital stay for the Device group, during the 
“Treatment” visit for the Control group and during the follow-up period for all subjects. 
All eCRF data collection will be performed through a secure web portal and all authorized 
personnel with access to the Electronic Data Capture (EDC) system must use an electronic 
signature access method to enter, review or correct data.  Electronic signature procedures 
shall comply with the CFR Title 21 Part 11 and the ICH Guidelines for Good Clinical 
Practice (GCP) (Topic E6, April 2000) Section 5.5.3.  Passwords and electronic signatures 
will be strictly confidential.   
The Sponsor’s monitors (or designees) will review all electronic case report forms.  The 
Sponsor’s data management group will perform all data management activities, including 
data review, database cleaning, and issuing and resolving data queries, and documentation of 
the systems and procedures to be used.     
All eCRF data will be downloaded from the EDC system and reformatted for analysis in a 
data structure acceptable to Abbott Vascular.   The data will be subjected to consistency and 
validation checks within the EDC system and will be subject to supplemental validation 
following download.   
Completed eCRFs with the date-and-time stamped electronic audit trail indicating the user, 
the data entered, and any reason for change (if applicable) will be archived at the 
investigator’s site and a backup copy archived with Abbott Vascular. 
11.1 
Source Documentation 
IDE regulations (21 CFR 812) and GCPs require that the Investigator maintain information 
in the subject’s medical records that corroborates data collected on the eCRFs.   Throughout 
the clinical trial duration, the sites’ investigators will maintain complete and accurate 
documentation including but not limited to medical records, clinical trial progress records, 
laboratory reports, electronic case report forms, signed informed consent forms, device 
accountability records, correspondence with the IRB/EC and clinical trial monitor or sponsor, 
adverse event reports, and information regarding subject discontinuation or completion of the 
clinical trial/investigation.  Any source documentation (procedure reports, imaging studies, 
lab reports, death certificates, etc.) that is sent to the sponsor, reviewing committees, or the 
core lab, should have all subject identifiers removed and replaced with the subject number.  
In order to comply with these regulatory requirements/GCP the following information should 
be included in the subject record at a minimum and if applicable to the investigation: 
• Medical history/physical condition of the subject before involvement in the trial 
sufficient to verify Clinical Investigational Plan entry criteria 

 
 
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• Dated and signed notes on the day of entry into the trial referencing the sponsor, 
Clinical Investigational Plan number, subject ID number and a statement that 
informed consent was obtained 
• Dated and signed notes from each subject visit (for specific results of procedures and 
exams) 
• Adverse events reported and their resolution including supporting documents such as 
discharge summaries, catheterization laboratory reports, ECGs, and lab results 
including documentation of site awareness of SAEs and of investigator device 
relationship assessment of SAEs. 
• Study required laboratory reports and 12-lead ECGs, signed and dated for review and 
annotated for clinical significance of out of range results. 
• Notes regarding Clinical Investigational Plan-required and prescription medications 
taken during the trial (including start and stop dates) 
• Subject’s condition upon completion of or withdrawal from the trial 
• Any other data  required to substantiate data entered into the CRF 
11.2 
Electronic Case Report Form Completion 
 
Primary data collection based on source-documents and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the Clinical Investigational 
Plan and eCRF completion.  eCRF data will be collected for all enrolled patients.  Sponsor or 
designee will provide clinical monitoring as specified in Section 10.8 Monitoring. 
11.3 
Site Record Retention 
The sponsor will archive and retain all documents pertaining to the trial as per the applicable 
regulatory record retention requirements. The Investigator must obtain permission from 
Sponsor in writing before destroying or transferring control of any clinical trial/investigation 
records. 
12 Ethical Consideration 
12.1 
Institutional Review Board/Ethics Committee Review 
Institutional Review Board (IRB) or Ethics Committee (EC) approval for the Clinical 
Investigational Plan and informed consent form will be obtained by the Principal Investigator 

 
 
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at each investigational site prior to participation in this clinical trial/investigation.  The 
approval letter must be signed by the IRB/EC chairman or authorized representative prior to 
the start of this clinical trial and a copy must be provided to the Sponsor.  No changes will be 
made to the Clinical Investigational Plan or informed consent form without appropriate 
approvals, including IRB/EC, the Sponsor, and/or the regulatory agencies.  
Until the clinical trial/investigation is completed, the Investigator will advise his/her IRB/EC 
of the progress of this clinical trial/investigation, per IRB/EC requirements.  Written approval 
must be obtained from the IRB/EC yearly to continue the clinical trial/investigation, 
according to each institution’s IRB/EC requirements.  Further, any amendments to the 
Clinical Investigational Plan as well as associated informed consent form changes will be 
submitted to the IRB/EC and written approval obtained prior to implementation, according to 
each institution’s IRB/EC requirements. Acknowledgement/approval by the IRB/EC of the 
protocol amendment must be documented in writing prior to implementation of the protocol 
amendment.  Copies of this documentation must also be provided to the Sponsor. 
No investigative procedures other than those defined in this Clinical Investigational Plan will 
be undertaken on the registered subjects without the written agreement of the IRB/EC and the 
Sponsor. 
13 Risk Analysis 
Patients with untreated clinically significant functional MR are highly symptomatic, have a 
high rate of heart failure hospitalizations, poor quality of life and impaired functional 
capacity.  Current options to treat their FMR include medical management and mitral valve 
repair or replacement surgery. 
Medical management of patients with MR is intended to reduce symptoms and improve 
quality of life; yet medical management does not treat the mechanical malcoaptation of the 
mitral valve leaflets, and therefore is not a long-term treatment solution for their MR.  Mitral 
valve surgery, on the other hand, is an invasive approach and in functional MR, there is 
limited evidence that the benefits of mitral valve surgery outweigh the risks.  Mitral valve 
surgery is not recommended as standard of care in the most recent 2013 ACCF/AHA Heart 
Failure guidelines, in which mitral valve surgery is considered a class IIb recommendation6.  
In this clinical trial, the overall risk versus benefit analysis of the MitraClip System is based 
on weighing the potential risks and benefits of the MitraClip System against the risks and 
benefits associated with no MitraClip intervention.  
13.1 
Potential Risk 
The potential risks associated with the MitraClip procedure can be grouped into two 
categories.  First, there are potential risks associated with standard cardiac catheterization, 
including transseptal catheterization, the transesophageal echocardiogram (TEE) probe and 

 
 
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the potential risks of general anesthesia.  Second, there are potential risks uniquely associated 
with the use of the MitraClip System. 
Risks associated with standard cardiac catheterization, TEE probe and anesthesia include, but 
are not limited to, the following: 
• Death  
• Myocardial infarction 
• Stroke or transient ischemic attack (TIA) 
• Cardiac arrest  
• Shock, Anaphylactic or Cardiogenic 
• Cardiac perforation  
• Cardiac tamponade/Pericardial Effusion 
• Hematoma 
• Arterio-venous fistula 
• Coagulopathy 
• Bleeding 
• Hemorrhage requiring transfusion  
• Infection  
• Endocarditis  
• Septicemia 
• Pain 
• Dizziness 
• Dyskinesia 
• Arrhythmias  
• Atrial fibrillation 

 
 
