A Contemporary, Prospective Study Evaluating Real-world Experience of Performance and Safety for the Next Generation of MitraClip® Devices (EXPAND)
Conditions: Mitral Valve Regurgitation, Mitral Regurgitation
Sponsor: Abbott Medical Devices

MitraClip® EXPAND Study 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
Page 1 of 68 
Do not distribute or reproduce with the prior written permission of Abbott 
17-518: The MitraClip® EXPAND Study 
A Contemporary, Prospective Study Evaluating Real-world Experience of 
Performance and Safety for the Next Generation of MitraClip® Devices 
Version Number 
2.0 
Date 
26 June 2018 
Primary 
Investigators:  
OUS:  
Prof. Francesco Maisano 
University Hospital Zurich 
Switzerland 
US: 
Dr. Saibal Kar 
Cedars Sinai 
Los Angeles, CA 
Planned Number of 
Sites and Region(s) 
Up to 60 sites in Europe and the U.S. 
Abbott Medical 
Expert 
Ihsen Merioua, MD 
Director, Medical Affairs Structural Heart 
Study Type 
Prospective, Multi-Center, Single-Arm, International, Post Market 
Observational Study 
Sponsor 
/ 
Study 
Monitor 
Abbott  
3200 Lakeside Drive, Santa Clara, CA 95054 
Electronic Data 
Capture  
ORACLE CLINICAL 
Core Laboratories 
A core laboratory (core-lab) will be utilized to make echocardiographic 
assessments on a subset of patients enrolled into this study. The core-
lab will be identified at a later stage of the study. 
Clinical Events 
Committee 
An independent clinical events committee (CEC) will be established to 
adjudicate major adverse events in this study. The CEC will be 
established at a later stage of the study. 
Steering Committee 
Dr. Rodrigo Estévez-Loureiro 
Hospital Universitario Puerta de 
Hierro-Majadahonda 
Madrid, Spain 
Prof. Ulrich Schäfer 
University Hospital Hamburg-
Eppendorf  
Hamburg, Germany 
Dr. Carmelo Grasso   
University of Catania   
Catania, Italy       
Dr. Paul Sorajja 
Minneapolis Heart Institute at Abbott 
Northwestern Hospital 
Minneapolis, MN 
Prof. Jörg Hausleiter 
Medizinische Klinik und 
Poliklinik I der Ludwig 
München, Germany 
Dr. Ralph Stephan von Bardeleben 
Universitätsmedizin der Johannes 
Gutenberg 
Mainz, Germany 
Dr. Scott Lim 
University of Virginia 
Charlottesville, Virginia 
Prof. Stephan Windecker 
Swiss Cardiovascular Center 
Bern, Switzerland 
Protocol Author 
Erin Tims, MS, CCRP,  
Clinical Advisor - Abbott Structural Heart 
Redacted Version  A 
Nov 15, 2021

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 2 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Table of Contents 
TABLE OF CONTENTS .................................................................................................................. 2 
COMPLIANCE STATEMENT: ......................................................................................................... 5 
PROTOCOL SUMMARY ................................................................................................................. 6 
1.0 
INTRODUCTION .................................................................................................................. 8 
1.1 
Study Design .................................................................................................................... 8 
1.2 
Study Objective ................................................................................................................ 9 
2.0 
BACKGROUND AND RATIONALE ...................................................................................... 9 
2.1 
Background ...................................................................................................................... 9 
2.1.1 
MitraClip® Clinical Trials Conducted for Approval ......................................................... 9 
2.1.2 
MitraClip® Post-Market Clinical Studies ...................................................................... 11 
2.1.3 
Mitral Valve Anatomies: Impact on MitraClip Use and Outcomes ................................ 12 
2.2 
Study Rationale .............................................................................................................. 13 
2.3 
Summary of Device ........................................................................................................ 14 
2.3.1 
Name of the Device .................................................................................................... 14 
2.3.2 
Indication for Use ........................................................................................................ 14 
2.3.3 
Description of the Device ............................................................................................ 14 
3.0 
STUDY FLOW AND FOLLOW-UP SCHEDULE ................................................................. 15 
3.1 
Number of Subjects ........................................................................................................ 15 
3.2 
Overall Flow of the Study and Follow-up Schedule ......................................................... 16 
3.3 
Measures Taken to Avoid and Minimize Bias.................................................................. 16 
3.3.1 
Study Flow .................................................................................................................. 16 
3.3.2 
Clinical Events Committee .......................................................................................... 17 
3.3.3 
Steering Committee .................................................................................................... 17 
3.4 
Early Termination of the Clinical Study ........................................................................... 17 
4.0 
STUDY ENDPOINTS ......................................................................................................... 17 
4.1 
Safety and Performance Measures ................................................................................. 17 
4.2 
Acute Measures .............................................................................................................. 17 
4.3 
Clinical Measures ........................................................................................................... 18 
4.4 
Functional Improvement Measures ................................................................................. 18 
4.5 
Site Reported Echocardiographic Measures ................................................................... 18 
4.6 
Core Lab Subgroup: ....................................................................................................... 19 
5.0 
SUBJECT SELECTION AND WITHDRAWAL .................................................................... 19 
5.1 
Subject Population .......................................................................................................... 19 
5.1.1 
Anatomy Complexity ................................................................................................... 19 
5.2 
Subject Screening and Informed Consent ....................................................................... 20 
5.2.1 
Subject Screening ....................................................................................................... 20 
5.2.2 
Informed Consent ....................................................................................................... 20 
5.3 
Eligibility Criteria ............................................................................................................. 21 
5.3.1 
Inclusion Criteria ......................................................................................................... 21 
5.3.2 
Exclusion Criteria ........................................................................................................ 21 
5.4 
Subject Enrollment and Inclusion .................................................................................... 21 
5.5 
Subject Discontinuation .................................................................................................. 21 
5.6 
Total Expected Duration of the Study ............................................................................. 22 
5.7 
Expected Duration of Each Subject’s Participation ......................................................... 22 
5.8 
Number of Subjects Required to be Included in the Study .............................................. 22 
5.9 
Estimated Time Needed to Select this Number ............................................................... 22 
5.10 
Study Completion ........................................................................................................... 22 
6.0 
TREATMENT AND FOLLOW-UP ASSESSMENTS ............................................................ 23 
6.1 
Pre-Treatment ................................................................................................................ 23 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 3 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
6.1.1 
Protocol Required Medications ................................................................................... 23 
6.1.2 
Clinical Assessments .................................................................................................. 23 
6.1.3 
Pre-treatment Imaging ................................................................................................ 23 
6.2 
Index Procedure ............................................................................................................. 23 
6.2.1 
Treatment ................................................................................................................... 24 
6.3 
Post-Procedure ............................................................................................................... 24 
6.3.1 
Final (Post-procedure) Imaging ................................................................................... 24 
6.4 
Subject Follow-up ........................................................................................................... 24 
6.4.1 
Follow-Up Imaging ...................................................................................................... 24 
7.0 
ADVERSE EVENTS ........................................................................................................... 25 
7.1 
Definitions ....................................................................................................................... 25 
7.1.1 
Adverse Event ............................................................................................................ 25 
7.1.2 
Serious Adverse Event ............................................................................................... 25 
7.1.3 
Device Deficiency/Device Malfunction ........................................................................ 26 
7.2 
Device Relationship ........................................................................................................ 26 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting ................................... 26 
7.3.1 
Adverse Event Reporting ............................................................................................ 26 
7.3.2 
Device Deficiency/Device Malfunction Reporting ........................................................ 27 
7.3.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .............. 27 
8.0 
ADJUDICATION OF EVENTS ............................................................................................ 27 
8.1 
The Clinical Events Committee (CEC) ............................................................................ 27 
9.0 
STATISTICAL ANALYSIS .................................................................................................. 28 
9.1 
Statistical Overview ........................................................................................................ 28 
9.2 
Analysis Populations....................................................................................................... 28 
9.3 
Sample Size Calculations and Assumptions ................................................................... 28 
9.3.1 
Planned Interim Analyses ........................................................................................... 28 
9.4 
Statistical Analyses ......................................................................................................... 28 
9.4.1 
Endpoint Analysis ....................................................................................................... 28 
9.4.2 
Subgroup Analysis ...................................................................................................... 29 
9.4.3 
Handling of Multiplicity Issues ..................................................................................... 29 
9.4.4 
Criteria for Early Termination of the Study for Efficacy ................................................ 29 
9.4.5 
Procedures for Accounting for Missing, Unused or Spurious Data .............................. 29 
9.4.6 
Pooling Strategy ......................................................................................................... 29 
9.5 
Deviations from the Original Statistical Plan ................................................................... 29 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................................................... 29 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................... 29 
11.1 
Selection of Clinical Sites and Investigators .................................................................... 29 
11.2 
Protocol Amendments .................................................................................................... 30 
11.3 
Training .......................................................................................................................... 30 
11.3.1 
Site Training ............................................................................................................ 30 
11.3.2 
Training of Sponsor’s Monitors ................................................................................ 30 
11.4 
Monitoring ....................................................................................................................... 30 
11.5 
Deviations from Protocol ................................................................................................. 31 
11.6 
Quality Assurance Audit ................................................................................................. 31 
11.7 
Sponsor Auditing ............................................................................................................ 31 
11.8 
Committees .................................................................................................................... 32 
11.8.1 
Steering Committee ................................................................................................ 32 
11.8.2 
Clinical Events Committee (CEC) ........................................................................... 32 
12.0 
DATA HANDLING AND RECORD KEEPING ..................................................................... 32 
12.1 
Source Documentation ................................................................................................... 33 
12.2 
Electronic Case Report Form Completion ....................................................................... 33 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 4 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
12.3 
Record Retention ............................................................................................................ 33 
13.0 
ETHICAL CONSIDERATION .............................................................................................. 33 
13.1 
Institutional Review Board/Medical Ethics Committee Review ........................................ 33 
14.0 
PUBLICATION POLICY ..................................................................................................... 34 
15.0 
RISK ANALYSIS ................................................................................................................ 34 
15.1 
Anticipated Clinical Benefits ............................................................................................ 34 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ........................... 35 
15.3 
Residual Risks Associated with the Investigational Device ............................................. 35 
15.4 
Risks Associated with Participation in Clinical Study....................................................... 36 
15.5 
Possible Interactions with Protocol-Required Concomitant Medications ......................... 36 
15.6 
Steps that will be Taken to Control or Mitigate the Risks ................................................ 36 
15.7 
Risk to Benefit Rationale ................................................................................................ 36 
APPENDIX I:   
MITRACLIP XTR PMCF CLINICAL STUDY PROTOCOL .................................. 37 
APPENDIX II: 
ABBREVIATIONS AND ACRONYM................................................................... 38 
APPENDIX III: 
 DEFINITIONS .................................................................................................... 40 
APPENDIX IV:     LITERATURE REVIEW AND SUMMARY OF PRECLINICAL TRIALS .............. 47 
APPENDIX V: 
 MONITORING PLAN ......................................................................................... 63 
APPENDIX VI:     CONTACT INFORMATION ................................................................................ 64 
APPENDIX VII:    FORESEEABLE ADVERSE EVENTS ............................................................... 65 
APPENDIX VIII:  SUMMARY OF CHANGES ................................................................................ 66 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 5 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
 
COMPLIANCE STATEMENT:  
 
This Study will be conducted in accordance with this Protocol, the Declaration of Helsinki, applicable 
Good Clinical Practices and applicable regulations (e.g., US 21 CFR Part 50, 21 CFR Part 56, and 
OUS ISO14155) and the appropriate local legislation(s). The most stringent requirements, guidelines 
or regulations must always be followed. The conduct of the study will be approved by the appropriate 
Institutional Review Board (IRB)/Ethics Committee (EC) of the respective site and by the applicable 
regulatory authorities. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 6 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
PROTOCOL SUMMARY 
 
Protocol Name 
and Number 
17-518:  The MitraClip® EXPAND Study 
Title 
A contemporary, prospective study evaluating real-world experience 
of performance and safety for the next generation of MitraClip® 
devices (EXPAND) 
Objectives 
To confirm the safety and performance of the next generation 
MitraClip® NTR System and MitraClip® XTR System in a 
contemporary, real-world setting. 
Devices 
MitraClip® NTR and MitraClip® XTR Systems 
Targeted number 
of subjects  
Up to 1,000 subjects at a maximum of 60 sites in Europe and the US 
will be in the MitraClip EXPAND Study 
 
The study will group subjects into cohorts for analysis based upon pre-
determined anatomical characteristics. 
Study Design 
Prospective, Multi-Center, Single-Arm, International, Post Market, 
Observational Study 
Endpoints  
Safety  
• Major Adverse Events (MAE) at 30 days 
 
Performance 
• Mitral Regurgitation (MR) Reduction to <2+ at 30 days  
 
Acute Measures: 
• 
Acute Procedural Success (APS)  
• 
Acute Device Success 
• 
Procedure Time 
• 
Device Time 
• 
Number of Clips Implanted 
• 
Number of Attempted Grasps 
• 
Use of MitraClip NTR or MitraClip XTR 
• 
Device-Related Complications 
• 
User Feedback 
• 
In-hospital MAE 
• 
MR Reduction to ≤1+ at 30 days 
 
 
Clinical Measures (Discharge, 1, 6 and 12 months): 
• 
All-cause Mortality  
• 
Heart Failure Hospitalization 
• 
MAE 
• 
Device-Related Complications 
 
 
Functional improvement Measures (Baseline, Discharge & 12 months):  
• 
New York Heart Association (NYHA) class improvement 
• 
Quality of Life (QOL) improvement conducted by Kansas City 
Cardiomyopathy Questionnaire (KCCQ) 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 7 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
 
 
 
 
Echo Measures (Baseline, Post Procedure, 1, & 12 months): 
Based on Site Reported Echocardiogram data for all subjects  
• 
MR Severity Grade 
• 
Effective Regurgitant Orifice Area (EROA) 
• 
Coaptation Measures (length and depth) 
• 
Flail Measures (gap and width) 
• 
Grasping Area Anatomy  
• 
Chordal Support 
• 
Regurgitant Jet(s) Position and Quantity 
• 
Tricuspid Regurgitant (TR) Severity 
 
Core Lab Subgroup: 
Echocardiograms from a minimum of 100 subjects will be sent to a 
Core Lab for assessment  
Subject Follow-up 
Echocardiogram: Discharge, 30 days and 12 Months  
Clinical Visit: 30 days and 12 Months 
Phone Call:  6 Months  
Inclusion Criteria 
1. Subjects who give consent for study participation 
2. Subjects scheduled to receive the MitraClip per the current approved 
indications for use  
3. Subjects with Symptomatic MR (≥3+) 
Exclusion Criteria 1. Subjects participating in another clinical study that may impact the 
follow-up or results of this study.   

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 8 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
1.0 
INTRODUCTION 
The MitraClip® System received Conformité Européene approval (CE Mark) in 2008 and US Food 
and Drug administration (FDA) Approval in 2013 for percutaneous treatment of patients with mitral 
regurgitation (MR).  MR stems from two main etiologies: degenerative MR (DMR), characterized by 
a prolapse or flail of one or more segments of the mitral leaflets and functional MR (FMR), which 
manifests as a malcoaptation of leaflets caused by localized or generalized dysfunction / scarring of 
the left ventricle.  The MitraClip is implanted during a procedure with echocardiographic and 
fluoroscopic guidance while the patient is under general anesthesia. A trans-septal catheterization is 
performed to access the left heart and the guide catheter is then percutaneously inserted into the 
femoral vein.  The MitraClip device is positioned and then used to grasp and join the mitral valve 
leaflets at the maximum coaptation location resulting in fixed approximation of the mitral leaflets.1,2  
The MitraClip System has been shown to be safe and effective in over 4,500 patients in clinical trials 
and more than 50,000 patients in worldwide use to date.  Abbott is now introducing the next 
generation MitraClip NTR and MitraClip XTR Systems.  Both of these systems have an update that 
adds a modification to the delivery catheter of the current MitraClip NT System.  The MitraClip XTR 
System also introduces an additional implant size which has longer arms on the clip implant that are 
designed to assist with grasping of the mitral leaflets.  The MitraClip NTR and MitraClip XTR Systems 
have not yet been evaluated in a clinical study.   
 
The MitraClip EXPAND Study (A Contemporary, Prospective, Multi-center Study Evaluating Real-
world Experience of Performance and Safety for the Next Generation of MitraClip Devices) is 
designed to confirm the safety and performance of the MitraClip NTR System and MitraClip XTR 
System.  The data collected in this study will be used to evaluate device outcomes and characterize 
trends in patient selection for MitraClip therapy in contemporary real-world use.  Specifically, the 
analysis will separate patients into cohorts based on anatomical characteristics to compare modern 
day use to use in early clinical studies.  Moreover, the data will be assessed to identify patient or 
mitral valve anatomical characteristics that may be most appropriate for these next generation 
devices.   Clinical outcomes and Echocardiographic measures will be assessed in the context of 
historical data.   
 
A subset of subjects in the MitraClip EXPAND Study will become part of the MitraClip XTR Post 
Market Clinical Follow-up (PMCF) Study (Appendix I). Data from the MitraClip XTR PMCF Study will 
be used to fulfill the regulatory requirement for PMCF associated with the CE mark approval of the 
MitraClip XTR System.  
 
The MitraClip EXPAND Study will be conducted on commercial MitraClip NTR System and MitraClip 
XTR System that have received CE Mark and/or FDA approval as required.   
 
1.1 
Study Design 
This is a Prospective, Multi-Center, Single-Arm, International, Post Market, Observational Study 
designed to collect real-world data on the use of the next generation MitraClip NTR and MitraClip 
XTR Systems.  Up to 1,000 commercial patients from the EU or US will be included in the analysis 
 
 
1  Kar, Saibal, The Percutaneous Valve Repair: Adding life to years, J Am Coll Cardiol. 2013 Sep 
17;62(12):1062-1064 
2  Maisano, Francesco, Buzzatti, Nicola, Taramasso, Maurizio, and Alfieri, Ottavio, Mitral Transcatheter 
Technologies.  Rambam Maimonides Medical Journal.   July 2013, Volume 4, Issue 3, e0015 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 9 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
for The MitraClip EXPAND Study.  Follow-up echocardiograms will be collected at 30 days and 12 
months post-procedure visits with an additional clinical follow-up visit or phone call at 6 months.   
 