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• Emboli (air or thrombus) 
• Vascular trauma, dissection or occlusion 
• Peripheral ischemia 
• Fever or hyperthermia 
• Prolonged angina 
• Pulmonary congestion 
• Pulmonary thrombo-embolism 
• Hypotension/hypertension 
• Renal insufficiency or failure 
• Allergic reaction(anesthetic, contrast Heparin, nickel alloy, latex)Drug reaction to 
anti-platelet/anticoagulation agents/contrast media  
• Nausea/vomiting  
• Prolonged ventilation  
• Respiratory failure/atelectasis/pneumonia 
• Gastrointestinal bleeding or infarct  
• Aneurysm or pseudo-aneurysm 
• Deep venous thrombus (DVT) 
• Dyspnea  
• Edema 
• Esophageal irritation 
• Esophageal perforation or stricture 
• Lymphatic complications  
• Multi-system organ failure 
• Mesenteric ischemia 

 
 
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• Urinary tract infection 
• Vessel spasm 
• Vessel perforation or laceration 
• Worsening heart failure 
• Wound dehiscence 
• Skin injury or tissue changes due to exposure to ionizing radiation 
Potential risks specifically associated with the use of the MitraClip System include, but are 
not limited to, the following: 
• MitraClip System component(s) embolization  
• MitraClip erosion, migration or malposition  
• MitraClip Device thrombosis  
• Failure to deliver MitraClip to the intended site 
• Worsening mitral regurgitation 
• Mitral stenosis 
• Mitral valve injury  
• Failure to retrieve MitraClip System components 
• Hemolysis  
• Conversion to standard valve surgery 
• Atrial septal defect requiring intervention 
• Single leaflet device attachment (SLDA) 
• Emergency cardiac surgery 
• Dislodgement of previously implanted devices 
• Chordal entanglement/rupture 
• Injury to mitral valve complicating or preventing later surgical repair 

 
 
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13.2 
Risk Management Procedures 
Risks associated with the use of the MitraClip System are minimized through device design, 
Investigator selection and training, pre-specified subject eligibility requirements, study 
monitoring to ensure adherence to the Clinical Investigational Plan and the use of an 
independent Data Monitoring Committee. 
Specifically, the risk management strategy includes the following 
• AEs will be recorded per Section 8: Adverse Events of this Clinical Investigational 
Plan and will be reported and monitored throughout the follow-up period.  
• The sites will be notified of unexpected adverse device effects and other safety 
concerns that could negatively impact the safety of the subjects if such issues arise. 
• All investigators will be trained on the device, the IFU, and the trial protocol prior to 
participating in the clinical trial.  Retraining of the investigators will be conducted if 
deviations from recommended use are noted or updates to the IFU are implemented. 
• The compliance of clinical sites to the protocol will be monitored.  Corrective and 
preventative actions will be implemented based on the nature and number of protocol 
deviations observed 
13.2.1 Device Design 
The design of the MitraClip System includes many features aimed at minimizing potential 
risks.  The major safety features of the device are described below: 
• The MitraClip device is designed with the ability to grasp, capture and release the 
mitral valve leaflets. This can be performed repeatedly to reposition the device to 
optimize MR reduction.  When MR reduction is acceptable, the device is deployed. If 
acceptable MR reduction is not achieved, the steps can reversed and the device is not 
implanted.   
• The MitraClip device is designed with a series of frictional elements that engage the 
surface of the leaflets to capture and retain the leaflets.   
• The MitraClip device is intended to capture and independently retain two leaflets.  In 
the event the device is not properly attached or detaches from one leaflet, capture of 
the opposing leaflet by the device reduces the likelihood of device embolization.  
• The MitraClip device is covered with polyester fabric to promote tissue in-growth 
which anchors the device to the leaflets.   

 
 
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• The MitraClip device has been designed to withstand the forces exerted on it during 
the cardiac cycle and the device is constructed from well-characterized, 
biocompatible materials that have undergone extensive testing.  Chronic animal 
studies, FEA (finite element analysis) modeling, and accelerated fatigue testing has 
established an acceptable fatigue life of the MitraClip device. 
• Three distinct detachment mechanisms requiring multiple steps are required to fully 
deploy the device from the delivery catheter. 
• The device is designed to be atraumatic to the valve tissue to minimize the risk of 
altering future surgical repair options. 
13.2.2 Investigator Selection and Training 
Only operators (must be investigators) who are skilled in the manipulation of catheter-based 
technology in the vasculature and heart, and have a good understanding of the risks 
associated with these manipulations will be selected for this trial.  In addition, site 
investigators will undergo training on the techniques required to optimally place the device 
on the mitral leaflets. 
As required, CT surgeons will have the training and support necessary to assist with device 
explant, if necessary.  See Section 10.7.1 Site Training for additional details. 
13.2.3 Ensuring Strict Adherence to the Clinical Investigational Plan 
The COAPT Trial will be carefully monitored by the Sponsor monitor (or designee) to ensure 
adherence to the Clinical Investigational Plan. All adverse events and device deficiencies will 
be reported to Abbott Vascular and will be monitored internally for safety surveillance 
purposes. 
13.2.4 Data Monitoring Committee (DMC) 
A Data Monitoring Committee will review safety and effectiveness data.  See Section 10.5 
for details.  
13.3 
Potential Benefit 
Data obtained from previous clinical trials with the MitraClip device has shown that subjects 
experience (post-procedure) clinically and statistically significant improvements in quality of 
life, heart failure symptoms, functional capacity and left ventricular volumes and dimensions.  
Additional potential benefits of the use of the MitraClip System include, but may not be 
limited to, the following: 

 
 
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• Reduction in heart failure hospitalization rate 
• Improved symptomatic status and quality of life  
• Improved LV function as measured by reverse remodeling of the LV 
• Reduced mortality 

 
 
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APPENDIX A: Definitions 
The following definitions will be used in the COAPT Clinical Investigational Plan.  All 
events constituting primary or secondary endpoints will be adjudicated by the independent 
Clinical Events Committee (except embolization, which will be site reported, and Mitral 
Valve Stenosis and SLDA, which will be assessed by Echocardiography Core Lab), along 
with relationship to the MitraClip device or procedure.   
ATRIAL FIBRILLATION (AF) – Heart Rhythm Society Guidelines 
Paroxysmal: Recurrent (≥ 2) atrial fibrillation episodes that terminate spontaneously 
within 7 days. 
Persistent:  Atrial fibrillation that is sustained beyond 7 days, or lasting less than 7 
days but necessitating pharmacologic or electrical cardioversion. 
Longstanding Persistent AF: Continuous atrial fibrillation of greater than 1 year 
duration. 
Permanent:  Atrial fibrillation in which cardioversion has failed or not been 
attempted.  
 
CARDIOVASCULAR DEATH (VARC) 
Cardiovascular death is defined by the Valve Academic Research Consortium 
(VARC)19 as any one of the following: 
– Any death due to proximate cardiac cause (e.g. MI, cardiac 
tamponade, worsening heart failure) 
– Unwitnessed death and death of unknown cause 
– All procedure-related deaths, including those related to a complication 
of the procedure or treatment for a complication of the procedure 
– Death caused by non-coronary vascular conditions such as 
cerebrovascular disease, pulmonary embolism, ruptured aortic 
aneurysm, dissecting aneurysm, or other vascular disease 
                                                 
19 Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for transcatheter aortic valve 
implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll 
Cardiol 2011;57:253-269. 

 
 
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DEVICE OR PROCEDURE RELATED ADVERSE EVENT 
Adverse events that are adjudicated by the Clinical Events Committee as probably, 
possibly or definitely device and/or procedure related, regardless of temporal 
relationship to the MitraClip procedure.  For events reported by the site that are not 
adjudicated by the Clinical Events Committee, the device relationship will be 
reported based on site reports.   
Examples of device-related adverse events are myocardial perforation, Single Leaflet 
Device Attachment, embolization of the MitraClip device or MitraClip System 
components, iatrogenic atrial septal defect, or the need for mitral valve replacement 
instead of repair due at least in part to the MitraClip procedure or the presence of the 
MitraClip device. 
MITRACLIP DEVICE EMBOLIZATION 
Detachment of the deployed MitraClip device from both mitral leaflets. 
ENDOCARDITIS 
Defined as a diagnosis of endocarditis based on the following Duke criteria. 
Duke Criteria  
(From The ACC/AHA Guidelines for the Management of Patients with Valvular Heart 
Disease, JACC, Vol 32, No.5,November 1, 1998:pg1541, Table 21) 
Pathological Criteria 
 
Microorganisms: culture or histology in a vegetation, in a vegetation 
that has embolized, or in an intracardiac abscess, or  
 
Pathological lesions: vegetation or intracardiac abscess present, 
confirmed by histology showing active endocarditis 
 
OR 
 
Clinical Criteria 
 
Major Criteria 
Persistently positive blood cultures: 
Typical organisms for endocarditis: Streptococcus viridans, S bovis, 
“HACEK” group, community acquired Staphylococcus aureus or 
enterococci, in the absence of a primary focus  
Persistent bacteremia:  
≥ 2 positive cultures separated by ≥12 hours or ≥ 3 positive cultures 
≥ 1 h apart or 70% blood culture samples positive if ≥ 4 are drawn 
Evidence of endocardial involvement 

 
 
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Positive echocardiogram 
Oscillating vegetation 
Abscesses 
Valve perforation 
New partial dehiscence of prosthetic valve 
New valvular regurgitation 
 
Minor Criteria 
Predisposing heart condition: 
MVP, bicuspid aortic valve, rheumatic or congenital heart disease, 
intravenous drug use  
Fever 
Vascular phenomena:  
Major arterial emboli, septic pulmonary emboli, mycotic aneurysm, 
intracranial hemorrhage, Janeway lesions 
Immunologic phenomena 
Glomerulonephritis,  Osler's nodes, Roth spots , and rheumatoid 
factor 
Positive blood culture: not meeting major criteria  
Echocardiogram: positive but not meeting major criteria 
 
Diagnosis 
2 major criteria or 
1 major plus 3 minor criteria or 
5 minor criteria 
 
EXTREMELY HIGH SURGICAL RISK 
The subject has co-morbidities such that the calculated STS mortality risk by either 
the replacement or repair calculator is ≥ 8%, or the subject has one or more individual 
co-morbidities that result in extremely high predicted operative risk of stroke or death 
as determined by the Central Eligibility Committee.   
FUNCTIONAL MITRAL REGURGITATION 
Defined as global or regional left ventricular wall motion abnormalities causing 
leaflet restriction or tethering with or without dilatation of the mitral annulus, but with 
no significant abnormalities of the mitral apparatus, except mild focal thickening 
thought to be related to aging. No leaflet flail or other evidence of degenerative MR 
may be present even in the presence of global or regional LV systolic dysfunction. 
GUIDELINE DIRECTED MEDICAL THERAPY (GDMT) 
Guideline Directed Medical Therapy (GDMT) is defined as per the 2013 ACCF/AHA 
Heart Failure Guidelines and specified below.  As described in the guidelines, 

 
 
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randomized controlled trials in patients with heart failure have primarily enrolled 
patients with a reduced left ventricular ejection fraction (LVEF ≤35% or ≤40%; i.e. 
heart failure with reduced EF).  It is only in these patients that efficacious therapies 
have been demonstrated to date.  Importantly, patients may also develop symptomatic 
heart failure with “borderline” EF (LVEF of 41% to 49%).  Many heart failure 
specialists choose to use the same medications at the same target doses to treat 
patients with borderline EF, especially those with severe MR, as they use to treat 
reduced EF patients.  Therefore, GDMT as defined below for patients with reduced 
EF will be applied for patients with preserved EF in the current study. 
Note: subjects must be on maximum tolerated dose, i.e., maximum dose unless the 
subject has documented intolerance to the maximum dose.    
Drug Class 
Drug Name 
INITIAL  
Daily Dose(s) 
MAXIMUM  
Daily Dose(s) 
ACE-
Inhibitors 
(ACE-I) 
 
Captopril 
6.25 mg TID 
50 mg TID 
Enalapril 
2.5 mg BID 
10 to 20 mg BID 
Fosinopril 
5 to 10 mg QD 
40 mg QD 
Lisinopril 
2.5 to 5 mg QD 
20 to 40 mg QD 
Perindopril 
2 mg QD 
8 to 16 mg QD 
Quinapril 
5 mg BID 
20 mg BID 
Ramipril 
1.25 to 2.5 mg QD 
10 mg QD 
Trandolapril 
1 mg QD 
4 mg QD 
Angiotensin- 
Receptor 
Blocker (ARB) 
 
Candesartan 
4 to 8 mg QD 
32 mg QD 
Losartan 
25 to 50 mg QD 
50 to 150 mg QD 
Valsartan 
20 to 40 mg BID 
160 mg BID 
Aldosterone 
Antagonists 
 
Spironolactone 
12.5 to 25 mg QD 
25 mg QD or BID 
Eplerenone 
25 mg QD 
50 mg QD 
Beta-Blockers 
Bisoprolol 
1.25 mg QD 
10 mg QD 
Carvedilol 
3.125 mg BID 
25 mg BID if subject is <85kgs* 
50 mg BID if subject is >85kgs* 
Carvedilol Controlled 
Release 
10 mg QD 
80 mg QD 
Metoprolol succinate 
extended release 
12.5 to 25 mg QD 
200 mg QD 
Vasodilators 
(nitrate and 
hydralazine):   
Fixed dose 
combination (424) 
37.5 mg hydralazine / 
20 mg isosorbide 
dinitrate TID 
75 mg hydralazine / 
40 mg isosorbide dinitrate TID 
Hydralazine + 
isosorbide dinitrate 
(429) 
Hydralazine: 25 to 50 
mg (TID or QID) + 
isosorbide dinitrate: 20 
to 30 mg (TID or QID) 
Hydralazine: 300 mg (QD in 
divided doses) + isosorbide 
dinitrate: 120 mg (QD in divided 
doses) 
 
This minimally includes an ACE-inhibitor (ACE-I) at stable doses for 30 days prior 
to subject registration in the trial, if tolerated, and a beta blocker (carvedilol, sustained 
release metoprolol succinate, or bisoprolol) for 90 days prior to subject registration in 
the trial, if tolerated, with a stable up-titrated dose for 30 days prior to subject 

 
 
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registration in the trial.  This also includes an Angiotensin II Receptor Blocker (ARB) 
at stable doses for 30 days prior to subject registration in the trial, if tolerated, when 
ACE-I is not tolerated.  Stable is defined as no more than a 100% increase or a 50% 
decrease in dose. 
If the subject is intolerant to ACE-I, ARB, or beta blockers, documented evidence 
must be available.  In those intolerant to both ACE-I and ARB, combination therapy 
with hydralazine and oral nitrate should be considered.  Therapeutic equivalence for 
ACE-I substitutions is allowed within the trial registration stability timelines.  
Aldosterone receptor antagonists [or mineralocorticoid receptor antagonists] are 
recommended in patients with NYHA class II-IV heart failure and who have LVEF of 
35% or less, unless contraindicated, to reduce morbidity and mortality.  Patients with 
NYHA class II should have a history of prior cardiovascular hospitalization or 
elevated plasma natriuretic peptide levels to be considered for aldosterone receptor 
antagonists.  If aldosterone inhibitor therapy is to be administered, it must be initiated 
and optimized at least 30 days prior to trial registration. Stability criteria are the same 
as for other neurohormonal antagonists.  Eplerenone requires dosage stability for 30 
days prior to subject registration in the trial similar to the other agents.  Diuretics may 
be used as necessary to keep the subject euvolemic.  All heart failure therapeutics and 
dosages should be documented in the electronic case report forms. 
As described in the 2013 ACCF/AHA Heart Failure Guidelines, randomized 
controlled trials in patients with heart failure have primarily enrolled patients with a 
reduced left ventricular ejection fraction (LVEF ≤35% or ≤40%; i.e. heart failure with 
reduced EF).  It is only in these patients that efficacious therapies have been 
demonstrated to date. 
 