The study will group subjects into cohorts for analysis based upon select pre-defined mitral valve 
anatomic criteria. This approach is supported by recent literature that shows an evolution of the use 
of MitraClip in which a significant percentage of cases presented in post-market studies differ in 
patient selection from the cases included in early clinical studies (ie. EVEREST, EVEREST II)3,4,5,6.  
The analysis of these cohorts will allow for the evaluation of outcomes and identification of trends in 
patient selection and outcomes in contemporary real-world use in the context of historical MitraClip 
data. 
 
1.2 
Study Objective 
The primary objective is to confirm the safety and performance of the next generation MitraClip® NTR 
and MitraClip® XTR Systems within a contemporary real-world setting.   
 
2.0 
BACKGROUND AND RATIONALE 
2.1 
Background 
2.1.1 
MitraClip® Clinical Trials Conducted for Approval 
The MitraClip® System was studied in the United States as an investigational device beginning with 
the EVEREST I trial in July 2003 (IDE G030064).  A total of 55 patients were enrolled.  The EVEREST 
I Feasibility trial was the first prospective, multi-center trial to evaluate the safety and effectiveness of 
the MitraClip System in patients with 3+ or 4+ MR in surgical candidates.  The trial demonstrated 
mechanistic feasibility of implant and safety of the MitraClip System and procedure. Acute procedural 
success was achieved in 70.9% of patients with a majority of patients (83.3%) experiencing a 
reduction in MR severity to 2+ or less at discharge.  At 5 years, freedom from death was 86.4% and 
freedom from mitral valve surgery was 55.1%7.  
 
 
3 A Study of the Evalve® Cardiovascular Valve Repair (MitraClip®) System Endovascular Valve Edge-to-
Edge REpair Study 
4 Boerlage-van Dijk K, et al,Mitral valve anatomy predicts outcome of MitraClip implantation, Int J Cardiol 
(2014) 
5Ambrožič J,, Bervar M,  Bunc M., Wien Klin Wochenschr. Initial Slovenian experience with MitraClip therapy: 
Careful selection of patients is crucial for optimal outcome.  2017 Dec 4. doi: 10.1007/s00508-017-1295-7. 
[Epub ahead of print] 
6 Lesevic H, Karl M, Braun D, Barthel P, Orban M, Pache J, Hadamitzky M, Mehilli J, Stecher L, Massberg S, 
Ott I, Schunkert H, Kastrati A, Sonne C, Hausleiter J.  Long-Term Outcomes after MitraClip Implantation 
According to the Presence or Absence of EVEREST Inclusion Criteria.  Am J Cardiol.  2017; 119:1255-1261 
7 IDE G030064/ P100009/A017 EVEREST I Final Clinical Report Version 1.0 - 17/Nov/2011  

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 10 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Following positive outcomes with the EVEREST I trial, EVEREST II was initiated. The EVEREST II 
Randomized Controlled Trial (RCT)8,9,10 was a prospective, multi-center, randomized controlled trial 
where patients with severe MR (3+ or 4+) were randomized in a 2:1 ratio to either receive the MitraClip 
device or undergo mitral valve surgery. The trial enrolled 279 patients: 184 treated with MitraClip and 
95 with surgery. The trial met both primary safety and effectiveness endpoints. MR reduction to 2+ or 
less at 5 years was in 82.1% of MitraClip patients and 97.6% of surgery patients.  Improvement in 
NYHA Functional Class was demonstrated in both groups, with 91.5% of MitraClip patients and 97.6% 
of surgery patients free from New York Heart Association (NYHA) Functional Class III or IV symptoms 
at 5 years.  The results demonstrate the continued safety, durability of effectiveness and clinical 
benefit of the MitraClip device through 5 years11.  
 
The EVEREST II trial included a separate study to evaluate the safety and effectiveness of the 
MitraClip System in patients with 3+ or 4+ MR considered to be at high risk of surgical mortality.  The 
EVEREST II High Risk Registry (HRR) study enrolled 78 patients at 25 centers.  Implant success in 
the EVEREST II HRR was high with 96.2% of patients implanted with one (59.0%) or two (37.2%) 
MitraClip devices.  At 5 years, MR reduction was sustained to ≤2+ in 73.9% of surviving patients with 
paired data and to ≤1+ in 47.8% of surviving patients with paired data.  Through 5 years, a total of 42 
(53.8%) deaths occurred in the EVEREST II HRR12.  This mortality rate is as expected due to the 
high risk nature of the patient population.   
 
A continued access study, EVEREST II REALISM, sustained data collection on the use of the 
MitraClip System in “real world” conditions.  There were two arms (High Risk and Non-High Risk) in 
the REALISM study.  A total of 271 patients were enrolled in the non-high risk arm of REALISM.  
Reduction to MR ≤2+ was achieved in 89% of patients at 30 days and in 84% of patients at 12 months.  
A similar trend was observed at subsequent follow-ups with a majority (>75%) of patients with MR 
severity remaining consistently mild to moderate13.  A total of 628 patients were enrolled in the high 
risk arm of REALISM.  A majority of patients had multiple pre-existing co-morbidities at baseline and 
were considered high risk for mitral valve surgery.  Reduction of MR ≤2+ was achieved in 90% of 
patients at discharge/30 days and in 85% of patients at 12 months.  A similar trend was observed at 
subsequent follow-ups with a majority (>80%) of patients with MR severity remaining consistently 
mild to moderate14.  
 
 
8 Mauri L, Garg P, Massaro JM, Foster E, Glower D, Mehoudar P, Powell F, Komtebedde J, McDermott E, 
Feldman T.  The EVEREST II Trial: Design and Rationale for a Randomized Study of the Evalve MitraClip 
System Compared with Mitral Valve Surgery for Mitral Regurgitation.  Am Heart J.  2010; 160:23-29. 
9 Feldman T, Foster E, Glower DD, 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, Mauri L, Investigators EI.  Percutaneous 
Repair or Surgery for Mitral Regurgitation.  N Engl J Med.  2011; 364:1395-1406. 
10 Feldman T, Kar S, Elmariah S, Smart SC, Trento A, Siegel RJ, Apruzzese P, Fail P, Rinaldi MJ, Smalling 
RW, Hermiller JB, Heimansohn D, Gray WA, Grayburn PA, Mack MJ, Lim DS, Ailawadi G, Herrmann HC, Acker 
MA, Silvestry FE, Foster E, Wang A, Glower DD, Mauri L, Investigators EI.  Randomized Comparison of 
Percutaneous Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II.  J Am Coll Cardiol.  
2015; 66:2844-2854. 
11 EVEREST II Randomized Controlled Trial (RCT) -0401– Five Year Final Report, Report Version 1.0 - 
03/Nov/2014 
12 EVEREST II High Risk Registry (HRR) – 0401 - Five Year Final Report, Report Version 1.0 – 
03/Nov/2014 
13 EVEREST II REALISM– Non-High Risk   2017 Annual Report, Protocol #0401- Clinical Investigation Report 
Ver 1.0  - 24/APR/2017 
14 EVEREST II REALISM– High Risk 2017 Annual Report, Protocol #0401- Clinical Investigation Report Ver 
1.0   24/Apr/2017 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 11 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
2.1.2 
MitraClip® Post-Market Clinical Studies 
In 2008, based upon data from the EVEREST I study, the MitraClip® received CE mark approval for 
commercial use in Europe and was indicated for the reconstruction of the insufficient mitral valve for 
tissue approximation. Clinical evidence generated from EVEREST I, EVEREST II, EVEREST II HRR, 
and EVEREST II REALISM led to FDA approval in 2013 of the MitraClip® system for the treatment 
of patients with severe MR who are at prohibitive risk for surgery.   
 
In the time since these approvals, a number of post-market clinical studies have been conducted on 
the MitraClip.  All of these studies have provided continued evidence of the safety and performance 
of the MitraClip System.  The studies for Europe and the US are summarized in the Table 1.   
 
Table 1.  Summary of Post-Market MitraClip® Studies 
 
Study Reference 
Study Design 
Study Population 
Study Outcome 
Franzen et al.15 
Analysis from 
Hamburg 
University Heart 
Center 
Examine MitraClip use in high 
surgical risk patients not 
meeting EVEREST criteria 
51 subjects 
35 (69%) would have 
been excluded from 
EVEREST I & II 
MitraClip successful in 
treatment of patients outside of 
EVEREST criteria 
ACCESS-EU16 
(EU study 
sponsored by 
Abbott) 
Two-phase prospective, 
single-arm looking at health 
economics and clinical 
567 subjects 
77.1% FMR 
84.9% NYHA III or IV 
High surgical risk 
MitraClip implant success 
99.6% 
78.9 %MR reduction <2+ at 1yr 
Improved 6MWT, NYHA and 
QOL17 
Getting Reduction 
of Mitral 
Insufficiency by 
Percutaneous Clip 
Implantation 
GRASP Registry18 
Prospective Single-center 
study at Ferrarotto Hospital in 
Catania, Italy.  Site heart team 
led enrollment criteria 
117 high surgical risk 
76% FMR 
98% MR3+/4+ 
63% met EVEREST 
criteria 
100% Acute procedural success 
Post Procedure MR Reduction 
1+ (63%) 2+ (37%) 
KM Freedom from MAE 96.4% 
at 30 days and 75.8% at 1 yr 
German 
TRanscatheter 
Mitral Valve 
Interventions 
(TRAMI) Registry 
Had both prospective and 
retrospective enrollment.  
828 prospective 
patients at 21 sites 
97% implant success 
1.4±0.6 clips/case 
85.2% MR reduced to none/ mild 
Mortality 4.5% 1 m /20.3% 1 yr 
 
 
15 Franzen O, Baldus S, Rudolph V, Meyer S, Knap M, Koschyk D, Treede H, Barmeyer A, Schofer J, Costard-
Jackle A, Schluter M, Reichenspurner H, Meinertz T.  Acute Outcomes of MitraClip Therapy for Mitral 
Regurgitation in High-Surgical-Risk Patients: Emphasis on Adverse Valve Morphology and Severe Left 
Ventricular Dysfunction.  Eur Heart J.  2010; 31:1373-1381. 
16 Maisano F, Franzen O, Baldus S, Schafer 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 1-Year 
Results from the ACCESS-EU, a Prospective, Multicenter, Nonrandomized Post-Approval Study of the 
MitraClip Therapy in Europe.  J Am Coll Cardiol.  2013; 62:1052-1061. 
17 ACCESS-EU Phase I Study Final Clinical Report, Version 1.0, 20/Aug/2012 
18 Grasso C, Capodanno D, Scandura S, Cannata S, Imme S, Mangiafico S, Pistritto A, Ministeri M, Barbanti 
M, Caggegi A, Chiaranda M, Dipasqua F, Giaquinta S, Occhipinti M, Ussia G, Tamburino C.  One- and Twelve-
Month Safety and Efficacy Outcomes of Patients Undergoing Edge-to-Edge Percutaneous Mitral Valve Repair 
(from the GRASP Registry).  Am J Cardiol.  2013; 111:1482-1487. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 12 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Several TRAMI reports have 
been published 19,20 
(from the largest 
publication21) 
70%FMR 
94% Severe MR 
The Transcatheter 
Valve Treatment 
Sentinel Pilot 
Registry22 
European Society of 
Cardiology Euro Observational 
Research Programme 
conducted at 25 centers in 8 
European countries  
628 patients  
72% FMR 
EuroSCORE 
20.4±16.7% 
(indicates high risk) 
95.4% Acute procedural success 
98.2% MR Reduction ≤2+ post-
procedure  
94% MR Reduction ≤2+ at 1 yr 
15.3% Mortality at 1 yr 
TVT Registry 
(Transcatheter 
Valve Treatment)  
A Joint Initiative 
Society of 
Thoracic 
Surgeons (STS) & 
American College 
of Cardiology 
(ACC)  
A platform for: 1) device and 
procedural surveillance; 2) 
quality assurance and 
improvement initiatives; and 3) 
efficient conduct of studies that 
will speed US access to new 
devices and support the 
expansion of device labeling 
(Sorajja et al.23 -most 
recent publication)   
2,952 patients at 145 
sites  
85.9% DMR 
17.5% (FMR only 
8.6%; mixed 8.9%). 
93% MR 3+/ 4+ MR 
93% MR reduction ≤2+ 
61.8% MR grade ≤1+ 
5.2% 30-day Mortality 
37.9% 1 yr death and HF re-
hospitalization (24.7% DMR) 
 
2.1.3 Mitral Valve Anatomies: Impact on MitraClip Use and Outcomes 
As the MitraClip therapy matures, there has been an increasing interest in exploring the potential for 
use in broader mitral valve anatomies.  The recommended criteria were established early in MitraClip 
use during the EVEREST II Study.  Some recent data have examined the true impact of these criteria 
on patient selection and MR outcomes; a few studies are described below.   
 
Attizzani et al.24 analyzed the outcomes of patients enrolled in the GRASP registry according to 
baseline echocardiographic criteria.  A total of 78 patients that met EVERST criteria (EVERESTon) 
 
 
19 Baldus S, Schillinger W, Franzen O, Bekeredjian R, Sievert H, Schofer J, Kuck KH, Konorza T, Mollmann H, 
Hehrlein C, Ouarrak T, Senges J, Meinertz T, investigators GTMVI.  MitraClip Therapy in Daily Clinical Practice: 
Initial Results from the German Transcatheter Mitral Valve Interventions (TRAMI) Registry.  Eur J Heart Fail.  
2012; 14:1050-1055. 
20 Schillinger W, Hunlich M, Baldus S, Ouarrak T, Boekstegers P, Hink U, Butter C, Bekeredjian R, Plicht B, 
Sievert H, Schofer J, Senges J, Meinertz T, Hasenfuss G.  Acute Outcomes after MitraClip Therapy in Highly 
Aged Patients: Results from German Transcatheter Mitral Valve Interventions (TRAMI) Registry. 
EuroIntervention. 2013; 9:84-90. 
21 Puls M, Lubos E, Boekstegers P, von Bardeleben RS, Ouarrak T, Butter C, Zuern CS, Bekeredjian R, Sievert 
H, Nickenig G, Eggebrecht H, Senges J, Schillinger W.  One-Year Outcomes and Predictors of Mortality after 
MitraClip Therapy in Contemporary Clinical Practice: Results from the German Transcatheter Mitral Valve 
Interventions Registry.  Eur Heart J.  2016; 37:703-712. 
22 Therapy in Contemporary Clinical Practice: Results from the German Transcatheter Mitral Valve Interventions 
Registry.  Eur Heart J.  2016; 37:703-712. 
23 Sorajja P, Vemulapalli S, Feldman T, Mack M, Holmes DR Jr, Stebbins A, Kar S, Thourani V, Ailawadi G.  
Outcomes With Transcatheter Mitral Valve Repair in the United States: An STS/ACC TVT Registry Report.  J 
Am Coll Cardiol. 2017;70(19):2315-2327. 
24 Attizzani GF, Ohno Y, Capodanno D, Cannata S, Dipasqua F, Imme S, Mangiafico S, Barbanti M, Ministeri 
M, Cageggi A, Pistritto AM, Giaquinta S, Farruggio S, Chiaranda M, Ronsivalle G, Schnell A, Scandura S, 
Tamburino C, Capranzano P, Grasso C.  Extended Use of Percutaneous Edge-to-Edge Mitral Valve Repair 
Beyond EVEREST (Endovascular Valve Edge-to-Edge Repair) Criteria: 30-Day and 12-Month Clinical and 
Echocardiographic Outcomes from the GRASP (Getting Reduction of Mitral Insufficiency by Percutaneous Clip 
Implantation) Registry.  JACC Cardiovasc Interv.  2015; 8:74-82. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 13 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
were compared to 93 patients that did not meet EVEREST Criteria (EVERESTOFF)) which included 35 
patients with LVEF ≤25%, 28 patients with LV end systolic diameter >55 mm, 34 patients with 
coaptation depth ≥11 mm, and 10 patients with a flail width ≥15 mm.  High rates of acute procedural 
success were achieved in both groups (97.8% and 100% for EVERESTOFF and EVERESTON, 
respectively). At 30-days, the rate of MAEs (i.e. primary safety endpoint) was comparable between 
groups (2.6% vs. 6.5%, respectively, p=0.204).  Reduction in MR severity, symptomatic 
improvements, and re-hospitalizations for heart failure were comparable between the two groups.  At 
1 year, Kaplan-Meier freedom from the freedom from death, surgery for mitral valve dysfunction, or 
grade ≥3+ MR at 12 months was demonstrated in 71.4% and 76.2%, respectively, in the EVERESTOFF 
and EVERESTON groups.  Approximately 90% of surviving patients in both groups had sustained MR 
reduction to ≤2+.   
 
In more recent 2016 publication, Lesevic et al.25 retrospectively analyzed patients treated with the 
MitraClip® device and compared the procedural success, long-term outcomes, repair durability, and 
prognostic factors.  Patients were grouped into the EVEREST group (N=59) or non-EVEREST group 
(N=75) according to the presence or absence of EVEREST inclusion criteria.  Acute procedural 
success was achieved in 95.5% of patients with no difference between EVEREST (97%) and non-
EVEREST (95%) patients.  There was no statistically significant difference in the number of device 
implanted between the two groups.  A similar mean acute MR reduction was achieved in both groups 
(-2.3±0.9 vs -2.2±1, respectively; p=0.497).  At a mean follow-up of 3.5 years, recurring MR ≥3+ was 
more frequent in non-EVEREST patients than in EVEREST patients (28% vs 45%; p=0.066).  Re-
interventions for recurring MR were more frequently required in non-EVEREST patients than in 
EVEREST patients, including second MitraClip device interventions (2% vs 13%; p=0.085) and mitral 
valve surgeries (9% vs 28%; p=0.047).  Flail width was found to be an independent predictor for re-
intervention, whereas flail gap ≥10 mm displayed a strong trend (flail width: adjusted HR 11.2, 95% 
CI 2.6 to 48.3; p=0.001; flail gap: adjusted HR 3.1, 95% CI 0.9 to 11.5; p=0.077).   
These data suggest that a closer look at the impact of mitral valve anatomy for MitraClip patient 
selection and outcomes is warranted to understand the appropriate real-world applications of the 
therapy.  In the context of the introduction of the next generation MitraClip System, this analysis can 
be used to identify the mitral valve anatomical characteristics that may benefit most from the attributes 
of this device iteration (i.e. improved delivery and longer arms on the implant).  This is the basis for 
the MitraClip EXPAND Study.  
 