However, patients may also develop symptomatic heart failure with “borderline” EF 
(LVEF of 41% to 49%).  Many Heart Failure Specialists choose to use the same 
medications at the same target doses to treat patients with borderline ejection fraction, 
especially those with severe MR, as they use to treat reduced EF patients; therefore, 
GDMT as defined for patients with reduced EF will be applied for patients with 
preserved EF. 
 
The Angiotensin Receptor-Neprilysin Inhibitor (ARNI) Sacubitril/Valsartan 
(EntrestoTM) and the sinoatrial node modulator Ivabradine (CorlanorTM) may be used 
as specified in the 2016 update* to the 2013 ACCF/AHA Guideline for the 
Management of Heart Failure.  Use of these two agents is not required.  However, if 
used, these drugs must be applied in accordance with the CIP as any other major 
change of GDMT described in the CIP.  Specifically, after a major change in 
medication or dose (and stabilization on the maximum dose tolerated), a TTE is 
required after 30 days to ensure that the subject still has symptomatic functional MR 
(≥3+), and meets all criteria for enrollment.  Per the 2016 Guideline update, ACE-I 
remains a Class I indication, and a subject should not be on both ACE-I and ARNI.   
 

 
 
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*Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological 
Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A 
Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical 
Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68:1476-88. 
 
HOSPITALIZATION (ALL-CAUSE) 
Defined as admission to inpatient unit or ward in the hospital for at least 24 hours, 
including emergency department stay.  Excludes hospitalizations planned for pre-
existing conditions, unless there is worsening in the baseline condition. 
Hospitalizations will be adjudicated by the Clinical Events Committee as Heart 
Failure or Other Cardiovascular hospitalization (see definitions below for Heart 
Failure and Other Cardiovascular hospitalizations). 
HEART FAILURE HOSPITALIZATION 
Defined as an event that meets the following criteria of either (A and B and C) 
or D:  
A) Requires hospitalization with treatment in any inpatient unit or ward in the 
hospital for at least 24 hours, including emergency department stay,  
AND 
B) Subject has clinical signs and/or symptoms of heart failure, including new 
or worsening dyspnea, orthopnea, paroxysmal nocturnal dyspnea, increasing 
fatigue, worsening functional capacity or activity intolerance, or signs and/or 
symptoms of volume overload,  
AND 
C) Results in intravenous (e.g., diuretic or vasoactive therapy) or invasive 
(e.g., ultrafiltration, IABP, mechanical assistance) treatment for heart failure.  
For the purpose of the Clinical Investigational Plan, overnight stays at nursing 
home facilities, physical rehab or extended care facilities, including hospice, 
do not meet the Clinical Investigational Plan definition of hospitalization.  All 
hospitalizations, including the index hospitalization for the MitraClip 
procedure, if complicated by acute worsening heart failure that would have 
prompted an admission to hospital for heart failure, AND requires intravenous 
or invasive treatment AND hospitalization is extended by 24 hours, as defined 
above, will also be considered a heart failure hospitalization.  Elective heart 
failure “tune-ups” that occur following the MitraClip procedure and prolong 
hospitalization will not count as a heart failure hospitalization.    
OR 

 
 
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D) Subject arrives in emergency department with clinical presentation 
meeting the criteria of heart failure, but dies in the emergency department 
before hospital admission. 
OTHER CARDIOVASCULAR HOSPITALIZATION 
Defined as treatment in any inpatient unit or ward in the hospital for at least 
24 hours, including emergency department stay for conditions such as 
coronary artery disease, acute myocardial infarction, hypertension, cardiac 
arrhythmias, cardiomegaly, pericardial effusion, atherosclerosis and peripheral 
vascular disease, not related to heart failure as defined. 
NON-CARDIOVASCULAR HOSPITALIZATION 
Hospitalizations that are not heart failure or other cardiovascular 
hospitalizations, as defined above, will be categorized as non-cardiovascular 
hospitalizations. 
INDEX PROCEDURE   
The procedure in which the MitraClip device implant is first attempted. First attempt 
of the MitraClip is when the subject is prepared for the procedure and groin is 
punctured for the transseptal procedure.   

 
 
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LOCAL SITE HEART TEAM 
The Local Site Heart Team must consist of, at a minimum, the CT Surgeon and Heart 
Failure specialist investigators. 
MAJOR BLEEDING  
Major bleeding is defined as bleeding ≥ Type 3 based on a modified Bleeding 
Academic Research Consortium (BARC)20 definition: 
• 
Type 3  
o Type 3a  
 
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided  
hemoglobin drop is related to bleed)  
 
Any transfusion with overt bleeding 
o Type 3b  
 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin 
drop is related to bleed)  
 
Cardiac tamponade 
 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 
Bleeding requiring intravenous vasoactive agents 
o Type 3c  
 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal) 
 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
 
Intraocular bleed compromising vision 
• 
Type 4: CV Surgery-related bleeding  
o Perioperative intracranial bleeding within 48 h 
o Reoperation after closure of sternotomy for the purpose of controlling bleeding 
                                                 
20 Mehrana R, Rao SV, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus 
report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. 

 
 
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o Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
o Chest tube output ≥2L within a 24-h period 
• 
Type 5: Fatal bleeding  
o Type 5a  
 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
o Type 5b  
 
Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation  
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL hemoglobin) 
†Cell saver products are not counted 
 
MITRAL VALVE STENOSIS 
Defined as a mitral valve orifice area of less than 1.5 cm2 as measured by the 
Echocardiography Core Laboratory. 
MODIFIED RANKIN SCALE SCORE DESCRIPTIONS 
0:  
No symptoms at all 
1:  
No significant disability despite symptoms; able to carry out all usual duties 
and activities 
2:  
Slight disability; unable to carry out all previous activities, but able to look 
after own affairs without assistance 
3:  
Moderate disability; requiring some help, but able to walk without assistance 
4:  
Moderately severe disability; unable to walk without assistance and unable to 
attend to own bodily needs without assistance 
5:  
Severe disability; bedridden, incontinent and requiring constant nursing care 
and attention 
6:  
Dead 
MITRACLIP PROCEDURE ATTEMPT 
 
Defined as administration of anesthesia for the MitraClip procedure. 
MYOCARDIAL INFARCTION 
Myocardial infarction (MI) classification and criteria for diagnosis is defined as 
follows:  
Peri-procedural MI (≤ 72 hours after MitraClip procedure) 

 
 
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Mandatory: CK-MB (preferred) ≥10x ULN within 72 hrs. post-MitraClip 
procedure in patient with normal baseline CK-MB  
OR 
Mandatory: CK-MB ≥5x ULN within 72 hrs. post-MitraClip procedure in patient 
with normal baseline CK-MB plus new pathological Q-waves in ≥2 contiguous 
leads, or new LBBB  
Post-surgery 
 