A full review of MitraClip studies and commercial literature was conducted and is shown in Appendix 
III. 
 
2.2 
Study Rationale 
The primary objective of the MitraClip EXPAND study is to confirm the safety and performance of the 
MitraClip® NTR and MitraClip® XTR Systems in a contemporary real-world setting.  The rationale for 
conducting this study is as follows: 
• 
This study will provide first-hand clinical evidence of safety and performance of these next 
generation MitraClip Systems.     
• 
This study will satisfy post-market clinical follow-up (PMCF) required as a condition of CE 
Mark approval for the MitraClip NTR and MitraClip XTR Systems.  A subset of patients will be 
analyzed as part of the MitraClip XTR PMCF Study (Appendix 1) to fulfill this requirement.   
 
 
25 Lesevic H, Karl M, Braun D, Barthel P, Orban M, Pache J, Hadamitzky M, Mehilli J, Stecher L, Massberg S, 
Ott I, Schunkert H, Kastrati A, Sonne C, Hausleiter J.  Long-Term Outcomes after MitraClip Implantation 
According to the Presence or Absence of EVEREST Inclusion Criteria.  Am J Cardiol.  2017; 119:1255-1261. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 14 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
• 
The device iterations on the MitraClip NTR (improved delivery) and MitraClip XTR (improved 
delivery and longer clip arms on implant) may offer an advantage in some mitral valve 
anatomies; this study will begin to identify populations that can benefit most from these next 
generation MitraClip Systems.    
• 
Recent literature has indicated an evolution in patient selection in MitraClip therapy; this study 
will evaluate outcomes and characterize trends for MitraClip therapy in contemporary real-
world use in the context of historical MitraClip data. 
 
2.3 
Summary of Device 
2.3.1 
Name of the Device 
This study will include patients, who will undergo commercial procedures with the MitraClip® NTR 
System and/or MitraClip® XTR System after required approval of the device is obtained.   
 
2.3.2 
Indication for Use 
MitraClip® procedures for this study will be conducted in accordance with the Instructions for Use 
(IFU) that is approved for the region where the implant is taking place. 
 
2.3.3 
Description of the Device 
The MitraClip System is comprised of the Clip Delivery System (CDS) and Steerable Guide Catheter 
(SGC). The CDS is introduced into the body through the SGC. The Clip Delivery System is used to 
advance and manipulate the implantable clip 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 Steerable Guide Catheter provides a conduit to 
access the mitral valve and with the addition of Steerable Sleeve to position the Clip relative to the 
valve. The Delivery Catheter is designed to deliver and deploy the Clip. The Steerable Guide and Clip 
Delivery System are steered and actuated by the use of control knobs, levers and fasteners (Figure 
1). 
 
 
 
The new MitraClip NTR System and MitraClip XTR System have a modification to the Delivery 
Catheter (DC) of the current MitraClip NT System intended to make the procedure easier, more 
precise, more predictable, and to optimize manufacturability of the product.  
 
The implantable Clip is fabricated with metal alloys and polyester fabric that are commonly used in 
cardiovascular implants. The Clip can be repeatedly opened, closed and inverted by deliberate 
Figure 1.  Proximal End of MitraClip NTR and MitraClip XTR Systems 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 15 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
manipulations of the Delivery Catheter Handle. The Clip positions are designed to allow the Clip to 
grasp and approximate the leaflets of the mitral valve.  
 
The MitraClip XTR System has the same modified CDS as MitraClip NTR system but incorporates 
the additional implant size.  Specifically, the arms on the implant of the MitraClip XTR System are 
longer than the clip implant in the MitraClip NTR System.  This is intended to assist with leaflet 
grasping (Figure 2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.0 
STUDY FLOW AND FOLLOW-UP SCHEDULE 
3.1 
Number of Subjects 
Eligible consecutive patients that present for a MitraClip procedure should be consented.  Once a 
patient has provided written informed consent, the patient is considered enrolled.  Upon 
echocardiographic verification that there is no evidence of intracardiac, inferior vena cava (IVC) or 
femoral venous thrombus per IFU requirements; the MitraClip procedure should be attempted for all 
enrolled patients.  A procedure is considered attempted when the MitraClip delivery system is 
introduced into the femoral vein.  Only enrolled patients with an attempted MitraClip procedure will 
be included in the analysis population.  Patients that have an attempted procedure, but no MitraClip 
implant will be followed for 30 days only. 
 
Patients that do not give consent or patients with a thrombus identified on the pre-treatment 
echocardiogram are not eligible for the EXPAND Study and will not be part of the analysis population.  
If the thrombus is medically treated and resolved at a later date, a patient may be re-consented for 
the EXPAND Study if they are eligible for a new attempted MitraClip procedure. 
 
Up to 1,000 consented subjects with confirmation of no thrombus who have a MitraClip procedure 
attempted will be included for analysis in the MitraClip EXPAND Study.  The Study will be conducted 
at a maximum of 60 centers in the EU and the US.  A site maximum of 100 subjects will be enforced 
so that no site will be permitted to submit data for more than 10% of the study population. 
 
Figure 1.  MitraClip NTR & MitraClip XTR Clip Implant  

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 16 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
3.2 
Overall Flow of the Study and Follow-up Schedule 
Enrolled patients that receive a MitraClip implant should undergo study follow-up per standard of care.  
Follow-up data on clinical assessment should be submitted for a 30-day visit, 6-month visit or phone 
call and 12-month visit.  Echocardiograms are required to be submitted for the baseline, discharge, 
30-day and 12-month time points.  All Echocardiograms conducted during the study period (required 
by protocol or not) will be collected by the Sponsor (see Table 2 for the Clinical Assessment 
Schedule).  Patients that have an attempted procedure, but no MitraClip implant will be followed for 
30 days only. 
 
The first 220 European patients treated with the MitraClip XTR in the MitraClip EXPAND Study with 
evaluable APS data will be included in the XTR PMCF Study as described in Appendix 1. 
 
Subjects with evaluable echocardiograms may be selected for a more detailed assessment by an 
independent core lab. Pre-defined criteria will be used to identify eligible subjects for this assessment. 
A minimum of 100 subjects will be randomly selected from this eligible population. 
 
Figure 3 outlines the flow of the Study. 
 
Figure 3: Study Flow 
 
 
3.3 
Measures Taken to Avoid and Minimize Bias 
3.3.1 
Study Flow 
Study sites are instructed to consent consecutive subjects prior to MitraClip procedure.  All patients 
eligible to receive a MitraClip (i.e. no evidence of thrombus) will included in the study analysis. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 17 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
 
3.3.2 
 Clinical Events Committee 
The safety endpoint for the study will include oversight by an independent CEC which will issue the 
final decision on reported MAEs.   
 
3.3.3 
Steering Committee 
An independent steering committee will have oversight on the study. 
 
3.4 
Early Termination of the Clinical Study 
No formal statistical rule for early termination of this study is defined. 
 
The Sponsor reserves the right to discontinue the study at any stage or reduce the follow up period 
with suitable written notice to the investigator. Possible reason(s) may include, but are not limited to: 
• 
Unanticipated adverse device effect (UADE) occurs and it presents an unreasonable risk to 
the participating subjects. 
• 
The Steering Committee makes a recommendation to stop or terminate the study  
Should the study be discontinued by the Sponsor, patients will be followed up as per routine hospital 
practice with device related Adverse Events (AEs) being reported to the Sponsor as per 
vigilance/commercial reporting requirements. 
 
In the event of study termination, the investigator shall return all clinical study materials to the Sponsor, 
and provide a written statement as to why the premature termination has taken place to the IRB/EC 
(if applicable). All applicable Clinical Investigation documents shall be subject to the same retention 
policy as detailed in section 12 of the Protocol entitled, ‘Data Handling and Record Keeping’.  
 
4.0 
STUDY ENDPOINTS 
4.1 
Safety and Performance Measures 
 
• 
Safety  
The assessment of safety will include all occurrences through 30 days post procedure.  
Occurrence of Major Adverse Events (MAE) at 30 days  
MAE is defined as a composite of all-cause Death, Myocardial Infarction, Stroke, or non-
elective Cardiovascular (CV) surgery for device related complications (CEC adjudicated).   
 
• 
Performance  
The assessment of performance measures will include all data reported at 30-day visits for 
this study.   
MR Reduction to ≤2+ at 30 days   
 
4.2 
Acute Measures 
• 
Acute Procedural Success (APS) defined as successful implantation of the MitraClip® device 
with resulting MR severity of 2+ or less on discharge Echocardiogram (30-day 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 18 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
echocardiogram will be used if discharge is unavailable or uninterpretable). Subjects who die 
or undergo mitral valve surgery before discharge are considered to be an APS failure 
• 
Acute Device Success defined as successful implant of the MitraClip device without the 
occurrence of a Device-Related Complication (including mitral valve stenosis, device 
embolization, Single Leaflet Device Attachment (SLDA),  Iatrogenic atrial septal defect, or 
myocardial perforation) through discharge.   
• 
Use of MitraClip NTR or MitraClip XTR:  to include the percentage of cases with each device 
and an assessment of reason for device selection  
• 
Procedure Time: defined as the time elapsed from the first intravascular catheter placement 
or trans-esophageal echocardiogram (TEE) to the removal of the last catheter and TEE 
• 
Number of Clips Implanted 
• 
Number of Attempted Grasps defined as the number of attempts to stabilize leaflets by the 
open Clip 
• 
User feedback  
• 
Device-Related Complications defined as the occurrence of one the following adverse events 
that is determined by investigator assessment to be probably, possibly or definitely related to 
the MitraClip device.    
‒ Mitral valve stenosis 
‒ SLDA 
‒ Device Embolization 
‒ Iatrogenic atrial septal defect 
‒ Myocardial perforation 
‒ Need for mitral valve replacement instead of repair due at least in part to the MitraClip 
procedure or the presence of the MitraClip device 
• 
In-hospital MAE defined as the number of MAEs that occur prior to discharge from 
hospitalization in which MitraClip Procedure was performed 
• 
MR Reduction to ≤1+ at 30 days 
 
4.3 
Clinical Measures  
(Discharge, 1, 6 and 12 months): 
• 
All-cause Mortality  
• 
Heart Failure Hospitalization 
• 
MAE as defined above  
• 
Device-Related Complications as defined above 
 
4.4 
Functional Improvement Measures  
(Baseline, Discharge & 12 months) 
• 
New York Heart Association (NYHA) functional class improvement 
• 
Quality of Life (QOL) assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ)  
 
4.5 
Site Reported Echocardiographic Measures  
(Baseline, Post Procedure, 1, & 12 months):  
• 
MR Severity Grade 
• 
Effective Regurgitant Orifice Area (EROA) as measured by measured by PISA method 
• 
Coaptation Measures (depth/length) 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 19 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
‒ Coaptation depth: Coaptation depth is defined as the distance from the plane of the 
mitral valve annulus to the first point of leaflet coaptation in the atrial-to-ventricular 
direction in the four-chamber view. 
‒ Coaptation length: Coaptation length is defined as the vertical length of leaflets that is 
in contact, or is available for contact, during systole in the atrial-to-ventricular direction 
in the four-chamber view. 
• 
Flail Measures (gap/width) 
‒ Flail Gap: Measured as the greatest distance between the ventricular side of the flail 
segment to the atrial side of the opposing leaflet. This distance is measured 
perpendicular to the plane of the annulus in two views and the largest measurement 
is used. The two views for measurement are the four-chamber long axis (LAX) view 
and the left ventricular outflow tract (LVOT) view. 
‒ Flail Width: Measured as the width of the leaflet segment that moves in and out of 
plane during systole in the short axis (SAX) view. 
• 
Grasping Area Anatomy (measure cleft or scallop if significant) 
• 
Assess chordal support 
• 
Regurgitant Jet(s) Position and Quantity 
• 
TR Severity: None, Mild, Moderate or Severe 
 
4.6 
Core Lab Subgroup: 
Subjects with evaluable echocardiograms may be selected for a more detailed assessment by an 
independent core lab. Pre-defined criteria will be used to identify eligible subjects for this assessment. 
A minimum of 100 subjects will be randomly selected from this eligible population. 
 
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This MitraClip® EXPAND Study will enroll male and female subjects with symptomatic mitral 
regurgitation who satisfy the inclusion and exclusion criteria and who are treated with the next 
generation MitraClip NTR System and/or MitraClip XTR System. The study will conduct analysis on 
approximately 1,000 subjects. Subjects must provide written informed consent prior to their data being 
submitted to the Study. 
 
5.1.1 
Anatomy Complexity 
For analysis, subjects will be sorted into two groups based on valve anatomies identified to be 
important for MitraClip placement  26, 27, 28 
 
 
 
26 Boerlage-van Dijk K, et al,Mitral valve anatomy predicts outcome ofMitraClip implantation, Int J Cardiol 
(2014) 
27 Ambrožič J, Cvijič M, Bervar M,  Bunc M., Wien Klin Wochenschr. Initial Slovenian experience 
with MitraClip therapy : Careful selection of patients is crucial for optimal outcome.  2017 Dec 4. doi: 
10.1007/s00508-017-1295-7. [Epub ahead of print] 
28 Lesevic H, Karl M, Braun D, Barthel P, Orban M, Pache J, Hadamitzky M, Mehilli J, Stecher L, Massberg S, 
Ott I, Schunkert H, Kastrati A, Sonne C, Hausleiter J.  Long-Term Outcomes after MitraClip Implantation 
According to the Presence or Absence of EVEREST Inclusion Criteria.  Am J Cardiol.  2017; 119:1255-1261. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 20 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Group 1 (Complex Subjects): 
 
If one or more of the following characteristics are present:  
• 
Primary Jet outside of A2P2 
• 
Presence of more than one significant jet 
• 
Wide Jet 
• 
Small Valve 
• 
Calcified landing zone 
• 
Minimal leaflet tissue for attachment (due to small coaptation length or too much coaptation 
depth) 
• 
Presence of severely degenerative leaflets or wide flail gaps or widths 
 
Group 2 (Non-Complex Subjects): 
 
All subjects who do not qualify as a complex subject will be classified as Non-Complex subjects 
whose characteristics are similar to subjects enrolled in the EVEREST II trial.  
 
5.2 
Subject Screening and Informed Consent 
5.2.1 
Subject Screening 
The hospital will follow their standard of care procedures for determining if a patient is eligible for 
treatment with a MitraClip® System.  Consecutive MitraClip patients should be asked to provide 
consent for participation in the study if they are eligible per the inclusion/exclusion criteria (see section 
5.2.3). Upon echocardiographic verification that there is no evidence of intracardiac, inferior vena 
cava (IVC) or femoral venous thrombus per IFU requirements; the MitraClip procedure should be 
attempted.  The procedure is considered attempted when the MitraClip delivery system is introduced.  
All consented patients with an attempted MitraClip procedure will be included in the study analysis. 
 
5.2.2 
Informed Consent 
Patient Informed Consent Form must receive approval of Sponsor and EC/IRB prior to beginning 
enrollment into the MitraClip® EXPAND Study. 
 
The Investigator or designee, who has been trained on the Protocol, will explain the nature and scope 
of the study, potential risks and benefits of participation, and answer questions for the subjects.  For 
this study the subject will be treated per standard of care and must consent only to data collection 
(including echocardiogram) and follow-up visit schedule.  All subjects (or legally authorized subjects’ 
representatives if applicable) must sign, date and time (if required) the Institutional Review Board 
(IRB)/Ethics Committee (EC) approved informed consent prior to any clinical study-specific 
procedures. Obtaining the consent and provisioning of a copy to the subject, along with the date and 
time must be documented in the subject’s medical records. In addition, the signed informed consent 
must be kept in the subject’s medical records. 
 
At sites in the United States, an authorization for use and disclosure of the subject’s protected health 
information, in accordance with the Health Insurance Portability and Accountability Act (HIPAA), must 
be 
obtained 
from 
the 
subject 
or 
their 
legally 
authorized 
representative. 
Per 
site 
requirements/preference HIPAA elements may be incorporated into the Informed Consent Form (ICF) 
or it may exist as a standalone document. 
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 21 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
If approved by IRB/ EC, subjects from vulnerable populations may be enrolled in the study.  ISO14155 
definition of vulnerable population: Defined as subject whose willingness to volunteer in a clinical 
investigation could be unduly influenced by the expectation, whether justified or not, of benefits 
associated with participation or of retaliatory response from senior members of a hierarchy in case of 
refusal to participate.  Examples of populations which may contain vulnerable subjects include: 
Individuals with lack of or loss of autonomy due to immaturity or through mental disability, persons in 
nursing homes, children, impoverished persons, subjects in emergency situations, ethnic minority 
groups, homeless persons, nomads, refugees, and those incapable of giving informed consent. Other 
vulnerable subjects include, for example, members of a group with a hierarchical structure such as 
university students, subordinate hospital and laboratory personnel, employees of the sponsor, 
members of the armed forces, and persons kept in detention. 
 
5.3 
Eligibility Criteria 
Consecutive MitraClip patients should be screened per the criteria listed below.  Assessment for 
eligibility criteria is based on medical records of the site and interview with a candidate subject. 
Subjects must meet ALL of the inclusion criteria to be considered for the clinical study. If ANY of the 
exclusion criteria are met, the subject is excluded from the clinical study.   Consecutive patients 
meeting these criteria should be asked to provide consent for participation in the EXPAND Study. 
 
5.3.1 
Inclusion Criteria 
1. Subjects who give consent for study participation 
2. Subjects scheduled to receive the MitraClip per the current approved indications for use  
3. Subjects with Symptomatic MR (≥3+) 
 
5.3.2 
Exclusion Criteria 
1. Subjects participating in another clinical study that may impact the follow-up or results of this 
study.   
 
5.4 
Subject Enrollment and Inclusion  
The patient is considered enrolled upon signing and dating an informed consent for participation.  
Consecutive enrolled patients with an attempted MitraClip procedure will be included in the analysis 
population.   
 
5.5 
Subject Discontinuation 
Subjects shall remain in the study until completion of the required follow-up period; however, a 
subject’s participation in any clinical study 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 withdrawal by physician as clinically-indicated 
• 
Subject lost-to follow-up as described below  
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 22 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will provide this 
information to the Sponsor. Investigators must also report this to their respective IRB/EC as defined 
by their institution’s procedure(s).  
 
No additional follow–up will be required or data recorded from subjects once withdrawn, except for 
the status (deceased/alive). 
 
Lost-to-Follow-up: 
 
If the subject misses two consecutive scheduled follow up time points and the 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 contact time point: 
• 
A minimum of 2 telephone calls on different days over a 30-day period to contact the subject 
should be recorded in the source documentation, including date, time and initials of site 
personnel trying to make contact. 
• 
If these attempts are unsuccessful, a letter (certified if applicable) should be sent to the subject. 
• 
If a subject misses one or more non-consecutive follow-up contact time points it will be 
considered a missed visit. The subject may then return for subsequent visits. If the subject 
misses two consecutive time points 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. 
 
5.6 
Total Expected Duration of the Study 
The time to complete the Study is estimated to be approximately 2 years.   
 
5.7 
Expected Duration of Each Subject’s Participation 
The expected duration of participation for subjects is approximately 12 months.   
 
5.8 
Number of Subjects Required to be Included in the Study 
Approximately 1,000 subjects will be included for analysis in the Study. 
 
5.9 
Estimated Time Needed to Select this Number  
The estimated time to include 1,000 analysis patients is about 1 year.   
 
5.10 
Study Completion 
A Study Completion eCRF must be completed when: 
• 
the subject is considered lost to follow-up per the above definition or  
• 
the subject withdraws from the Study or 
• 
the investigator withdraws the subject from the Study or 
• 
the subject has died or 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 23 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
• 
upon Study completion (e.g., 1 year follow-up time point has been reached) or 
• 
sponsor termination of Study 
 
Sponsor must be notified of the reason for subject discontinuation. The site will provide this 
information on the electronic case report form (eCRF). Investigators must also report this to their 
EC/IRB as defined by their institution’s procedure. Subjects will not be replaced. 
 
6.0 
TREATMENT AND FOLLOW-UP ASSESSMENTS 
6.1 
Pre-Treatment 
Patients presenting with MR appropriate for treatment with the MitraClip® will undergo screening per 
standard hospital procedure in accordance with approved labelling.  If a MitraClip procedure is 
considered appropriate (with agreement from local a heart team when required) and the patient meets 
the screening criteria for the study (i.e. Symptomatic MR≥3+ and not participating in another study) 
the site shall obtain consent from the patient.  All efforts should be made by the site to obtain consent 
from consecutive eligible patients.  Echocardiographic verification that there is no evidence of 
intracardiac, IVC or femoral venous thrombus is required prior to MitraClip procedure per the MitraClip 
IFU.   The MitraClip procedure should be attempted for all consented patients with no evidence of 
thrombus. 
 
6.1.1 
Protocol Required Medications 
All medication shall be administered per standard of care procedures for patients that undergo a 
MitraClip® procedure.   
 
6.1.2 
Clinical Assessments 
Baseline assessment should be conducted per standard of care.  Baseline information to be reported 
into the study include at minimum:  medical history, age, weight, heart rate, blood pressure, history 
of heart failure hospitalizations, MR severity, and New York Heart Association (NYHA) Functional 
Class.  A baseline QOL conducted by the KCCQ is required to be recorded and submitted for the 
study.  If a 6-minute walk test is conducted as standard of care at baseline, these results will be 
collected in the EXPAND Study.   
 
6.1.3 
Pre-treatment Imaging 
Pre-Treatment Transthoracic Echocardiogram (TTE) and Transesophageal Echocardiogram (TEE) 
should be conducted per standard of care for a MitraClip® Procedure.  Copies of all Echocardiograms 
will be collected by the Sponsor for future reference and may be compared to follow-up 
echocardiograms.  
 
6.2 
Index Procedure 
Please refer to IFU for instructions on handling and preparation of the MitraClip® System. All 
Investigators must read and understand the IFU that accompanies the Device.  
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 24 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
6.2.1 
Treatment  
The MitraClip® procedure should be conducted in accordance with standard of care practice and 
approved labelling.  All consecutive consented patients with an attempted MitraClip procedure will be 
entered into the study.  A procedure is considered attempted when the MitraClip delivery system is 
introduced.   
 
NOTE FOR U.S. Sites Only:  In order to permit device reimbursement, please enter required data 
into the TVT Registry per your standard processes for all EXPAND Study cases.  The data collected 
in this registry does not replace the data collected by the TVT Registry.    
 
6.3 
Post-Procedure 
Post Clinical Assessments and Laboratory / Clinical Tests should be conducted per standard of care.  
Post-procedure information to be reported for this study include at minimum:  adverse events, device 
performance, concurrent procedures, MR severity and NYHA Functional Class.   
 
6.3.1 
Final (Post-procedure) Imaging 
Prior to discharge a TTE should be conducted per standard of care.  The discharge TTE will be 
collected by the Sponsor for future reference and may be compared to baseline and/or follow-up 
TTEs.   
 
6.4 
Subject Follow-up  
Follow-up is conducted per standard of care visits shown below.  All follow-up assessment, visit or 
phone, should include a review for adverse events occurring since the last visit.  Results from the 
KCCQ survey are required to be recorded and submitted at the 30-day and 12-month visits.  Visit 
should be scheduled relative to the date of the MitraClip Procedure.  If a 6-minute walk test is 
conducted as standard of and was conducted at baseline; results for 6-minute walk test at 30day and 
12-months visits will be collected in the EXPAND Study.   
 
Visits at: 
• 
30 days (30 days -14 days / +60 days)  
• 
12 months (365 days - 30 days / +90 days)   
 
Phone call or visit at: 
• 
6 months (180 days - 30 days / +90 days) 
 
6.4.1 
Follow-Up Imaging 
At the 30-day and 12-month follow-up visits a TTE should be conducted per standard of care.  TTEs 
will be collected by the Sponsor for future reference and may be compared to baseline and/or follow-
up TTEs. 
 
During the follow-up period for this study (12 months) any unscheduled echocardiograms, either TEE 
or TTE, should be submitted to the Sponsor. 
 
Table 2 outlines the assessment schedule for this study. 
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 25 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Table 2.  Clinical Assessment Schedule 
Required Assessments to be Collected 
Pre-
Treatment 
Treatment DIS 
30-D 
6-M 
1-Y 
-14/+60 
days 
-30/+90 
days 
-30/+90 
days 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Medical Exam and Reporting of Vitals 
X 
 
X 
X 
 
X 
NYHA Classification 
X 
 
X 
X 
 
X 
KCCQ Survey 
X 
 
 
X 
 
X 
6 Minute Walk Test  
(Only if standard of care) 
X 
 
 
X 
 
X 
Adverse Events1 
 
X 
X 
X 
X 
X 
Transthoracic Echocardiography (TTE) 
X 
X2 
X 
X 
 
X 
Transesophageal Echocardiography (TEE)  
X 
X2 
 
 
 
 
Unscheduled Echocardiogram (TTE or TEE)  
 
 
X 
X 
X 
X 
1. Adverse Events to be collected in this study include: cardiovascular events, device-related complications (as 
defined in section 4.2), and events classified as MAEs (as defined in section 4.1)  
2.  TTE and TEE during treatment should be submitted for the study only if capturing TTE and TTE echoes is part 
of standard of care. 
 
 
7.0 
ADVERSE EVENTS 
To comply with worldwide standards and guidelines on clinical study adverse event reporting, Abbott 
has developed uniform and worldwide applicable standard definitions and reporting timelines to be 
used and adhered to by the investigators.  
 
7.1 
Definitions 
7.1.1 
Adverse Event 
An adverse event (AE) 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 medical device. 
 
Note 1: This definition includes events related to the device  
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to the MitraClip® 
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 product, whether or 
not related to the medicinal product. 
 
7.1.2 
Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a 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 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 26 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
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. 
A planned hospitalization for pre-existing condition, or a procedure required by the Clinical Protocol, 
without a serious deterioration in health, is not considered to be a serious adverse event. 
 
7.1.3 
Device Deficiency/Device Malfunction 
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. 
 
A device malfunction (DM) is the failure of a device to meet its performance specifications or 
otherwise perform as intended, when used in accordance with the IFU or protocol. 
 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that a product or device caused or 
contributed to an AE is to be determined by the Investigator and recorded on the appropriate eCRF 
form. Determination should be based on assessment of temporal relationships, evidence of 
alternative etiology, medical/biologic plausibility, and patient condition (pre-existing condition). 
 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting 
7.3.1 
Adverse Event Reporting  
The Investigator will monitor the occurrence of AEs for each subject during the course of the clinical 
study and report as required by this Protocol. AEs need to be collected on the appropriate AE eCRF 
form. Additional information with regards to an adverse event should be updated within the 
appropriate case report form. 
Adverse Events to be reported during this study include: all cardiovascular events, device-related 
complications (as defined in section 4.2), and events classified as MAEs (as defined in section 
4.1).  These AEs should be reported starting from the time that the MitraClip delivery system is 
introduced to the femoral vein through the 12-month follow up visit in cases with a MitraClip 
implant.  In cases with an attempted MitraClip Procedure, but no implant, AEs are only collected 
through 30 days post attempted procedure.   
 
The investigator should report all required SAEs to the Sponsor as soon as possible but no later than 
3 calendar days from the day the 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. 
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 27 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
A fax form will be made available to allow the investigator to report required SAEs in the event the 
entry cannot be made in the EDC. This does not replace the EDC reporting system. All information 
must still be entered in the EDC system as soon as feasible. 
 
Serious adverse events that occurred in the user or persons other than the study subject should not 
be entered in the EDC system, however need to be reported via the Product Experience Report Form . 
 
The Investigator will further report the SAE to the local IRB/EC according to reporting requirements. 
 
7.3.2 
Device Deficiency/Device Malfunction Reporting 
All device deficiencies/malfunctions should be reported within the Electronic Data Capture (EDC) 
System on the appropriate eCRF form no later than 3 calendar days from the day the 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. 
 
A fax form will be made available to allow the investigator to report device deficiencies/malfunctions 
in the event that the entry cannot be made in the EDC.  This does not replace the EDC reporting 
system. All information must still be entered in the EDC system as soon as feasible. 
 
In case a device deficiency/malfunction occurred before the patient ID has been assigned, the device 
deficiency should be reported to the Sponsor via the Product Experience Report Form .   
 
The device, if not implanted or not remaining in the subject, should be returned to Abbott. 
 
Device deficiencies/malfunctions should be reported to the IRB/EC per the investigative site’s local 
requirements. 
 
7.3.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor 
The Sponsor will report the SAEs and DDs to the country regulatory authority, per local and regional 
requirements.  
 
 
8.0 
ADJUDICATION OF EVENTS 
8.1 
The Clinical Events Committee (CEC) 
A Clinical Events Committee is comprised of qualified physicians who are not investigators in the 
study. The CEC will review and adjudicate pre-specified events reported by investigators or identified 
by the Safety & Surveillance personnel/designate for the study as documented in a CEC Manual of 
Operations (MOP). 
 
 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 28 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
9.0 
STATISTICAL ANALYSIS 
The following section describes the statistical methods for the clinical study. Details on 
statistical analyses are maintained in a separate Statistical Analysis Plan (SAP). 
 
9.1 
Statistical Overview 
This is a post-market multicenter study of consecutive consenting patients have an attempted 
treatment with the MitraClip® NTR System and/or MitraClip® XTR System at participating centers. 
The study will include up to 1,000 subjects for analysis.   
 
9.2 
Analysis Populations 
 
  
 
9.3 
Sample Size Calculations and Assumptions 
A sample size of 1000 subjects is expected to adequately capture data on a wide range of subjects 
with primary or secondary MR, subjects with or without complex valve anatomy, and subjects from 
Europe and the United States.  
 
 
 
 
9.3.1 
Planned Interim Analyses 
There is no planned interim analysis to claim success of the study.    Accumulating data from this 
study will be made public per the Publication Plan for the study. 
 
9.4 
Statistical Analyses 
9.4.1 
Endpoint Analysis 
The intent of this study is to collect contemporary data in a real-world setting.  All endpoints for this 
study will support a post-market assessment of device safety and performance.  Descriptive analysis 
will be performed on the study data.  Depending on the type of data (e.g., continuous or categorical), 
statistical methods described in this section below will be used.  
 
For continuous variables, such as age, means, standard deviations, and 95% confidence intervals 
for the mean will be calculated.  
 
For binary variables such as APS, counts, percentages, and 95% confidence intervals based on Exact 
Clopper-Pearson method will be calculated.    
 
For time to event data such as all-cause mortality, Kaplan-Meier analyses will be performed.  
 
For recurrent event data such as recurrent heart failure hospitalizations at pre- and post-procedure, 
data will be analyzed using a generalized linear model, such as Poisson regression model.  
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 29 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Results from this study will be presented within the context of the literature on the MitraClip. 
 
9.4.2 
Subgroup Analysis 
 
  
 
9.4.3 
Handling of Multiplicity Issues 
Details will be defined in the Statistical Analysis Plan (SAP).   
 
9.4.4 
Criteria for Early Termination of the Study for Efficacy 
No formal statistical rule for early termination of the study is defined.  
9.4.5 
Procedures for Accounting for Missing, Unused or Spurious Data 
All analyses will be based on available data with missing data excluded. Any unused or spurious data 
will be noted as appropriate in the clinical report.  
 
9.4.6 
Pooling Strategy 
Details on pooling strategy can be found in the SAP. 
 
9.5 
Deviations from the Original Statistical Plan 
Any major changes to the statistical plan will be documented in an amendment to the statistical plan. 
Less significant changes to the planned analyses will be documented in the final report. 
 
 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents in order for clinical 
study-related monitoring, audits, IRB/EC review and regulatory inspections to be performed. 
Subjects providing informed consent are agreeing to allow Sponsor and/or its designee access and 
copying rights to pertinent information in their medical records concerning their participation in this 
clinical study. The investigator will obtain, as part of the informed consent, permission for clinical 
study monitors or regulatory authorities to review, in confidence, any records identifying the subjects 
in this clinical study. This information may be shared with regulatory agencies; however, Sponsor 
undertakes not to otherwise release the subject's personal and private information. 
 
 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Selection of Clinical Sites and Investigators 
Sponsor will select investigators qualified by training and experience, to participate in this MitraClip 
Post Market study. Sites will be selected based upon review of a recent site assessment, if applicable, 
and the qualifications of the Principal Investigator or multidisciplinary team at the site. 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 30 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
11.2 
Protocol Amendments 
Approved Protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment. The Principal Investigator is responsible for notifying the IRB/EC or 
equivalent committee of the Protocol amendment (administrative changes) or obtaining IRB’s/EC’s 
approval of the Protocol amendment (changes in subject care or safety), according to the instructions 
provided by the Sponsor with the Protocol amendment. 
 
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. 
 
11.3 
Training 
11.3.1 
Site Training 
All Investigators/study 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. 
Over-the-phone or self-training may take place as required. Training of Investigators/study personnel 
will include, but is not limited to, the Protocol requirements, device usage, electronic case report form 
completion and study personnel responsibilities. All Investigators/study personnel that are trained 
must sign a training log (or an equivalent) upon completion of the training. Prior to signing the training 
log, Investigator/study personnel must not perform any study-related activities that are not considered 
standard of care at the site.  
 
11.3.2 
Training of Sponsor’s Monitors 
Sponsor and/or designated monitors will be trained to the Protocol, case report forms and device 
usage (as appropriate). Documentation of this training will be according to written procedures. 
 
11.4 
Monitoring 
Per the Monitoring Plan, centralized monitoring will occur through routine internal data review. This 
monitoring is designed to identify missing and inconsistent data, data outliers, and potential CIP 
deviations that may be indicative of site non-compliance. On-site monitoring may occur at the 
discretion of the Sponsor. 
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following 
criteria are met: 
 
The investigator understands and accepts the obligation to conduct the research study according to 
the Protocol and applicable regulations, and has signed the Investigator Agreement or the Clinical 
Study Agreement. 
 
The Investigator and his/her staff have sufficient time and facilities to conduct the study and that they 
have access to an adequate number of appropriate subjects to conduct the study.  
 
Source documentation (including original medical records) 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 case report forms, and device information.  
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 31 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
If monitoring visits are scheduled, the Investigator/site will permit access to such records. A 
monitoring visit sign-in log will be maintained at the site. The Investigator will agree to dedicate an 
adequate amount of time to the monitoring process. The Investigator and/or research coordinator will 
be available for monitoring visits. It is expected that the Investigator will provide the study monitor 
with a suitable working environment for review of study-related documents. 
 
11.5 
Deviations from Protocol 
The Investigator will not deviate from the Protocol for any reason without prior written approval from 
Sponsor except in cases of medical emergencies, when the deviation is necessary to protect the 
rights, safety and well-being of the subject or eliminate an apparent immediate hazard to the subject. 
In that event, the Investigator will notify Sponsor immediately by phone or in writing. All deviations 
must be reported to the Sponsor. In subject-specific deviations from the Protocol, a Protocol deviation 
case report form will be completed. The occurrence of Protocol deviations will be monitored by the 
Sponsor for evaluation of investigator compliance to the Protocol and regulatory requirements and 
dealt with according to written procedures. Investigators will inform their IRB/EC or equivalent 
committee of all Protocol deviations in accordance with their specific IRB/EC or equivalent committee 
reporting policies and procedures.  
 