Mandatory: CK-MB ≥10x ULN (preferred) within 24 hrs. of cardiothoracic 
surgery plus 1 of the following: 
 
• New pathological Q-waves in ≥2 contiguous leads or new persistent LBBB on 
ECG ≥30 min. and ≤72 hrs. post-CABG cardiothoracic surgery, or 
• New substantial wall motion abnormalities by imaging except new septal or 
apical abnormalities. 
Spontaneous MI (>72 hours after MitraClip procedure) - this definition also 
applies to Control group subjects or Device group subjects who do not 
undergo the MitraClip procedure 
Any one of the following criteria: 
• Detection of rise and/or fall of cardiac biomarkers (CK-MB) with at least 
one value above the upper limits of normal (ULN), together with evidence 
of myocardial ischemia with at least one of the following:  
o ECG changes indicative of new ischemia [new ST-T changes or 
new left bundle branch block (LBBB)] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall 
motion abnormality 
• Sudden, unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by 
presumably new ST elevation, or new LBBB, and/or evidence of fresh 
thrombus by coronary angiography and/or at autopsy, but death occurring 
before blood samples could be obtained, or at a time before the appearance 
of cardiac biomarkers in the blood. 
• Pathological findings of an acute myocardial infarction. 

 
 
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NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA CLASS) 
Class I 
Patients with cardiac disease but without resulting limitations of 
physical activity. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  Patients are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  Patients are comfortable at rest.  Less than ordinary physical 
activity causes fatigue, palpitation dyspnea, or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased. 
NON-CARDIOVASCULAR DEATH 
Any death not covered by the definitions for Cardiovascular Death, such as death 
caused by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or 
trauma. 
NON-ELECTIVE (i.e., URGENT or EMERGENT) CARDIOVASCULAR SURGERY for 
DEVICE RELATED COMPLICATIONS 
Cardiovascular surgical procedure performed for device related complication 
requiring surgery within 24 hours of onset of adverse event.  If non-urgent surgery 
was performed within 24 hours of the onset of the adverse event but was not required 
within this timeframe, it will not be considered “non-elective”.   Examples of Device 
Related Complications are myocardial perforation, Single Leaflet Device Attachment, 
embolization of the MitraClip device or MitraClip System components, iatrogenic 
atrial septal defect, or the need for mitral valve replacement instead of repair due at 
least in part to the MitraClip procedure or the presence of the MitraClip device. 
OPTIMAL THERAPY  
Subjects with current or prior symptoms of heart failure and reduced LVEF should be 
on stable, optimal standard of care therapy according to current guidelines for heart 
failure in the United States.  This includes Guideline Directed Medical Therapy 
(GDMT) defined as per the 2013 ACCF/AHA Heart Failure Guidelines (see 
definition for Guideline Directed Medical Therapy). 
Additionally, it is recognized that approximately two-thirds of patients with HF have 
underlying CAD (ischemic cardiomyopathy).  Therefore, it is imperative that 
appropriate treatment for CAD be used in COAPT, according to the ACC/AHA 
Guidelines for Heart Failure.  Specific recommendations listed in those guidelines are 
listed as follows: 

 
 
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• Use of nitrates and beta blockers for the treatment of angina,  
• Coronary revascularization according to recommended guidelines in patients who 
have both HF and angina,  
• Patients with coronary artery disease and HF should be treated in accordance with 
recommended guidelines for chronic stable angina,    
• Use of antiplatelet agents for prevention of MI and death in patients with HF who 
have underlying coronary artery disease  
Subjects registered in COAPT should be treated with ICD and or CRT, as per the 
following guidelines, prior to subject registration in the trial: 
• An implantable cardioverter-defibrillator is recommended as secondary 
prevention to prolong survival in subjects with current or prior symptoms of 
HF and reduced LVEF who have a history of cardiac arrest, ventricular 
fibrillation, or hemodynamically destabilizing ventricular tachycardia.  
• Implantable cardioverter-defibrillator therapy is recommended for primary 
prevention of sudden cardiac death to reduce total mortality in subjects with 
non-ischemic dilated cardiomyopathy or ischemic heart disease at least 40 
days post-MI, a LVEF less than or equal to 35%, and NYHA functional class 
II or III symptoms while receiving chronic optimal medical therapy, and who 
have reasonable expectation of survival with a good functional status for more 
than 1 year  
• Subjects with LVEF of less than or equal to 35%, sinus rhythm, left bundle-
branch block (LBBB), a QRS duration of ≥ 150 ms, and NYHA functional 
class III or ambulatory class IV symptoms despite recommended optimal 
medical therapy, should receive cardiac resynchronization therapy, with or 
without an ICD, unless contraindicated  
In addition, revascularization (i.e., percutaneous coronary intervention, etc.) should 
occur prior to subject registration in the trial as applicable. 
QUALIFYING TRANSTHORACIC ECHOCARDIOGRAM (TTE)  
Qualifying TTE is defined as the TTE performed within 90 day prior to subject 
registration for confirmation of MR severity by the ECL.  
PROLONGED VENTILATION 
Defined as pulmonary insufficiency requiring ventilatory support for greater than 48 
hours post-catheterization. 

 
 
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SERIOUS ADVERSE EVENT (SAE) 
If the AE meets any of the criteria below, it is regarded as serious adverse event 
(SAE).  
a) Led to a death, 
b) Led to a serious deterioration in health that either: 
1) Resulted in a life-threatening illness or injury, or 
2) Resulted in a permanent impairment of a body structure or a body function, 
or 
3) 
Required 
in-patient 
hospitalization 
or prolongation 
of 
existing 
hospitalization, or 
4) Resulted in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function. 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
d) An important medical event that may not result in death, be life-threatening, or 
require hospitalization but may be considered serious when, based upon appropriate 
medical judgment, may jeopardize the subject and/or may require intervention to 
prevent one of the outcomes listed in this definition 
NOTE 1: This includes device deficiencies that might have led to a serious adverse 
event if a) suitable action had not been taken or b) intervention had not been made or 
c) if circumstances had been less fortunate. These are handled under the SAE 
reporting system. 
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure 
required by the Clinical Investigation Plan, without a serious deterioration in health, 
is not considered to be a serious adverse event. 
SINGLE LEAFLET DEVICE ATTACHMENT (SLDA) 
Defined as unilateral MitraClip detachment from one leaflet, as assessed by the 
Echocardiography Core Laboratory or during mitral valve surgery.   Reasons for 
MitraClip Detachment include leaflet tearing, MitraClip unlocking, MitraClip fracture 
or inadequate MitraClip placement.  Not included are any fractures or other failures 
of the MitraClip that do not result in MitraClip detachment from one or both leaflets.   

 
 
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STROKE and TIA 
Stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction.  Stroke may be classified as ischemic or hemorrhagic with appropriate 
sub-definitions.  Ischemic stroke is defined as an acute episode of focal cerebral, 
spinal, or retinal dysfunction caused by infarction of central nervous system tissue.  
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid 
hemorrhage.  A stroke may be classified as undetermined if there is insufficient 
information to allow categorization as ischemic or hemorrhagic. 
An entity closely related to ischemic stroke is transient ischemic attack (TIA).  TIA is 
defined as a transient episode of focal neurological dysfunction caused by brain, 
spinal cord, or retinal ischemia, without acute infarction.  The difference between 
TIA and ischemic stroke is the presence of infarction.  In the absence of affirmative 
evidence confirming the presence or absence of infarction, a symptom duration of 24 
hours will be used to distinguish TIA from ischemic stroke.  By definition, TIA does 
not produce lasting disability. 
The assessment of disability resulting from the stroke will be performed by the 
modified Rankin Scale (mRS).  Assessment of the mRS should occur at all scheduled 
visits through 24 months and at 90 days after stroke onset.  This approach will 
maximize the detection of new strokes, assist in ongoing evaluation of events 
previously determined to be TIAs, and provide an accepted and reliable indicator of 
the long-term impact of a given stroke.  A disabling stroke is one that results (at 90 
days after stroke onset) in an mRS score of 2 or more and in an increase of at least 
one mRS category from the individual’s pre-stroke baseline.  A non-disabling stroke 
is one that results (at 90 days after stroke onset) in an mRS score of less than 2 or that 
does not result in an increase of at least one mRS category from an individual’s pre-
stroke baseline. 
Although imaging (typically, MRI for acute and chronic ischemia and haemorrhage, 
and CT for acute and chronic haemorrhage and chronic ischemia) is often used to 
supplement the clinical diagnosis of stroke, a diagnosis of stroke may be made on 
clinical grounds alone.   
Diagnostic criteria 
Acute episode of a focal or global neurological deficit with at least one of the following: change in level 
of consciousness, hemiplegia, hemiparesis, numbness or sensory loss affecting one side of the 
body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs or 
symptoms consistent with stroke 
Stroke – Duration of a focal or global neurological deficit ≥24 h; OR <24 h if available neuroimaging 
documents a new hemorrhage or infarct; OR the neurological deficit results in death 
TIA – Duration of a focal or global neurological deficit <24 h, any variable neuroimaging does not 
demonstrate a new hemorrhage or infarct 
No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain tumor, trauma, 

 
 
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infection, hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in 
conjunction with designated neurologist* 
Confirmation of the diagnosis by at least one of the following: 
Neurologist or neurosurgical specialist 
Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds 
alone 
Stroke classification 
Ischemic – An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of 
central nervous system tissue 
Hemorrhagic – An acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage 
A stroke may be classified as undetermined if there is insufficient information to allow categorization as 
ischemic or hemorrhagic 
Stroke definitions† 
Disabling stroke –  a mRS score of 2 or more at 90 days and an increase of at least one mRS category 
from an individual’s pre-stroke baseline 
Non-disabling stroke – a mRS score of less than 2 at 90 days or one that does not result in an increase of 
at least one mRS category from an individual’s pre-stroke baseline 
*Patients with non-focal global encephalopathy will not be reported as a stroke without unequivocal 
evidence of cerebral infarction based upon neuroimaging studies (CT scan or Brain MRI). 
†Modified Rankin Scale assessments should be made by qualified individuals according to a certification 
process. 
 
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT  
Unanticipated serious adverse device effect (USADE) refers to any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects. 
UNPLANNED HEART FAILURE VISIT 
An "unplanned heart failure visit" is considered to include unscheduled office visits 
or Emergency Department (ED) visits that meet the definition for Heart Failure 
hospitalization, with the exception of the 24 hour requirement. 
VULNERABLE POPULATION (ISO14155 Definition) 
Individuals with mental disability, persons in nursing homes, children, impoverished 
persons, persons in emergency situations, homeless persons, nomads, refugees, and 
those permanently incapable of giving informed consent.  Vulnerable populations 
also may include members of a group with a hierarchical structure such as university 
students, subordinate hospital and laboratory personnel, employees of the Sponsor, 
members of the armed forces, and persons kept in detention. 

 
 
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APPENDIX B: Echocardiography Protocol  
Inclusion criteria and study endpoints will be determined with serial echocardiography 
performed at the individual investigational sites and interpreted at the Echocardiography 
Core Laboratory (ECL).  The independent ECL will be responsible for the review and 
assessment of all echocardiograms obtained on registered subjects.  The following guidelines 
should be followed for study echocardiograms.  Site echocardiographic analysis will be 
performed by the Site’s Echo Investigator.  All measures required by the eCRF should be 
completed or noted when not possible. 
I. 
General Echocardiographic Procedures 
1. The EKG signal should be clearly visible on all frames. 
2. Echocardiograms should be identified by the subject number assigned for the 
purpose of the trial.  The eCRF will identify subject number and the date of 
the visit. 
3. Echocardiographic images will be acquired and exported/transferred in digital 
format and saved as a DICOM image.   
4. Height will be measured at the time of the first echocardiogram and weight 
will be measured and recorded on the eCRF at the time of each 
echocardiogram.  
5. Blood pressure and heart rate will be recorded at the start of the echo study on 
the echo worksheet. 
6. Variance maps should be turned off for the study. 
7. An intravenous catheter may be placed for administration of left-sided 
contrast agent if needed for visualization of endocardial borders to enable 
accurate measurement of LV volumes.  If a contrast agent is used for the 
baseline echocardiogram, it should also be used for all subsequent follow-up 
echocardiograms. 
8. Site will provide a completed worksheet to accompany the digital DICOM 
echocardiogram for each echo study.  For purposes of quality control, the site 
personnel are instructed to make and record all of the measurements and 
calculations required on the worksheet for reference for each screening echo 
study. 
9. It is recommended that each site identify a single sonographer to perform all 
echo studies for a single subject, and that one echocardiography system be 
used for the image acquisition to the extent possible.   

 
 
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II. 
Echocardiographic Protocol for Image Acquisition 
For the echocardiogram, the patient will be positioned in left lateral recumbency or in 
the position that permits optimal imaging.  It is strongly recommended that an 
echocardiography bed with a dropout be used if available.  With digital archiving, at 
least 3 cardiac cycles for normal sinus rhythm or paced, and at least 5 cardiac cycles 
for Afib are requested.  Unless otherwise specified, depth should be adjusted to 
maximize the image while including all necessary structures.  All images will be 
acquired at end-expiration held during quiet respiration.  Harmonic imaging should be 
employed to optimize visualization of endocardial borders.  All spectral pulsed wave 
(PW) and continuous wave (CW) Doppler will be performed at a sweep speed of 100 
mm/sec.  Color Doppler Nyquist limits will be adjusted to the range of 50 – 70 
cm/sec, unless otherwise specified. 
1. PLAX with and without magnification of the left ventricular outflow tract; 
with and without color flow Doppler interrogation of the aortic and mitral 
valves.  Careful attention will be paid to identifying the vena contracta of the 
mitral regurgitant jet using zoom views.  The vena contracta is the narrowest 
portion (or the “neck”) of the jet as it crosses the valve leaflets.  The Nyquist 
limit should be set between 50 and 70 cm/sec and a zone of proximal jet 
acceleration should be identified on the ventricular aspect of the leaflets. 
2. PSAX at the mid-papillary muscle level.  
3. PSAX at the tips of the mitral valve leaflets to identify the minimum diastolic 
orifice of the mitral valve. When a MitraClip implant is present each mitral 
valve orifice should be imaged separately. 
4. PSAX at the level of the mitral valve when both anterior and posterior leaflets 
are visualized.  Position the Color Doppler scan box over the mitral orifice to 
visualize the regurgitant jet origin. 
5. Basal PSAX (at the aortic valve level).  Pulsed Doppler sample of pulmonary 
flow at the level of the pulmonary valve to measure pulmonary velocity time 
interval (VTI) opening and closing transients of the pulmonary valve should 
be recorded.  Optimization of the pulmonary valve annulus for measurement 
of the pulmonary annular diameter. 
6. Apical 4-chamber view, with and without color flow interrogation of mitral 
and tricuspid valves.  The color flow Doppler interrogation should include the 
entire left atrium taking care to include wall-impinging eccentric jets in the 
region of interest.  Gain should be adjusted to reduce excess noise.  Spectral 
Doppler interrogation in this view includes: 
a. PW Doppler of mitral inflow at mitral leaflet tips. 