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 and/or delegate 
• 
Telephoning the investigator and/or delegate 
• 
Corresponding with the investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the Protocol 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.  
 
11.6 
Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical study records, including 
source documentation, for inspection and duplication during a Quality Assurance audit. In the event 
that an investigator is contacted by a Regulatory Agency in relation to this clinical study, the 
Investigator will notify Sponsor immediately. The Investigator and Research Coordinator must be 
available to respond to reasonable requests and audit queries made during the audit process. The 
Investigator must provide Sponsor with copies of all correspondence that may affect the review of the 
current clinical study (e.g., Form FDA 483, Inspectional Observations, Warning Letters, Inspection 
Reports, etc.). Sponsor may provide any needed assistance in responding to regulatory audits. 
 
11.7 
Sponsor Auditing 
In the event that an Investigator is contacted by a Regulatory Agency in relation to this clinical study, 
the Investigator will notify the Sponsor immediately and IRB/EC as appropriate. 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 study (e.g., Form FDA 483, 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 32 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
Inspectional Observations, and Warning Letters). The Sponsor may provide any needed assistance 
in responding to regulatory inspections. 
 
11.8 
Committees  
11.8.1 
Steering Committee 
The Steering Committee will be led by two study Co-Primary Investigators (Co-PIs) whose names 
are specified on the cover page of this Protocol. In addition to the 2 Co-PIs, 8 key opinion leaders 
(whose names are also specified on the cover page of the protocol) will form the study Steering 
Committee. The Sponsor will be represented by at least one person each from the Clinical Science 
and Clinical Program Management groups. The Chairman of the core laboratories and other 
sponsor’s personnel may also participate in the Committee meetings if appropriate. Meeting minutes 
from this committee will be filed with the sponsor. 
 
The Steering Committee is responsible for overseeing the scientific and operational aspects of the 
study. This committee will meet regularly to monitor study progress, general data collection and non-
compliance with the study protocol at individual centers, to review operational issues that may arise 
and warrant a Protocol amendment or other corrective action and to determine policy regarding any 
publications arising from data generated from the performance of the study. 
 
11.8.2 
Clinical Events Committee (CEC) 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of qualified 
physicians who are not participants in the study. The CEC will review and adjudicate events as 
defined in the CEC charter and according to definitions provided in this Protocol.   
 
 
12.0 
DATA HANDLING AND RECORD KEEPING 
Data Management will include documentation of the systems and procedures used in data collection 
for the duration of the study. 
 
All CRF 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. Passwords and electronic signatures will be strictly 
confidential. 
 
All CRF data will be downloaded from the EDC system and reformatted into a data structure 
acceptable to Abbott. The data will be subjected to consistency and validation checks within the EDC 
system and will be subject to supplemental validation following download. 
 
At the conclusion of the study, completed Case Report Form (CRF) images 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 for each site and a backup copy archived with Abbott. 
 
For the clinical study duration, the Investigator will maintain complete and accurate documentation 
including, but not limited to, medical records, clinical study progress records, laboratory reports, 
electronic case report forms, signed ICFs, device accountability records, correspondence with the 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 33 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
IRB/EC and clinical study monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the clinical study. 
 
12.1 
Source Documentation 
Regulations and Good Clinical Practice (GCP) require that the Investigator maintain information in 
the subject’s original medical records that corroborates data collected on the case report forms. 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 study: 
• 
Medical history/physical condition of the subject before involvement in the study sufficient to 
verify Protocol entry criteria 
• 
Dated and signed notes on the day of entry into the study referencing the Sponsor, Protocol 
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, Electrocardiograms (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, reviewed and annotated for clinical 
significance of out of range results. Note: With electronic medical records some clinical sites 
may be able to annotate that labs or ECG have been reviewed in the system. For those sites 
that do not have such capability the labs or ECG may be able to be printed or signed. Each 
study team should include protocol language regarding these processes that is most suitable 
for the specific study.  
• 
Notes regarding Protocol-required and prescription medications taken during the study 
(including start and stop dates) 
• 
Subject’s condition upon completion of or withdrawal from the study 
• 
Any other data required to substantiate data entered into the CRF 
 
12.2 
Electronic Case Report Form Completion 
Primary data collection based on source-documented hospital and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the Protocol and eCRF completion. 
eCRF data will be collected for all patients in the study.   
 
12.3 
Record Retention 
The Sponsor will archive and retain all documents pertaining to the study 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 study records. 
 
 
13.0 
ETHICAL CONSIDERATION 
13.1 
Institutional Review Board/Medical Ethics Committee Review 
Institutional Review Board (IRB)/ Ethics Committee (EC) approval for the Protocol, ICF and other 
written information provided to the patient will be obtained by the Principal Investigator at each prior 
to participation in this clinical study. The approval letter must be received prior to the start of this 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 34 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
clinical study and a copy must be provided to the Sponsor. No changes will be made to the Protocol 
or ICF or other written information provided to the patient without appropriate approvals, including 
IRB/EC, the Sponsor, and/or the regulatory agencies.  
 
Until the clinical study is completed, the Investigator will advise his/her IRB/EC of the progress of this 
clinical study, per IRB/EC requirements. Ongoing written approval will be obtained from the IRB/EC 
according to each institution’s IRB/EC requirements. Further, any amendments to the Protocol as 
well as associated ICF changes will be submitted to the IRB/EC and written approval obtained prior 
to implementation, according to each institution’s IRB/EC requirements. 
 
 
14.0 
PUBLICATION POLICY 
The data and results from the study are the sole property of the Sponsor. The Sponsor shall have the 
right to access and use all data and results generated during the clinical study. The Investigators will 
not use the Clinical study-related data without the written consent of the Sponsor for any other 
purpose than for Clinical study completion or for generation of publication material, as referenced in 
the Clinical Study Site Agreement. The publication and/or presentation of results from a single clinical 
study site are not allowed until publication and/or presentation of the multi-center results. The Sponsor 
acknowledges that the study’s Principal Investigator intends to publish a multi-center publication 
regarding the clinical study results. The Sponsor must receive any proposed publication and/or 
presentation materials at least 60 days prior to the proposed date of the presentation or the initial 
submission of the proposed publication in order for the materials to be reviewed by the Sponsor in 
compliance with the Sponsor’s publication policy set forth in the Clinical Study Site Agreement. 
 
The Sponsor will be responsible for determining whether to register the Clinical study on 
www.clinicaltrials.gov or any other clinical study registration sites, in accordance with the International 
Committee of Medical Journal Editors guidelines, or any other applicable guidelines. In the event 
Sponsor determines that the Study should be registered, Sponsor shall be responsible for any such 
registration and results posting as required by ClinicalTrials.gov. Institution and/or Principal 
Investigator(s) shall not take any action to register the study. 
 
 
15.0 
RISK ANALYSIS 
15.1 
Anticipated Clinical Benefits 
The new MitraClip NTR System is a modification to the DC of the MitraClip NT System and is intended 
to make the procedure easier, more precise, more predictable, and to optimize manufacturability of 
the product.  The MitraClip XTR System, which includes the same modified DC and longer clip arms 
on the implant, was designed for grasping mitral leaflets.  Based on testing, grasping leaflets with 
MitraClip XTR will be easier in certain patients.  In design validation testing, differentiation of ease of 
grasping between MitraClip NT and MitraClip XTR Systems was found in a model which simulated a 
mixed functional/degenerative etiology procedure with a tethered posterior leaflet and a flailing 
anterior leaflet. The end result of both grasping procedures were successful as both MitraClip NT 
System and MitraClip XTR System were able to successfully grasp the coapt leaflets however the 
user was able to perform the steps in less attempts with MitraClip XTR. In other development tests 
prior to the design validation, both the MitraClip NT and MitraClip XTR devices were able to grasp 
leaflets equivalently. Subjects with such anatomies may therefore benefit from treatment with the 
MitraClip XTR.   Moreover, the improved DC may simplify the MitraClip procedure compared to the 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 35 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
current iteration of the MitraClip System.   Data from this study may help to elucidate this and to 
further identify the anatomical characteristics that can be treated with the MitraClip NTR or the 
MitraClip XTR device.   
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Per the MitraClip IFU, The ANTICIPATED EVENTS on Table 3 have been identified as possible.  
 
Table 3.  Potential Complications and Adverse Events (from MitraClip® IFU) 
Allergic reaction (anesthetic, contrast, Heparin, nickel alloy, latex) 
Aneurysm or pseudo-aneurysm 
Arrhythmias 
Atrial fibrillation 
Atrial septal defect requiring intervention 
Arterio-venous fistula 
Bleeding 
Cardiac arrest 
Cardiac perforation 
Cardiac tamponade / Pericardial Effusion 
Chordal entanglement/rupture 
Coagulopathy 
Conversion to standard valve surgery 
Death 
Deep venous thrombus (DVT) 
Dislodgement of previously implanted devices 
Dizziness 
Drug reaction to anti-platelet / anticoagulation agents / contrast 
media 
Dyskinesia 
Dyspnea 
Edema 
Emboli (air, thrombus, MitraClip Implant) 
Emergency cardiac surgery 
Endocarditis 
Esophageal irritation 
Esophageal perforation or stricture 
Failure to deliver MitraClip to the intended site 
Failure to retrieve MitraClip System components 
Fever or hyperthermia  
Gastrointestinal bleeding or infarct 
Hematoma 
Hemolysis 
Hemorrhage requiring transfusion 
Hypotension / hypertension 
Infection 
Lymphatic complications 
Mesenteric ischemia 
Mitral stenosis 
Mitral valve injury 
MitraClip Implant erosion, migration or malposition 
MitraClip Implant thrombosis 
MitraClip System component(s) embolization 
Multi-system organ failure 
Myocardial infarction 
Nausea/vomiting 
Pain 
Peripheral ischemia 
Prolonged angina 
Prolonged ventilation 
Pulmonary congestion 
Pulmonary thrombo-embolism 
Renal insufficiency or failure 
Respiratory failure / atelectasis / pneumonia 
Septicemia 
Shock, Anaphylactic or Cardiogenic 
Single leaflet device attachment (SLDA) 
Skin injury or tissue changes due to exposure to ionizing radiation 
Stroke or transient ischemic attack (TIA) 
Urinary tract infection 
Vascular trauma, dissection or occlusion 
Vessel spasm 
Vessel perforation or laceration 
Worsening heart failure 
Worsening mitral regurgitation 
Wound dehiscence 
 
15.3 
Residual Risks Associated with the Investigational Device 
This is a post-market study on an approved commercial device.  There is no investigational device 
being used as part of this study.   
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 36 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
15.4 
Risks Associated with Participation in Clinical Study 
Treatment with the MitraClip® device as part of this study is identical to treatment with the MitraClip® 
device outside of this study.  Participation in the study will not impact the MitraClip procedure or use 
of the MitraClip in any way.  Participation in the study requires submission of data that may or may 
not be protected heath information.  This information should be kept confidential, but there is a risk 
that some of the information could be unintentionally made non-confidential.  The risk of the this 
happening for this study is no greater than the risk of loss of confidentiality in any study.   
 
15.5 
Possible Interactions with Protocol-Required Concomitant Medications 
This is a post-market study being conducted under standard of care medications.  There are no 
protocol -required medications being used as part of this study.   
 
15.6 
Steps that will be Taken to Control or Mitigate the Risks 
Per the device IFU, “Use of the MitraClip Delivery System should be restricted to those physicians 
trained to perform invasive endovascular and transseptal procedures and to those physicians trained 
in the proper use of the system”.   
 
Risks associated with the use of the device during this clinical study are minimized through device 
design, investigator selection and training, pre-specified patient eligibility requirements, study 
monitoring to ensure adherence to the protocol. All adverse events and device deficiencies will be 
reported to Abbott and will be monitored internally for safety surveillance purposes. 
 
The contraindications, warnings and precautions are listed in the IFU that will be provided with all 
devices to be used during this study.  
 
15.7 
Risk to Benefit Rationale 
Subjects participating in this study will be receiving the latest technology in MitraClip which has been 
shown to be safe and effective in over 4,500 patients in clinical trials and more than 50,000 patients 
in worldwide use to date.  This is a post-market study being conducted on an approved device within 
the standard of care procedures.  The risks associated with receiving a MitraClip implant within this 
study are identical to the risks of receiving a MitraClip implant outside of the study. 
 
Subjects participating in the study have a small risk of loss of confidentiality as part of the data 
collection process.  This risk is mitigated to as low as possible with the use of data collection systems, 
methods and procedures that are used commonly in clinical research.  This includes the use of only 
validated electronic systems, the training of study personnel and the use of de-identified data for all 
data entry.  Based upon the established safety profile of the MitraClip device; the low risk of loss of 
confidentiality is adequately mitigated to justify use of the next generation MitraClip to treat patients 
for this study. 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
CONFIDENTIAL and PROPRIETARY  
 
 
 
 
Page 37 of 68 
Do not distribute or reproduce with the prior written permission of Abbott  
 
APPENDIX I:   
MITRACLIP XTR PMCF CLINICAL STUDY PROTOCOL
 
 
 
 
 
 
Defines a statistical analysis to be conducted for the first 220 European Patients in the EXPAND 
Study treated with the MitraClip XTR System  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 1 of 36 
  
 
 
 
 
 
 
 
17-518-1: MitraClip XTR PMCF Study 
 
A Post-Market Clinical Follow-up Assessment of the Safety and 
Performance the MitraClip XTR System 
 
 
Version Number 
2.0 
Date 
26 June 2018 
Planned Number of Sites and 
Region(s) 
Up to 50 sites in Europe 
 
Protocol Author  
Erin Tims, MS CCRP 
Senior Principal Clinical Research Scientist 
Abbott Structural Heart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 2 of 36 
  
 
 
Table of Contents 
1.0 
INTRODUCTION ........................................................................................................................ 6 
1.1 
Study Design .......................................................................................................................... 6 
1.2 
Study Objective ...................................................................................................................... 6 
2.0 
BACKGROUND INFORMATION ................................................................................................ 6 
2.1 
Literature Review .................................................................................................................... 6 
2.2 
Rationale for Conducting this Study ........................................................................................ 8 
2.3 
Summary of Device ................................................................................................................ 8 
2.3.1 
Name of the Device ...................................................................................................... 8 
2.3.2 
Indication for Use .......................................................................................................... 8 
2.3.3 
Description of the Device .............................................................................................. 8 
3.0 
FOLLOW-UP SCHEDULE .......................................................................................................... 9 
3.1 
Number of Subjects to be Enrolled ......................................................................................... 9 
3.2 
Overall Flow of the Study and Follow-up Schedule ................................................................. 9 
3.3 
Early Termination of the Clinical Study ................................................................................... 9 
4.0 
ENDPOINTS ............................................................................................................................ 10 
4.1 
Primary Endpoint .................................................................................................................. 10 
4.2 
Clinical Endpoints ................................................................................................................. 10 
4.3 
Success Criteria ................................................................................................................... 10 
5.0 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................... 10 
5.1 
Subject Population ................................................................................................................ 10 
5.2 
Subject Screening and Informed Consent............................................................................. 10 
5.2.1 
Subject Screening....................................................................................................... 10 
5.2.2 
Informed Consent ....................................................................................................... 11 
5.3 
Eligibility Criteria ................................................................................................................... 11 
5.3.1 
Inclusion Criteria ......................................................................................................... 11 
5.3.2 
Exclusion Criteria ........................................................................................................ 11 
5.4 
Subject Enrollment and Inclusion in Analysis ........................................................................ 11 
5.5 
Total Expected Duration of the Study ................................................................................... 11 
5.6 
Expected Duration of Each Subject’s Participation ............................................................... 12 
5.7 
Number of Subjects Required to be Included in the Study .................................................... 12 
5.8 
Estimated Time Needed to Select this Number .................................................................... 12 
5.9 
Subject Discontinuation ........................................................................................................ 12 
6.0 
TREATMENT AND EVALUATION OF SAFETY AND EFFICACY ............................................ 12 
6.1 
Pre-treatment ....................................................................................................................... 12 
6.1.1 
Clinical Assessments .................................................................................................. 13 
6.1.2 
Pre-treatment Imaging ................................................................................................ 13 
6.2 
Index Procedure ................................................................................................................... 13 
6.2.1 
Treatment Strategy or Treatment Procedures ............................................................. 13 
6.3 
Post-procedure ..................................................................................................................... 13 
6.4 
Subject Follow-up ................................................................................................................. 13 
7.0 
ADVERSE EVENTS ................................................................................................................. 14 
7.1 
Definitions............................................................................................................................. 14 
7.1.1 
Adverse Event ............................................................................................................ 14 
7.1.2 
Serious Adverse Event ............................................................................................... 14 
7.1.3 
Device Deficiency/Device Malfunction ........................................................................ 14 
7.2 
Device Relationship .............................................................................................................. 14 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting ......................................... 15 
7.3.1 
Adverse Event Reporting ............................................................................................ 15 
7.3.2 
Device Deficiency/Device Malfunction Reporting ........................................................ 15 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 3 of 36 
  
 
 
7.3.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .............. 15 
8.0 
ADJUDICATION OF EVENTS .................................................................................................. 16 
8.1 
The Clinical Events Committee (CEC) .................................................................................. 16 
9.0 
STATISTICAL ANALYSIS ........................................................................................................ 16 
9.1 
Statistical Overview .............................................................................................................. 16 
9.2 
Analysis Populations ............................................................................................................ 16 
9.3 
Sample Size Calculations and Assumptions ......................................................................... 16 
9.4 
Statistical Analyses ............................................................................................................... 17 
9.4.1 
Primary Endpoint Analysis .......................................................................................... 17 
9.4.2 
Clinical Endpoint Analyses .......................................................................................... 18 
9.4.3 
Handling of Multiplicity Issues ..................................................................................... 18 
9.4.4 
Procedures for Accounting for Missing, Unused or Spurious Data .............................. 18 
9.5 
Deviations from the Original Statistical Plan ......................................................................... 18 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................ 18 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 18 
11.1 
Selection of Clinical Sites and Investigators .......................................................................... 18 
11.2 
Protocol Amendments .......................................................................................................... 19 
11.3 
Training ................................................................................................................................ 19 
11.3.1 
Site Training ........................................................................................................... 19 
11.3.2 
Training of Sponsor’s Monitors ............................................................................... 19 
11.4 
Monitoring............................................................................................................................. 19 
11.5 
Deviations from Protocol ....................................................................................................... 20 
11.6 
Quality Assurance Audit ....................................................................................................... 20 
11.7 
Sponsor Auditing .................................................................................................................. 20 
12.0 
DATA HANDLING AND RECORD KEEPING ........................................................................... 20 
12.1 
Data Management/Data Analysis ......................................................................................... 20 
12.2 
Source Documentation ......................................................................................................... 21 
12.3 
Electronic Case Report Form Completion ............................................................................. 21 
12.4 
Record Retention .................................................................................................................. 21 
13.0 
ETHICAL CONSIDERATION .................................................................................................... 21 
13.1 
Medical Ethics Committee Review ........................................................................................ 21 
14.0 
RISK ANALYSIS ...................................................................................................................... 22 
14.1 
Anticipated Clinical Benefits ................................................................................................. 22 
14.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ................................. 22 
14.3 
Residual Risks Associated with the Investigational Device ................................................... 23 
14.4 
Risks Associated with Participation in Clinical Study ............................................................ 23 
14.5 
Possible Interactions with Protocol-Required Concomitant Medications ............................... 23 
14.6 
Steps that will be Taken to Control or Mitigate the Risks ...................................................... 23 
14.7 
Risk to Benefit Rationale ...................................................................................................... 24 
APPENDIX I - ABBREVIATIONS AND ACRONYMS ........................................................................... 25 
APPENDIX II - DEFINITIONS .............................................................................................................. 26 
APPENDIX III - CASE REPORT FORMS............................................................................................. 33 
APPENDIX IV - SUMMARY OF CHANGES ......................................................................................... 34 
 
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 4 of 36 
  
 
 
COMPLIANCE STATEMENT:  
 
This study will be conducted in accordance with this Plan, the Declaration of Helsinki, applicable Good 
Clinical Practices and applicable regulations including ISO14155 and the appropriate local legislation(s). 
The most stringent requirements, guidelines or regulations must always be followed. The conduct of the 
study will be approved by the appropriate Institutional Ethics Committee (EC) of the respective study site 
and by the applicable regulatory authorities. 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 5 of 36 
  
 
 
PROTOCOL SUMMARY 
 
 
 
Protocol 
Name 
and Number 
17-518-1: MitraClip XTR PMCF Study 
 
Title 
Post-Market Clinical Follow-up Assessment of the Safety and 
Performance the MitraClip XTR System 
Objectives 
The primary objective of this study to evaluate the safety and 
performance of the MitraClip XTR System in a post-market setting. 
Device 
MitraClip XTR System 
Targeted number 
of subjects  
A minimum of 220 subjects  
Subject Follow-up 
Clinical Visit: 30 days and 12 Months 
Phone Call:  6 Months  
Primary Endpoint 
Safety and Effectiveness  
Acute Procedural Success (APS) defined as successful implantation of 
the MitraClip XTR device with resulting MR severity of 2+ or less on 
discharge Echocardiogram (30-day echocardiogram will be used if 
discharge is unavailable or uninterpretable). Subjects who die or 
undergo mitral valve surgery before discharge are considered to be an 
APS failure 
Clinical Endpoints  • 
Major Adverse Event (MAE).  MAE defined as a composite of all-
cause Death, Myocardial Infarction, Stroke, or non-elective CV 
surgery for device related complications (CEC adjudicated) 
• 
 MR Severity 
• 
Device Related Adverse Events (including Mitral valve stenosis, 
device embolization, Single Leaflet Device Attachment (SLDA), 
Iatrogenic atrial septal defect, Myocardial perforation, 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)) 
• 
All-cause mortality  
• 
Recurrent heart failure hospitalization 
• 
New York Heart Association (NYHA) functional class improvement 
Inclusion Criteria 
1. Subjects scheduled to receive the MitraClip per the current approved 
indications for use  
2. Subjects who give consent for their participation 
3. Subjects with Symptomatic MR (≥3+) 
Exclusion Criteria 
1. Subjects participating in another clinical study that could impact the 
follow-up or results of this study.   

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 6 of 36 
  
 
 
1.0 
INTRODUCTION 
This clinical study protocol defines the MitraClip XTR PMCF study being conducted to confirm the safety 
and performance of the MitraClip XTR in a post-market setting.  The MitraClip XTR System introduces a 
new delivery catheter design intended to make procedure easier, more precise, more predictable, and to 
optimize manufacturability and an additional implant size intended to assist clinicians with leaflet grasping.  
Although there is extensive published clinical evidence on the safety and performance of the MitraClip 
system (see section 2.1), the safety and performance of the MitraClip XTR system has not yet been 
evaluated in a clinical study.   
 
This PMCF study will be conducted on commercial MitraClip XTR devices that have received CE Mark 
and will be used to fulfill the regulatory requirement for post-market clinical follow-up (PMCF). 
 
1.1 
Study Design 
This is a Post-Market, Multi-Center, International, Single-Arm, Prospective Study to assess the safety 
and performance of the next generation MitraClip XTR System by comparing the rate of acute procedural 
success after treatment with the MitraClip XTR to an expected rate based on historical MitraClip data.  
 
A minimum of 220 post-market, consecutive, consented, patients treated with the MitraClip XTR device 
in the EU will be included for analysis into the MitraClip XTR PMCF study.  Clinical follow-up visits will 
be requested at 30 days and at 12 months post-procedure with an additional clinical follow-up phone call 
at 6 months.  Reported adverse events through 12 months will be assessed to further confirm safety. 
 
1.2 
Study Objective 
The primary objective of this study is to assess the safety and performance of the MitraClip XTR System 
in a post-market setting. This study will be conducted in accordance with post market clinical follow-up 
requirements. 
 
 
2.0 
BACKGROUND INFORMATION 
2.1 
Literature Review 
The MitraClip System received approval for commercialization in Europe in March 2008, and is indicated 
for reconstruction of the insufficient mitral valve through tissue approximation.  Since approval, there 
have been a number of commercial studies in Europe on the MitraClip.   
 
ACCESS-EU29 was a two-phase prospective, single-arm, multicenter post-approval observational study 
of the MitraClip in Europe for the treatment of MR.  The primary objective was to gain information with 
respect to health economics and clinical care, and to provide further evidence of safety and effectiveness. 
Five hundred sixty-seven (567) patients were treated with the MitraClip.  One-year clinical follow-up was 
available in 487 patients.  Considering the high MitraClip device implant rate (99.6%, 565/567), the high 
rate of meaningful MR reduction (78.9%, 258/327 MR<2+), and the resulting improvements in 6-minute 
 
 
29 Maisano F, Franzen O, Baldus S, Schafer 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 1-Year Results 
from the ACCESS-EU, a Prospective, Multicenter, Nonrandomized Post-Approval Study of the MitraClip Therapy 
in Europe.  J Am Coll Cardiol.  2013; 62:1052-1061. 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 7 of 36 
  
 
 
walk (59.5 m difference, p<0.0001), Minnesota Living with Heart Failure Questionnaire quality of life score 
(13.5 point improvement, p<0.0001) and NYHA Functional Class (71.5% NYHA Class I or II, p<0.0001), 
at 1 year, the study is concluded that the MitraClip device provides an important therapeutic option for 
patients with significant mitral regurgitation, and is an especially important option for patients who may 
be considered high surgical risk. 
 
The GRASP registry was a single-center, prospective, observational study of consecutive high surgical 
risk patients with moderate-to-severe or severe MR undergoing percutaneous mitral valve repair with the 
MitraClip System at Ferrarotto Hospital (Catania, Italy).  The study does not have specific exclusion 
criteria; and the indication for MitraClip therapy was established by a multidisciplinary Heart Team.  The 
degree of preprocedural MR was quantified according to current guidelines by two expert 
echocardiographers.  A total of 117 consecutive patients underwent MitraClip implantation between 
August 2008 and October 2012 as part of the GRASP registry30.  MR grade 3+ or 4+ was present in 98% 
of patients, and NYHA functional class symptoms in 80% of patients.  Acute procedural success was 
achieved in all patients.  MR was reduced to 1+ and 2+ post-procedure in 63% and 37% of patients, 
respectively.  MAEs occurred in 4 patients (4.3%) at 30 days.  One patient died from gastrointestinal 
bleeding within 30 days. Results from the GRASP registry further support the safety and efficacy of the 
MitraClip device in a real-world setting.  
 
The German transcatheter mitral valve interventions (TRAMI) registry was initiated in August 2010 to 
collect data from clinical centers in Germany involved in transcatheter therapies for mitral valve disease.  
The registry comprises a retrospective part, including patients who have been treated at individual sites 
prior to study initiation, and a prospective part after study site initiation.  Follow-up for the retrospective 
part was not defined in the study protocol and was performed according to institutional practice.  Follow-
up for the prospective part was scheduled at 30 days and then at 1, 3, and 5 years.  Several reports on 
TRAMI have been published over the years31,32.  The largest prospective cohort was described by Puls 
et al.33.  A total of 828 patients were prospectively enrolled at 21 German sites between 2010 and 2013.  
One-year follow-up was available in 749 patients.  The MitraClip implant rate in this cohort was 97%, with 
an average of 1.4±0.6 clips implanted per procedure.    Mitral regurgitation was reduced from severe 
(94%) at baseline to none or mild in 85.2% of patients post procedure.  One patient died intra-operatively 
and in-hospital mortality was 2.4% (n=18).  No emergent cardiac surgery was required.  The rate of in-
hospital Major adverse cardiac and cerebrovascular events (MACCE) was 3.1%. These results 
demonstrate that treatment of significant MR with the MitraClip device is efficacious and results in 
 
 
30 Grasso C, Capodanno D, Scandura S, Cannata S, Imme S, Mangiafico S, Pistritto A, Ministeri M, Barbanti M, 
Caggegi A, Chiaranda M, Dipasqua F, Giaquinta S, Occhipinti M, Ussia G, Tamburino C.  One- and Twelve-Month 
Safety and Efficacy Outcomes of Patients Undergoing Edge-to-Edge Percutaneous Mitral Valve Repair (from the 
GRASP Registry).  Am J Cardiol.  2013; 111:1482-1487. 
31 Baldus S, Schillinger W, Franzen O, Bekeredjian R, Sievert H, Schofer J, Kuck KH, Konorza T, Mollmann H, 
Hehrlein C, Ouarrak T, Senges J, Meinertz T, investigators GTMVI.  MitraClip Therapy in Daily Clinical Practice: 
Initial Results from the German Transcatheter Mitral Valve Interventions (TRAMI) Registry.  Eur J Heart Fail.  2012; 
14:1050-1055. 
32 Schillinger W, Hunlich M, Baldus S, Ouarrak T, Boekstegers P, Hink U, Butter C, Bekeredjian R, Plicht B, Sievert 
H, Schofer J, Senges J, Meinertz T, Hasenfuss G.  Acute Outcomes after MitraClip Therapy in Highly Aged Patients: 
Results from the German Transcatheter Mitral Valve Interventions (TRAMI) Registry.  EuroIntervention.  2013; 9:84-
90. 
33 Puls M, Lubos E, Boekstegers P, von Bardeleben RS, Ouarrak T, Butter C, Zuern CS, Bekeredjian R, Sievert H, 
Nickenig G, Eggebrecht H, Senges J, Schillinger W.  One-Year Outcomes and Predictors of Mortality after MitraClip 
Therapy in Contemporary Clinical Practice: Results from the German Transcatheter Mitral Valve Interventions 
Registry.  Eur Heart J.  2016; 37:703-712. 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 8 of 36 
  
 
 
significant clinical improvements in a high proportion of TRAMI patients after 12 months.  In this cohort, 
failure to achieve procedural success had the highest hazard ratio for predicting 1-year mortality. 
 
The Transcatheter Valve Treatment Sentinel Pilot Registry is part of the European Society of Cardiology 
EuroObservational Research Programme and reports acute and 12-month follow-up results of 628 
consecutive patients treated between January 2011 and December 2012 in 25 centers in 8 European 
countries. Acute procedural success was high (95.4%) with no difference between FMR and DMR 
patients.  Overall, in-hospital mortality was 2.9%.  MR reduction to ≤2+ was achieved in 98.2% of patients 
post-procedure with no difference between MR etiologies.  At 1-year, MR was reduced to ≤2+ in 94.0% 
of patients and 58.6% had mild or no MR, with comparable results obtained for FMR and DMR.  The 
results of the pilot European Sentinel Registry demonstrated that procedural and late mortality was low 
and lower than expected in such a high-risk cohort, without differences between FMR and DMR.  These 
results confirm long-term benefits previously reported in other real-world registries. 
 
The totality of post-market clinical evidence supports the use of the MitraClip System for the treatment of 
MR.  The MitraClip XTR PMCF Study will assess the safety and performance of the next generation 
MitraClip XTR system to confirm that the new design also performs safely and with acceptable outcomes.   
 
2.2 
Rationale for Conducting this Study 
This Study will meet PMCF requirements to confirm safety and performance of the next generation 
MitraClip XTR System.  The primary analysis will be conducted using the endpoint of Acute Procedural 
Success (APS). APS is evaluated by taking into account both safety and performance by capturing safety 
events related to device failure (re-intervention or death) and performance by the assessment of MR 
(reduced MR to MR2+ or less). APS will be evaluated upon discharge from the hospital post procedure.  
A comparison to the APS rate established by historical clinical data will show the next generation 
MitraClip XTR System offers the safety and performance expected from MitraClip.  
 
2.3 
Summary of Device 
2.3.1 
Name of the Device 
Patients will be treated with MitraClip XTR System as part of this study after all required commercial 
approval for the device is obtained.   
 
2.3.2 
Indication for Use 
MitraClip XTR procedures for this study will be conducted in accordance with the Instructions for Use 
(IFU) that is approved for the region, where the implant is taking place.  
 
2.3.3 
Description of the Device 
The MitraClip System is intended for reconstruction of the insufficient mitral valve through tissue 
approximation. The MitraClip System comprises of the Clip Delivery System and Steerable Guide 
Catheter.  The Clip Delivery System is introduced into the body through the Steerable Guide Catheter.   
 
The MitraClip XTR System is an additional implant size to be used with a modified Delivery Catheter.  
The additional implant size is intended to assist clinicians with leaflet grasping.  The modified delivery 
caterer is designed to make the procedure more precise, more predictable, and to optimize 
manufacturability of the product.  

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 9 of 36 
  
 
 
3.0 
FOLLOW-UP SCHEDULE 
3.1 
Number of Subjects to be Enrolled 
Subjects who have provided written informed consent are considered enrolled.  Upon treatment with 
MitraClip XTR the subject will be included in this PMCF analysis.  A minimum of 220 commercial MitraClip 
XTR patients will be analyzed at a maximum of 50 centers in the EU as part of this PMCF study. 
 
3.2 
Overall Flow of the Study and Follow-up Schedule 
Consecutive eligible patients that present for MitraClip procedure should be consented for the MitraClip 
XTR PMCF Study.  Patients are included in the analysis upon completion of MitraClip XTR procedure.  
A schematic of the study flow for the study is shown in Figure 1.   
 
 
Figure 1: Schematic for Study Inclusion 
 
 
 
3.3 
Early Termination of the Clinical Study 
No formal statistical rule for early termination of the MitraClip XTR PMCF Study is defined.  
The Sponsor reserves the right to discontinue the study at any stage or reduce the follow up period with 
suitable written notice to the investigator. Possible reason(s) may include, but are not limited to: 
• 
Unanticipated adverse device effect (UADE) occurs and it presents an unreasonable risk to the 
participating subjects. 
• 
Further product development is cancelled. 
 
Should the study be discontinued by the Sponsor, patients will be followed up as per routine hospital 
practice with device related AEs being reported to the Sponsor as per vigilance/commercial reporting 
requirements.  Should this occur, the investigator shall return all clinical study materials to the Sponsor, 
and provide a written statement as to why the premature termination has taken place to the EC. 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 10 of 36 
  
 
 
4.0 
ENDPOINTS 
4.1 
Primary Endpoint 
The primary endpoint is Acute Procedural Success (APS).  This is defined as successful implantation of 
the MitraClip device with resulting MR severity of 2+ or less upon discharge Echocardiogram (30-day 
echocardiogram will be used if discharge is unavailable or uninterpretable). Subjects who die or undergo 
mitral valve surgery before discharge are an APS failure 
 
4.2 
 Clinical Endpoints  
Clinical Endpoints will be assessed at each study time point, all data reported at the 
corresponding study visit will be included for the study time point.      
• 
Major Adverse Events (MAE): defined as a composite of CEC adjudicated all-cause Death, 
Myocardial Infarction, Stroke, or non-elective CV surgery for device related complications 
• 
MR Severity 
• 
Device Related Adverse Events (including mitral valve stenosis, device embolization, single 
leaflet device attachment (SLDA), Iatrogenic atrial septal defect, myocardial perforation, 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) 
• 
All-cause mortality  
• 
Recurrent heart failure hospitalization 
• 
New York Heart Association (NYHA) functional class improvement 
 
4.3 
Success Criteria 
The MitraClip XTR PMCF Study will be successful if the lower one-sided 95% confidence interval (CI) of 
the observed APS rate for the study is greater than the Performance Goal (PG) of 80.7%.     
 
 
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This study will include an analysis of male and female consented subjects from the heart failure 
population who satisfy the inclusion and exclusion criteria and who are treated with the MitraClip XTR 
System. The study will include a minimum of 220 subjects.  
 