 
 
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b. PW Doppler of mitral inflow at the level of the mitral annulus at end-
diastole with a small sample volume.  
c. CW of the mitral inflow signal. 
d. CW of the mitral regurgitant jet with care to record a complete signal 
and maximize the peak velocity.  Contrast should be used to enhance 
this signal when incomplete and when a peak velocity cannot be 
determined.  NOTE: Occasionally eccentric CW jets may require 
interrogation of additional views (EG. PLAX, Apical 2C view) to 
obtain the true maximal jet velocity. 
e. CW of tricuspid regurgitant jet for estimation of pulmonary artery 
systolic pressure.  If jet is inadequate for measurement, this recording 
should be repeated following contrast injection (see below). 
f. PW Doppler of right pulmonary vein flow.  The sample volume 
should be placed at least 1 cm within the pulmonary vein, if possible. 
If jet is inadequate for measurement, this recording should be 
repeated following contrast injection (see below). 
g. Color flow Doppler visualization of PISA (proximal isovelocity 
surface area) using zoomed views for estimation of regurgitant orifice 
area.  The Nyquist limit will be lowered and the baseline shifted in 
the direction of flow (toward left atrium) to maximize the PISA 
signal.  The PISA aliasing velocity should be set to optimize the 
hemispheric shape of the proximal flow convergence region (usually 
30-40 cm). 
7. Anteriorly angulated 4-chamber view: 
a. Color flow Doppler to exclude aortic insufficiency.  If present, aortic 
insufficiency jet will be optimized to permit measurement of the 
pressure half time using CW Doppler. 
b. PW Doppler in left ventricular outflow tract positioned such that 
closing artifact but not opening artifact of the valve is visible. 
c. CW Doppler through the aortic valve. 
8. Apical 2-chamber view with and without color interrogation of the mitral 
valve. 
9. Apical long-axis (also known as 3-chamber) view with and without color flow 
interrogation of the mitral valve.  Zoom mode should also be used to identify 
the vena contracta and PISA in this view, as noted above. 

 
 
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10. Subcostal imaging of the inferior vena cava with and without a “sniff”. 
11. Color Doppler of inter-atrial septum to interrogate presence of ASD.   
12. Apical images of the left ventricle (LAX, 2- and 4-chamber views) should be 
collected taking care to minimize foreshortening.   
13. Contrast will be used for endocardial border delineation when the 
endocardium is not well visualized on the harmonic image.  For subjects with 
renal dysfunction, intravenous contrast should not be used during the 
procedure unless absolutely necessary.  Contrast can also be employed for 
enhancement of the tricuspid regurgitant and pulmonary venous flow signals.  
During the contrast imaging, the mechanical index should be adjusted to avoid 
bubble destruction artifacts (usually a mechanical index of 0.3-0.5), and 
contrast infusion rate adjusted to avoid obliteration of the mitral annulus.  
Ideally, the focus should be set at the mitral annulus level.  If a contrast agent 
is used for the baseline echocardiogram, it should also be used for all 
subsequent follow-up echocardiograms, unless subject experiences renal 
dysfunction. 
14. For follow-up post-MitraClip implant, images of the MitraClip(s) in the 
following four views should be collected both with and without color Doppler 
to verify MitraClip position: 
a. SAX – non-oblique at the Mitral Valve level 
b. PLAX 
c. Apical 4-chamber and long-axis 
d. Anterior and posterior Intercomissural (IC) images 

 
 
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APPENDIX C: Monitoring Exposure to Ionizing Radiation 
(1) Implanting Investigator Training   
Prior to treating patients with the MitraClip device, all implanting investigators shall 
complete the MitraClip therapy training curriculum, including training to this section of the 
study Clinical Investigational Plan.   
(2) Pre, Peri and Post-MitraClip Procedure   
The implanting investigator shall be responsible for patient radiation levels and shall ensure 
that radiation dose accumulation is continuously monitored during the procedure (NCRP 
2010).  Documentation of dose levels shall be in accordance with the individual requirements 
of the respective institution’s quality management program.  In addition, the following shall 
apply:   
a. Dose Measurements required for MitraClip procedure  
Where the fluoroscopy system has the functionality for the output of data, the following 
dose measurements shall be recorded in the subject records and reported in the eCRFs.   
• Total fluoro time:  to be reported in minutes 
• Total number of fluoro frames:  to be reported as whole numbers, no associated units  
• Air kerma-area product (PKA) (dose area product):  to be reported in Gy cm2 
• Air kerma at the reference point (Ka,r):  to be reported in Gy 
• Peak skin dose (Dskin, max):  to be reported in Gy 
Investigational centers that are unable to provide the information due to the limitations of 
their fluoroscopy systems are exempt from the reporting requirements. 
b. Substantial Radiation Dose Level (SRDL) 
The SRDL is a trigger level to initiate follow-up of a radiation dose that may produce a 
clinically relevant injury in an average patient.  Procedures, such as the MitraClip 
procedure, that are performed using biplane fluoroscopy systems are a special situation 
because the dose received from each plane should be considered independently when the 
fields do not overlap.  When they do overlap, the doses are additive and if it is uncertain 
whether the fields overlap, it should be assumed that they do. 
 

 
 
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The following are suggested values for first and subsequent notifications and the SRDL 
based upon a 100cm2 field at the subject’s skin.  The implanting investigator should 
adjust the notifications and the SRDL proportionally to the actual procedural field size.  
When the SRDL has been exceeded, the implanting investigator shall document the dose 
exceeded and the justification for the radiation dose level used (NCRP 2010).       
Suggested values for first and subsequent 
notifications and the SRDL (NCRP 2010) 
Dose Metric 
First 
Notification 
Subsequent 
Notifications 
(increments) 
SRDL 
Dskin,max 
 
2 Gy 
0.5 Gy 
3 Gy 
Ka,r 
 
3 Gy 
1 Gy 
5 Gy 
PKA 
 
300 Gy cm2* 
100 Gy cm2* 
500 Gy cm2* 
Fluoroscopy time 
 
30 min 
15 min 
60 min 
*  Assuming a 100 cm2 field at the subject’s skin.  For other field sizes, the PKA values should be adjusted proportionally 
to the actual procedural field size (e.g., for a field size of 50 cm2, the SRDL value for PKA would be 250 Gy cm2). 
 
i. 
Acute Evaluation 
Subjects should be advised of the possibility of a skin injury due to a tissue reaction, and 
should be told to examine the beam entrance site at 2-4 weeks after the procedure and 
report any observations to the site Principal Investigator or designee.  During the 7-day 
phone follow-up, the subject should be asked whether the subject has experienced a skin 
injury at or near the beam entrance site.  During the physical examination at the 30-day 
follow-up clinic visit, the site Principal Investigator or designee shall examine the 
integrity of the subject’s skin at or near the beam entrance site.  If there is evidence of 
skin injury, the site Principal Investigator or designee shall report it as an adverse event in 
accordance with the adverse event reporting requirements.  
ii. 
Long-term Evaluation 
The site Principal Investigator or designee is responsible for the ongoing collection and 
monitoring of radiation doses.  An examination of the subject’s skin at or near the beam 
entrance site shall be performed by the site Principal Investigator or designee.  If skin 
injury resulting from radiation exposure during the MitraClip procedure is ongoing 
beyond the 30-day follow-up, the site Principal Investigator or designee should arrange 
for follow-up care.  Observations of skin injury shall be reported as an adverse event in 
accordance with the adverse event reporting requirements.           