5.2 
Subject Screening and Informed Consent 
5.2.1 
Subject Screening 
The hospital will follow their standard of care procedures for determining if a patient is eligible for 
treatment with a MitraClip System.  Consecutive patients who present for their procedure should be 
asked to provide consent for participation in the MitraClip XTR PMCF Study if they are eligible per the 
inclusion/exclusion criteria.  Only patients that have a MitraClip XTR implanted will be included in the 
analysis. 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 11 of 36 
  
 
 
5.2.2 
Informed Consent 
Patient Information and Consent Form must receive approval of Sponsor and EC/IRB prior to beginning 
enrollment into the MitraClip XTR PMCF Study 
 
The Investigator or designee, who has been trained on the Study, will explain the nature and scope, 
potential risks and benefits of participation, and answer questions for the subjects.  The subject will be 
treated with the MitraClip System per standard of care and must consent only to data collection and 
follow-up visit schedule. All subjects (or legally authorized subjects’ representatives if applicable) must 
sign, date and time (if required) the Ethics Committee (EC) approved informed consent prior to any data 
is reported into the PMCF study.  Obtaining the consent and provisioning of a copy to the subject, must 
be documented in the subject’s medical records. In addition, the signed informed consent must be kept 
in the subject’s medical records. 
 
If approved by the EC, subjects from vulnerable populations may be enrolled in the study.  ISO14155 
definition of vulnerable population: Defined as subject whose willingness to volunteer in a clinical 
investigation could be unduly influenced by the expectation, whether justified or not, of benefits 
associated with participation or of retaliatory response from senior members of a hierarchy in case of 
refusal to participate.  Examples of populations which may contain vulnerable subjects include: 
Individuals with lack of or loss of autonomy due to immaturity or through mental disability, persons in 
nursing homes, children, impoverished persons, subjects in emergency situations, ethnic minority groups, 
homeless persons, nomads, refugees, and those incapable of giving informed consent. Other vulnerable 
subjects include, for example, members of a group with a hierarchical structure such as university 
students, subordinate hospital and laboratory personnel, employees of the sponsor, members of the 
armed forces, and persons kept in detention.   
 
5.3 
Eligibility Criteria 
Consented subjects treated commercially with the MitraClip XTR System will be considered.  All subjects 
must meet the criteria below before being included in the MitraClip XTR Study.  
 
5.3.1 
Inclusion Criteria 
1. Subjects scheduled to receive the MitraClip per the current approved indications for use  
2. Subjects who give consent for their participation 
3. Subjects with Symptomatic MR (≥3+) 
5.3.2 
Exclusion Criteria 
1. Subjects participating in another clinical study that could impact the follow-up or results of this 
study.   
 
5.4 
Subject Enrollment and Inclusion in Analysis 
The patient is considered enrolled upon signing and dating an informed consent for participation.  Only 
subjects that have an MitraClip XTR implant will be included in the analysis.  
 
5.5 
Total Expected Duration of the Study 
The time to complete the MitraClip XTR PMCF Study is estimated to be approximately 18 months. 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 12 of 36 
  
 
 
5.6 
Expected Duration of Each Subject’s Participation 
The final required visit for subjects in the MitraClip XTR PMCF Study is at 12 months post-procedure.  
Therefore, the expected duration of participation for subjects is approximately 12 months.  
 
5.7 
Number of Subjects Required to be Included in the Study 
A minimum of 220 subjects will be included in the MitraClip XTR PMCF Study 
 
5.8 
Estimated Time Needed to Select this Number  
The estimated time to include 220 patients is about 6 months.   
 
5.9 
Subject Discontinuation 
Subjects that are consented and receive a MitraClip XTR implant shall remain in the study until 
completion of the required follow-up period; however, a subject’s participation in any clinical study 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 withdrawal by physician as clinically-indicated 
• 
Subject lost-to follow-up as described below  
 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will provide this 
information to the Sponsor. Investigators must also report this to their respective EC as defined by their 
institution’s procedure(s). No additional follow–up will be required or data recorded from subjects once 
withdrawn, except for the status (deceased/alive).  However, if a subject withdraws due to problems 
related to the device safety or performance, the investigator shall ask for the subject's permission to 
follow his/her status/condition outside of the clinical study. 
 
Lost-to-Follow-up:  
If the subject misses two consecutive scheduled follow up time points and the attempts at contacting the 
subject 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.   
 
 
6.0 
TREATMENT AND EVALUATION OF SAFETY AND EFFICACY 
6.1 
Pre-treatment 
Patients presenting with MR appropriate for treatment with the MitraClip will undergo screening per 
standard hospital procedure.  If a MitraClip procedure is considered appropriate and the patient meets 
the screening criteria for the study (i.e. MR>3+, compliance with MitraClip approved labelling, and not 
participating in another study) the site shall obtain consent from the patient.  The consent will permit 
information about the patient to be submitted to the study after successful implantation of MitraClip XTR 
device.  No data may be entered into the study unless the informed consent is completed. 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 13 of 36 
  
 
 
6.1.1 
Clinical Assessments 
Upon completion of Informed Consent, baseline assessment should be conducted per standard of care.  
Baseline information to be reported into the study include at minimum:  medical history, weight, heart 
rate, blood pressure, MR severity and New York Heart Association (NYHA) Functional Class.   
 
6.1.2 
Pre-treatment Imaging 
Pre-Treatment TTE and TEE should be conducted per standard of care for a MitraClip Procedure.   
 
6.2 
Index Procedure 
Please refer to Instructions for Use (IFU) for instructions on handling and preparation of the XTR MitraClip 
System. All Investigators must read and understand the Instructions for Use (IFU) that accompanies the 
Device. 
 
6.2.1 
Treatment Strategy or Treatment Procedures 
The MitraClip procedure should be conducted in accordance with standard of care practice and approved 
labelling.  All consented patients that have the MitraClip XTR implanted will be entered into the study. 
 
6.3 
Post-procedure 
Post treatment TTEs/TEES, Clinical Assessments and Laboratory / Clinical Tests should be conducted 
per standard of care.  Post-procedure information to be reported for this study include at minimum:  
adverse events, MR severity and New York Heart Association (NYHA) Functional Class. 
 
6.4 
Subject Follow-up 
Follow-up is conducted per standard of care at 30 days and 12 months post-procedure.  A 6-month phone 
call is requested for patients in the study to assess for new adverse event.  Table 1 below outlines the 
follow-up schedule for this study.   
 
 
Table1.  Clinical Follow-Up Schedule 
 Required Assessments 
Pre-Treatment DIS 
30-D 
6-M 
1-Y 
-14/+60 
days 
-30/+9 
days 
-30/+9 
days 
Informed Consent 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Medical Exam and Reporting of Vitals 
X 
X 
X 
 
X 
NYHA Classification 
X 
X 
X 
 
X 
Adverse events and hospitalizations1 
X 
X 
X 
X 
X 
1. Adverse Events to collected in this study include: all cardiovascular events, device-related complications (as 
defined in section 4.2), and events classified as MAEs (as defined in section 4.2) 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 14 of 36 
  
 
 
7.0 
Adverse Events  
7.1 
Definitions 
7.1.1 
Adverse Event 
An adverse event (AE) 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 medical device. 
 
Note 1: This definition includes events related to the device  
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to the MitraClip 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 product, whether or not related 
to the medicinal product. 
 
7.1.2 
Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a 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. 
 
A planned hospitalization for pre-existing condition, or a procedure required by the Clinical Study Plan, 
without a serious deterioration in health, is not considered to be a serious adverse event. 
 
7.1.3 
Device Deficiency/Device Malfunction 
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.  
 
A device malfunction (DM) is the failure of a device to meet its performance specifications or otherwise 
perform as intended, when used in accordance with the instructions for use or CIP. 
 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that a product or device caused or contributed 
to an AE is to be determined by the Investigator and recorded on the appropriate eCRF form. 
Determination should be based on assessment of temporal relationships, evidence of alternative etiology, 
medical/biologic plausibility, and patient condition (pre-existing condition). 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 15 of 36 
  
 
 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting 
7.3.1 
Adverse Event Reporting  
The Investigator will monitor the occurrence of AEs for each subject during the course of the clinical study 
and report as required by this Protocol in section 7 per AE and SAE definitions. Adverse Events to 
reported during this study include: all cardiovascular events, device-related complications (as defined in 
section 4.2), and events classified as MAEs (as defined in section 4.2).  These AEs should be reported 
starting from the time that the MitraClip delivery system is introduced to the femoral vein through the 12-
month follow up visit. 
 
The investigator should report all required SAEs to the Sponsor as soon as possible but no later than 3 
calendar days from the day the 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. 
 
A fax form will be made available to allow the investigator to report required SAEs in the event the entry 
cannot be made in the EDC. This does not replace the EDC reporting system. All information must still 
be entered in the EDC system as soon as feasible. 
 
Serious adverse events that occurred in the user or persons other than the study subject should not be 
entered in the EDC system, however need to be reported via the SAE Notification Form. 
 
The Investigator will further report the SAE to the local IRB/EC according to the institution’s EC reporting 
requirements. 
 
7.3.2 
Device Deficiency/Device Malfunction Reporting 
All device deficiencies/malfunctions should be reported within the EDC System on the appropriate eCRF 
form no later than 3 calendar days from the day the 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 device, if not implanted or not remaining in the subject, should be returned to Abbott.   
 
Device deficiencies/malfunctions should be reported to the EC per the investigative site’s local 
requirements. A fax form will be made available to allow the investigator to report device 
deficiencies/malfunctions in the event that the entry cannot be made in the EDC. This does not replace 
the EDC reporting system. All information must still be entered in the EDC system as soon as feasible. 
 
7.3.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
The Sponsor will report the SAEs and Device Deficiencies to the country regulatory authority, per local 
and regional requirements.  
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 16 of 36 
  
 
 
8.0 
ADJUDICATION OF EVENTS 
8.1 
The Clinical Events Committee (CEC) 
The Clinical Events Committee is comprised of qualified physicians who are not investigators in the study. 
The CEC will review and adjudicate pre-specified events reported by study investigators or identified by 
the Safety & Surveillance for the study as documented in CEC Manual of Operations (MOPs). 
 
 
9.0 
STATISTICAL ANALYSIS 
9.1 
Statistical Overview  
This is a post-market multicenter study of consecutive consenting patients treated with the MitraClip XTR 
system at participating centers. The study will enroll a minimum of 220 subjects to collect clinical evidence 
for the MitraClip XTR system to characterize the use and outcomes associated with the device. The 
primary endpoint is Acute Procedural Success (APS). APS is defined as successful implantation of the 
MitraClip Implant with resulting MR severity of 2+ or less on discharge Echocardiogram (30-day 
echocardiogram will be used if discharge information is unavailable or uninterpretable). Subjects who die 
or undergo mitral valve surgery before discharge are considered as an APS failure. 
 
9.2 
Analysis Populations  
 
 
9.3 
Sample Size Calculations and Assumptions  
The sample size of a minimum 220 subjects is determined based on the endpoint of APS.  APS is defined 
as successful implantation of the MitraClip Implant with resulting MR severity of 2+ or less on discharge 
Echocardiogram. 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The powered endpoint of APS will be evaluated against a pre-specified clinical performance goal (PG). 
The power calculation is based on the following statistical hypotheses and assumptions: 
 
H0: APS rate ≤ PG 
 
HA: APS rate > PG 
 
 
34 Sorajja et al. J Am Coll Cardiol 2017;70:2315–27 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 17 of 36 
  
 
 
 
• 
 
 
 
• 
One-sided type I error rate = 0.05 
 
 
 
   
 
The sample size calculation was performed using PASS 15 (Hintze J, 2017, NCSS, LLC. Kaysville, Utah). 
 
9.4 
Statistical Analyses  
Descriptive analysis will be performed on baseline, APS, clinical and safety event data.  Depending on 
the type of data (e.g., continuous or categorical), statistical methods described in this section below will 
be used.  
 
For continuous variables, such as age, means, standard deviations, and 95% confidence intervals for 
the mean will be calculated.  
 
For binary variables such as APS, counts, percentages, and 95% confidence intervals based on Exact 
Clopper-Pearson method will be calculated, and p-values may be presented for hypothesis generating 
purposes. 
 
For time to event data such as all-cause mortality, Kaplan-Meier analyses will be performed.  
 
For recurrent event data such as recurrent heart failure hospitalizations at pre- and post-procedure, data 
will be analyzed using a generalized linear model, such as Poisson regression model. A p-value to 
measure the strength of evidence may be provided for descriptive purposes. 
 
9.4.1 
Primary Endpoint Analysis  
The exact test against PG will be performed for the primary endpoint in the analysis population. The null 
and alternative hypotheses will be of the following form: 
H0: APS rate ≤ PG 
HA: APS rate > PG 
 
APS is the Acute Procedural Success. 
 
 
 
 
 
  
 
 
 
 
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 18 of 36 
  
 
 
 
 
 
 
 
 
 
 
 
9.4.2 
Clinical Endpoint Analyses  
Clinical endpoints defined in section 4.0 will be summarized descriptively using methods described in 
Section 9.4. 
 
9.4.3 
Handling of Multiplicity Issues  
There is a single primary endpoint and hence no multiplicity adjustment is needed. 
 
9.4.4 
Procedures for Accounting for Missing, Unused or Spurious Data 
If Echocardiography assessed MR severity at discharge is unavailable or cannot be assessed, the 30-
day value will be used to assess APS.  All analyses will be based on available data with missing data 
excluded. Any unused or spurious data will be noted as appropriate 
 
9.5 
Deviations from the Original Statistical Plan 
Any major changes to the statistical plan will be documented in an amendment to the statistical plan. 
Less significant changes to the planned analyses will be documented in the final report. 
 
 
10.0 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents in order for clinical study-
related monitoring, audits, EC review and regulatory inspections to be performed. 
 
Subjects providing informed consent are agreeing to allow Sponsor and/or its designee access and 
copying rights to pertinent information in their medical records concerning their participation in this clinical 
study. The investigator will obtain, as part of the informed consent, permission for clinical study monitors 
or regulatory authorities to review, in confidence, any records identifying the subjects in this clinical study. 
This information may be shared with regulatory agencies; however, Sponsor undertakes not to otherwise 
release the subject's personal and private information. 
 
 
11.0 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Selection of Clinical Sites and Investigators 
Sponsor will select investigators qualified by training and experience, to participate in the study of the 
MitraClip XR device. Sites will be selected based upon review of a recent site assessment, if applicable, 
and the qualifications of the Principal Investigator or multidisciplinary team at the site. 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 19 of 36 
  
 
 
11.2 
Protocol Amendments  
Approved Protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment. The Principal Investigator is responsible for notifying the EC of the 
Protocol amendment (administrative changes) or obtaining EC’s approval of the Protocol amendment 
(changes in subject care or safety), according to the instructions provided by the Sponsor with the 
Protocol amendment. 
 
Acknowledgement/approval by the 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. 
 
11.3 
Training 
11.3.1 
Site Training 
All study 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. Over-the-phone or self-
training may take place as required. Training of study personnel will include, but is not limited to, the 
Protocol requirements, device usage, electronic case report form completion and study personnel 
responsibilities. All study personnel that are trained must sign a training log (or an equivalent) upon 
completion of the training. Prior to signing the training log, Investigator/study personnel must not perform 
any study-related activities that are not considered standard of care at the site.  
 
11.3.2 
Training of Sponsor’s Monitors 
Sponsor and/or designated monitors will be trained to the Protocol, case report forms and device usage 
(as appropriate). Documentation of this training will be according to written procedures. 
 
11.4 
Monitoring 
Sponsor and/or designee will monitor the study over its duration according to the pre-specified monitoring 
plan which will include the planned extent of source data verification.  
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following criteria 
are met:  
• 
The investigator understands and accepts the obligation to conduct the research study according 
to the Protocol and applicable regulations, and has signed the Investigator Agreement or the 
Clinical Study Agreement.  
• 
The Investigator and his/her staff have sufficient time and facilities to conduct the study and that 
they have access to an adequate number of appropriate subjects to conduct the study.  
• 
Source documentation (including original medical records) 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 case report forms, and device 
information.  
• 
The Investigator/site will permit access to such records. A monitoring visit sign-in log will be 
maintained at the site. The Investigator will agree to dedicate an adequate amount of time to the 
monitoring process. The Investigator and/or research coordinator will be available for monitoring 
visits. It is expected that the Investigator will provide the study monitor with a suitable working 
environment for review of study-related documents. 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 20 of 36 
  
 
 
11.5 
Deviations from Protocol 
The Investigator will not deviate from the Protocol for any reason without prior written approval from 
Sponsor except in cases of medical emergencies, when the deviation is necessary to protect the rights, 
safety and well-being of the subject or eliminate an apparent immediate hazard to the subject. In that 
event, the Investigator will notify Sponsor immediately by phone or in writing. All deviations must be 
reported to the Sponsor.   
 
11.6 
Quality Assurance Audit 
A Sponsor representative or designee may request access to all clinical study records, including source 
documentation, for inspection and duplication during a Quality Assurance audit. In the event that an 
investigator is contacted by a Regulatory Agency in relation to this clinical study, the Investigator will 
notify Sponsor immediately. The Investigator and Research Coordinator must be available to respond to 
reasonable requests and audit queries made during the audit process. The Investigator must provide 
Sponsor with copies of all correspondence that may affect the review of the current clinical study. Sponsor 
may provide any needed assistance in responding to regulatory audits. 
 
11.7 
Sponsor Auditing 
In the event that an Investigator is contacted by a Regulatory Agency in relation to this clinical study, the 
Investigator will notify the Sponsor immediately and EC as appropriate. 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 study.  The Sponsor may provide any needed assistance in 
responding to regulatory inspections. 
 
 
12.0 DATA HANDLING AND RECORD KEEPING 
12.1 
Data Management/Data Analysis 
Data Management will include documentation of the systems and procedures used in data collection for 
the duration of the study. All CRF 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. Passwords and electronic signatures will be 
strictly confidential. 
 