 
 
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APPENDIX D: Components of Frailty  
The following components of Frailty Index will be collected at baseline but will not be utilized to 
screen subjects for the trial. The assessment can be administered by either an investigator or 
research coordinator.  
1. Date of assessment 
                                _____/_____/____ (DD/MON/YYYY) 
2. Katz activities of daily living: Activities of Daily Living is assessed based on an evaluation 
of the functional independence or dependence of patients in bathing, dressing, going to toilet, 
transferring, continence, and feeding. Assess the following: 
BATHING -  
check one 
• Subject bathes self completely or needs help in bathing only a single part of 
the body such as the back, genital area or disabled extremity. 
• Subject needs help with bathing more than one part of the body, getting in 
or out of the tub or shower. 
• Requires total bathing. 
DRESSING -  
check one 
• Subject gets clothes from closets and drawers and puts on clothes and outer 
garments complete with fasteners. 
• May have help tying shoes. 
• Subject needs help with dressing self or needs to be completely dressed. 
TOILETING - 
check one 
• Subject goes to toilet, gets on and off, arranges clothes, cleans genital area 
without help. 
• Subject needs help transferring to the toilet, cleaning self or uses bedpan or 
commode. 
TRANSFERRING - 
check one 
• Subject moves in and out of bed or chair unassisted. Mechanical 
transferring aides are acceptable. 
• Subject needs help in moving from bed to chair or requires a complete  
CONTINENCE - 
check one 
• Subject exercises complete self-control over urination and defecation. 
• Subject is partially or totally incontinent of bowel or bladder. 
FEEDING -  
check one 
• Subject gets food from plate into mouth without help. Preparation of food 
may be done by another person. 
• Subject needs partial or total help with feeding or requires parenteral 
feeding. 
 
3. Grip strength: The grip strength test is used to determine the strength in each of the subject’s 
hands. 
Procedure: 
Equipment: Hand Dynamometer (will be provided by Sponsor if not available at the site) 
i. Illustrate the use of the instrument to the subject prior to testing. 

 
 
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ii. The subject should be in a seated position. Elbow should be at a 90 degree angle, with arm 
not resting on table or “pinned” against chest wall.  
iii. Ask the subject to squeeze the dynamometer with as much force as possible with the 
dominant hand, being careful to squeeze only once for each measurement. 
iv. Three trials should be made with a pause of about 10-20 seconds between each trial to 
avoid muscle fatigue. 
v. The grip strength in each of the 3 trials should be reported on the case report form. 
 
4. 15-feet Gait Test: The Gait Test measures, in seconds, the time a person takes walk 15 feet 
Procedure: 
i. Accompany the subject to the designated area, which should be well-lit, unobstructed, and 
contain clearly indicated markings at 0 and 15 feet 
ii. Position the subject with his/her feet behind and just touching the 0-foot start line 
iii. Instruct the subject to “Walk at your comfortable pace” until a few steps past the 15-feet 
mark (the subject should not start to slow down before the 15-feet mark) 
iv. Begin each trial on the word “Go” 
v. Start the timer with the first footfall after the 0-meter line 
vi. Stop the timer with the first footfall after the 15-foot line 
vii. Repeat 3 times, allowing sufficient time for recuperation between trials.  Record the time 
taken to walk 15 feet on each of 3 trials. If subject is unable to walk 15 feet, record the 
reason.  
 
Note: Subject may use a walking aid (cane, walker). If the subject is receiving an intravenous 
(IV) drip, he/she should perform the test without the IV only if it can be interrupted temporarily 
without any potential risk to the subject, if not, then the subject may perform the test pushing the 
IV pole. 
 
 

 
 
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APPENDIX E: ATS 6 Minute Walk Test Guidelines 

 
 
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APPENDIX F:  Rates of Foreseeable Adverse Events 
The potential risks associated with the MitraClip procedure are similar to those for standard 
cardiac catheterization techniques and the administration of anesthesia; however, all of the risks 
may not be known.  Although anticipated risks are described below, due to the nature of this 
study, there may also be other risks, which are not known at this time.  Additionally the risk of a 
device deficiency may occur, such as but not limited to; dislodgement of previously implanted 
devices and failure to retrieve MitraClip System components.  The ability of the MitraClip 
device to maintain long term MR reduction is unknown.   
The risks below have been grouped by expected seriousness, but may vary in seriousness.  The 
risks associated with the MitraClip procedure include, but are not limited to, the following (rates 
are derived from a cohort of 351 high surgical risk patients undergoing the MitraClip procedure 
in US clinical trials and from global MitraClip experience for 2012):   
1. Very Common:  ≥ 10%:  Nausea/ vomiting. 
2. Common:  ≥ 1.0% to <10%:  Aneurysm or pseudo-aneurysm; Arrhythmias; Atrial 
fibrillation; Bleeding disorders including Coagulopathy or Hemorrhage requiring 
transfusion; Cardiac arrest; Cardiac perforation; Death; Edema (swelling or fluid 
accumulation); Fever or hyperthermia (high body temperature); Gastrointestinal bleeding 
or infarct; Hypotension/hypertension (low or high blood pressure); Infection; Pain; Mitral 
valve injury; Myocardial infarction; Prolonged angina; Pulmonary congestion; Renal 
insufficiency or failure; Shock, Anaphylactic or Cardiogenic; Single leaflet device 
attachment (SLDA); Stroke or transient ischemic attack (neurologic complication lasting 
<24 hours); Vascular trauma, dissection, or occlusion; Vessel perforation or laceration; 
Worsening heart failure. 
3. Uncommon:  ≥ 0.1% to <1.0%:  Allergic reaction (anesthetic, contrast, Heparin, nickel 
alloy, latex);Drug reaction to anti-platelet/anticoagulation agents/contrast media; Arterio-
venous fistula; Atrial septal defect requiring intervention; Cardiac tamponade/Pericardial 
Effusion; Chordal entanglement/rupture; Conversion to standard valve surgery; Deep 
venous thrombosis (DVT); Dizziness, Dyspnea (shortness of breath); Emboli (air, 
thrombus, MitraClip device); Emergency cardiac surgery; Esophageal irritation; 
Esophageal perforation or stricture; Failure to deliver MitraClip to the intended site; 
Failure to retrieve MitraClip System or components; Hematoma; Infection; Septicemia; 
Injury to mitral valve complicating or preventing later surgical repair;  MitraClip erosion, 
migration or malposition; Multi-system organ failure; Peripheral ischemia; Urinary tract 
infection; Vessel spasm; Worsening mitral regurgitation.  
4. Rare:  ≥ 0.01% to <0.1%:  MitraClip Device thrombosis; MitraClip Device embolization; 
Prolonged ventilation (use of a breathing machine); Mitral stenosis; Respiratory 
failure/atelectasis (inability to expand the lungs fully)/pneumonia; Skin injury or tissue 
changes due to exposure to ionizing radiation. 

 
 
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5. Very Rare:   < 0.01% (including not reported AEs):  Dyskinesia; Endocarditis; 
Hemolysis; Lymphatic complications; Mesenteric ischemia; Pulmonary thrombo-
embolism; Wound dehiscence.