All CRF data will be downloaded from the EDC system and reformatted into a data structure acceptable 
to Abbott. The data will be subjected to consistency and validation checks within the EDC system and 
will be subject to supplemental validation following download. 
 
At the conclusion of the study, completed CRF images 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 for 
each study site and a backup copy archived with Abbott. 
 
For the clinical study duration, the Investigator will maintain complete and accurate documentation 
including, but not limited to, medical records, clinical study progress records, laboratory reports, 
electronic case report forms, signed ICFs, device accountability records, correspondence with the 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 21 of 36 
  
 
 
IRB/EC and clinical study monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the clinical study. 
 
12.2 
Source Documentation 
Regulations and GCP require that the Investigator maintain information in the subject’s original medical 
records that corroborates data collected on the case report forms. 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 study: 
• 
Medical history/physical condition of the subject before involvement in the study sufficient to verify 
Protocol entry criteria 
• 
Dated and signed notes on the day of entry into the study referencing the Sponsor, Protocol 
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 and lab results including documentation of site awareness of SAEs and of investigator 
device relationship assessment of SAEs. 
• 
Subject’s condition upon completion of or withdrawal from the study 
• 
Any other data required to substantiate data entered into the CRF 
 
12.3 
Electronic Case Report Form Completion 
Primary data collection based on source-documented hospital and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the Protocol and eCRF completion. eCRF 
data will be collected for all patients in the study.  
 
12.4 
Record Retention 
The Sponsor will archive and retain all documents pertaining to the study 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 study records. 
 
 
13.0 ETHICAL CONSIDERATION  
13.1 
Medical Ethics Committee Review  
Ethics Committee (EC) approval for the Protocol and ICF/other written information provided to the patient 
will be obtained by the Principal Investigator at each study site prior to participation in this clinical study. 
The approval letter must be received prior to the start of this clinical study and a copy must be provided 
to the Sponsor. No changes will be made to the Protocol or ICF or other written information provided to 
the patient without appropriate approvals, including EC, the Sponsor, and/or the regulatory agencies as 
needed.  
 
Until the clinical study is completed, the Investigator will advise his/her EC of the progress of this clinical 
study, per EC requirements.  
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 22 of 36 
  
 
 
14.0 RISK ANALYSIS 
14.1 
Anticipated Clinical Benefits 
The MitraClip XTR was designed for grasping mitral leaflets.  Based on testing, grasping leaflets with 
XTR will be easier in certain patients.  In design validation testing, differentiation of ease of grasping 
between NT and XTR was found in a model which simulated a mixed functional/degenerative etiology 
procedure with a tethered posterior leaflet and a flailing anterior leaflet. The end result of both grasping 
procedures were successful as both NT and XTR were able to successfully grasp and coapt leaflets 
however the user was able to perform the steps in less attempts with XTR. In other development tests 
prior to the design validation, both the NT and XTR devices were able to grasp leaflets equivalently. 
Subjects with such anatomies may therefore benefit from treatment with the MitraClip XTR.   Data from 
this study may help to further identify the anatomical characteristics that can be treated with the MitraClip 
XTR device.   
 
14.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Per the device IFU, the ANTICIPATED EVENTS on the table below have been identiﬁed as possible 
complications of the MitraClip procedure.  
Allergic reaction (anesthetic, contrast, Heparin, 
nickel alloy, latex) 
Aneurysm or pseudo-aneurysm 
Arrhythmias 
Atrial fibrillation 
Atrial septal defect requiring intervention 
Arterio-venous fistula 
Bleeding 
Cardiac arrest 
Cardiac perforation 
Cardiac tamponade / Pericardial Effusion 
Chordal entanglement/rupture 
Coagulopathy 
Conversion to standard valve surgery 
Death 
Deep venous thrombus (DVT) 
Dislodgement of previously implanted devices 
Dizziness 
Drug reaction to anti-platelet / anticoagulation 
agents / contrast media 
Dyskinesia 
Dyspnea 
Edema 
Emboli (air, thrombus, MitraClip Implant) 
Emergency cardiac surgery 
Endocarditis 
Esophageal irritation 
Esophageal perforation or stricture 
Failure to deliver MitraClip to the intended site 
Failure to retrieve MitraClip System components 
Fever or hyperthermia  
Gastrointestinal bleeding or infarct 
Hematoma 
Hemolysis 
Hemorrhage requiring transfusion 
Hypotension / hypertension 
Infection 
Lymphatic complications 
Mesenteric ischemia 
Mitral stenosis 
Mitral valve injury 
MitraClip 
Implant 
erosion, 
migration 
or 
malposition 
MitraClip Implant thrombosis 
MitraClip System component(s) embolization 
Multi-system organ failure 
Myocardial infarction 
Nausea/vomiting 
Pain 
Peripheral ischemia 
Prolonged angina 
Prolonged ventilation 
Pulmonary congestion 
Pulmonary thrombo-embolism 
Renal insufficiency or failure 
Respiratory failure / atelectasis / pneumonia 
Septicemia 
Shock, Anaphylactic or Cardiogenic 
Single leaflet device attachment (SLDA) 
Skin injury or tissue changes due to exposure to 
ionizing radiation 
Stroke or transient ischemic attack (TIA) 
Urinary tract infection 
Vascular trauma, dissection or occlusion 
Vessel spasm 
Vessel perforation or laceration 
Worsening heart failure 
Worsening mitral regurgitation 
Wound dehiscence 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 23 of 36 
  
 
 
 
14.3 
Residual Risks Associated with the Investigational Device 
This is a post-market study on an approved commercial device.  There is no investigational device being 
used as part of this study.   
 
14.4 
Risks Associated with Participation in Clinical Study 
Treatment with the MitraClip device as part of this study is identical to treatment with the MitraClip device 
outside of this study.  Participation in the study will not impact the MitraClip procedure or use of the 
MitraClip in any way.  Participation in the study requires submission of data that may or may not be 
protected heath information.  This information should be kept confidential, but there is a risk that some 
of the information could be unintentionally made non-confidential.  The risk of the this happening for this 
study is no greater than the risk of loss of confidentiality in any study. 
 
14.5 
Possible Interactions with Protocol-Required Concomitant Medications 
This is a post-market study being conducted under standard of care medications.  There are no protocol 
-required medications being used as part of this study. 
 
14.6 
Steps that will be Taken to Control or Mitigate the Risks 
Per the device IFU, the following contraindications, warnings and precautions will be provided with all 
devices to be used during this study.  
CONTRAINDICATIONS 
Patients with the following conditions should not be treated with the MitraClip System:   
Patients who cannot tolerate procedural anticoagulation or post procedural anti-platelet regimen 
Active endocarditis of the mitral valve 
Rheumatic mitral valve disease 
Evidence of intracardiac, inferior vena cava (IVC) or femoral venous thrombus  
 
WARNINGS 
The following anatomic considerations may result in suboptimal leaflet insertion and/or MitraClip implantation. 
Patients with these conditions who undergo the MitraClip procedure may have an increased risk of serious 
adverse events which may be minimized with proper device usage and echocardiographic assessment.  These 
events include the potential for increased procedure time, tissue injury, and/or worsening MR which may require 
additional MitraClip intervention or surgical treatment. 
• 
Severe leaflet calcification in the grasping area 
• 
Severe calcification of the annulus and/or subvalvular apparatus, such as the chordae tendinae 
• 
Severely restricted posterior leaflet 
• 
Cleft or perforation in the grasping area 
• 
Leaflet Flail gap ≥ 10 mm and/or Leaflet Flail width > 15 mm 
• 
Coaptation length < 2 mm 
• 
Intracardiac mass  
 
The following anatomic considerations may result in serious adverse events, including tissue injury, worsening 
MR or in the case of the mitral valve area, mitral stenosis. If these events were to occur they can require additional 
percutaneous or surgical intervention for treatment. The occurrence of these events can be minimized with 
appropriate preoperative evaluation of the valve anatomy and regurgitant jet. 
• 
Mitral valve orifice area < 4 cm2 
• 
Primary regurgitant jet outside of the A2-P2 area and/or presence of a clinically significant 2nd jet 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 24 of 36 
  
 
 
Patients with the following considerations in whom the Steerable Guide Catheter is used may have an increased 
risk of having a serious adverse event which may be avoided with preoperative evaluation and proper device 
usage. 
• 
Previous interatrial septal patch or prosthetic atrial septal defect (ASD) closure device which could 
result in significant difficulty in visualization or technical challenges during transseptal puncture and/or 
introducing the SGC into the left atrium. 
• 
Known or suspected unstable angina or myocardial infarction within the last 12 weeks could increase 
the procedural morbidity and mortality, due to increased hemodynamic stress secondary to general 
anesthesia. 
• 
Patients with active infection have an increased risk of developing an intraoperative and/or 
postoperative infection, such as sepsis or soft tissue abscess. 
• 
Known or suspected left atrial myxoma could result in thromboembolism and tissue injury due to 
difficulty with device positioning.  
• 
Recent cerebrovascular event (CVA) may increase the procedural morbidity associated with a 
transcatheter intervention, such as recurrent stroke. 
 
The MitraClip Implant should be implanted with sterile techniques using fluoroscopy and echocardiography (e.g. 
transesophageal [TEE] and transthoracic [TTE]) in a facility with on-site cardiac surgery and immediate access 
to a cardiac operating room.  
 
Read all instructions carefully.  Failure to follow these instructions, warnings and precautions may lead to 
device damage, user injury, or patient injury.  Use universal precautions for biohazards and sharps while 
handling the MitraClip System to avoid user injury. 
 
Use of the MitraClip System should be restricted to those physicians trained to perform invasive endovascular 
and transseptal procedures and those trained in the proper use of the system. 
 
For the Clip Delivery System and Steerable Guide Catheter only: this device is designed for single use only. 
Cleaning, re-sterilization and / or re-use may result in infections, malfunction of the device and other serious injury 
or death. 
 
PRECAUTIONS 
NOTE the “Use by” date specified on the package. 
 
Inspect all product prior to use. Do not use if the package is open or damaged, or if product is 
damaged. 
 
14.7 
Risk to Benefit Rationale  
Subjects participating in this study will be receiving the latest technology in MitraClip which has been 
shown to be safe and effective in over 4,500 patients in clinical trials and more than 50,000 patients in 
worldwide use to date.  This is a post-market study being conducted on an approved device within the 
standard of care procedures.  The risks associated with receiving a MitraClip implant within this study 
are identical to the risks of receiving a MitraClip implant outside of the study. 
 
Subjects participating in the study have a small risk of loss of confidentiality as part of the data collection 
process.  This risk is mitigated to as low as possible with the use of data collection systems, methods 
and procedures that are used commonly in clinical research.  This includes the use of only validated 
electronic systems, the training of study personnel and the use of de-identified data for all data entry. 
 
Based upon the established safety profile of the MitraClip device; the low risk of loss of confidentiality is 
adequately mitigated to justify use of the next generation MitraClip to treat patients for this study.   

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 25 of 36 
  
 
 
 
APPENDIX I - ABBREVIATIONS AND ACRONYMS 
 
A2-P2 
Second location on anterior and posterior leaflets 
AE 
Adverse Event 
APS 
Acute Procedural Success 
ASD 
Atrial Septal Defect 
CI 
Confidence Interval 
CRF 
Case Report Form 
CV 
Cardiovascular 
CVA 
Cardiovascular Accident 
DD 
Device Deficiency 
DM 
Device Malfunction 
DVT 
Deep venous thrombus 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EU 
European Union 
GRASP 
The GRASP Registry 
IFU 
Instructions for Use 
IVC 
Inferior Vena Cava 
MAE 
Major Adverse Event 
MitraClip XTR 
MitraClip XTR System 
MOPs 
Manual of Operations 
MR 
Mitral Regurgitation 
NYHA 
New York Heart Association 
PMCF 
Post Market Clinical Follow-Up 
SAE 
Serious Adverse Event 
SLDA 
Single leaflet device attachment 
TEE 
Transcatheter Esophageal Echocardiogram 
TIA 
Transient Ischemic Attack 
TRAMI 
Transcatheter Mitral Valve Interventions Study 
TTE 
Transcatheter Thoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Event 
USADE 
Unanticipated Serious Adverse Device Event 
 
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 26 of 36 
  
 
 
APPENDIX II - DEFINITIONS 
 
ANTICIPATED ADVERSE EVENT 
Derived from ISO14155, MEDDEV 2.7.3: an effect which by its nature, incidence, severity or outcome 
has been previously identified as “POTENTIAL COMPLICATIONS AND ADVERSE EVENTS”, as 
documented in the IFU or CIP (Appendix IV). 
 
DEATH (All Cause) 
All deaths regardless of cause.  Death is further divided into 2 categories 
 
1.  CARDIOVASCULAR DEATH (VARC) 
Per the Valve Academic Research Consortium (VARC)5 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 
 
2. NON-CARDIOVASCULAR DEATH 
Any death not covered by the VARC definitions of Cardiovascular Death, such as death caused 
by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma. 
 
 
DEVICE EMBOLIZATION 
Detachment of the deployed MitraClip from the leaflets as assessed by the study site. 
 
DEVICE THROMBOSIS 
Formation of an independently moving thrombus on any part of the MitraClip evidenced by 
echocardiography or fluoroscopy.  If the MitraClip is explanted or an autopsy is performed, this diagnosis 
should be confirmed. 
 
ENDOCARDITIS 
A diagnosis of endocarditis based on the following 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) 
 
Endocarditis is based on the confirmation of either Pathological Criteria or Clinical Criteria.   
 
Diagnosis for Clinical Criteria of Endocarditis must at least meet 1 of the following combinations: 
• 
2 major criteria or 
• 
1 major plus 3 minor criteria or 
• 
5 minor criteria 
 
Pathological Criteria 
 
Microorganisms: culture or histology in a vegetation, in a vegetation that has embolized, or 
in an intracardiac abscess, OR  
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 27 of 36 
  
 
 
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 
Positive echocardiogram 
Oscillating vegetation 
Abscesses 
Valve perforation 
New partial dehiscence of prosthetic valve 
New valvular regurgitation 
 
Minor Criteria 
Predisposing heart condition: 
Mitral Valve Prolapse, 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 
 
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.  
 
HEART FAILURE HOSPITALIZATION 
Defined as an event that meets the following criteria:  
 
A. Requires hospitalization with treatment in any inpatient unit or ward in the hospital for at least 
24 hours, including emergency department stay,  
 
AND 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 28 of 36 
  
 
 
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 this protocol, overnight stays at nursing home facilities, physical rehab or 
extended care facilities, including hospice, do not meet the protocol definition of hospitalization.   
 
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. 
 
MAJOR ADVERSE EVENT (MAE) 
MAE is a CEC-adjudicated composite of all-cause death, stroke, myocardial infarction, and non elective CV 
surgery for device related adverse events  
 
MAJOR BLEEDING  
Major bleeding is defined as bleeding ≥ Type 3 based on a modified Bleeding Academic Research 
Consortium (BARC)35 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  
 
 
35 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. 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 29 of 36 
  
 
 
o 
Perioperative intracranial bleeding within 48 h 
o 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
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 
 
MAJOR VASCULAR COMPLICATION 
Any major complication, relating to, or affecting, the circulatory system as a result of the MitraClip 
procedure, including new onset of any of the following:   
• 
Hematoma at access site >6 cm.; 
• 
Retroperitoneal hematoma; 
• 
Arterio-venous fistula; 
• 
Symptomatic peripheral ischemia/ nerve injury with clinical signs or symptoms lasting >24 hours;  
• 
Vascular surgical repair at catheter access sites;  
• 
Pulmonary embolism; 
• 
Ipsilateral deep vein thrombus; or 
• 
Access site-related infection requiring intravenous antibiotics and/or extended hospitalization. 
 
MYOCARDIAL INFARCTION 
Myocardial infarction (MI) classification and criteria for diagnosis is defined as follows:  
 
Peri-procedural MI (≤ 72 hours after MitraClip procedure) 
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)  
Any one of the following criteria: 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 30 of 36 
  
 
 
• 
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. 
 
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-ELECTIVE (i.e., URGENT or EMERGENT) CARDIOVASCULAR SURGERY FOR PROCEDURE 
OR DEVICE RELATED EVENTS 
Cardiovascular surgical procedure performed for device related complication requiring surgery within 24 
hours of onset of adverse event, including events found during scheduled follow-up.  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 that may 
lead to non-elective cardiovascular surgery include, myocardial perforation, Single Leaflet Device 
Attachment (confirmed by Echo Core Lab), embolization of the MitraClip or MitraClip System 
components, iatrogenic atrial septal defect, or the need for valve replacement instead of repair due at 
least in part to the MitraClip procedure or the presence of the MitraClip. 
 
SINGLE LEAFLET DEVICE ATTACHMENT (SLDA) 
Defined as unilateral MitraClip detachment from one leaflet as assessed by the study site and confirmed by 
the ECL.  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.   

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 31 of 36 
  
 
 
 
STROKE/CEREBROVASCULAR ACCIDENT and TIA 
Cerebrovascular Accident (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 or 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, 
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 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 32 of 36 
  
 
 
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. 
 
Undetermined – An acute episode where 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. 
 
 
Tricuspid Regurgitation Severity 
TR grading will be based on the 2017 ASE Guidelines (Zoghbi 2017)36:  Rating will be: none, mild, 
moderate, or severe.   
 
Unanticipated Adverse Device Effect [UADE] 
UADEs or 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 protocol 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.  All 
reported adverse events are reviewed by Sponsor so that UADEs/USADEs are identified and addressed.   
 
VULNERABLE POPULATION (ISO14155 Definition) 
Defined as subject whose willingness to volunteer in a clinical investigation could be unduly influenced 
by the expectation, whether justified or not, of benefits associated with participation or of retaliatory 
response from senior members of a hierarchy in case of refusal to participate.  Examples of populations 
which may contain vulnerable subjects include: Individuals with lack of or loss of autonomy due to 
immaturity or through mental disability, persons in nursing homes, children, impoverished persons, 
subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and 
those incapable of giving informed consent. Other vulnerable subjects may include, for example, 
members of a group with a hierarchical structure such as university students, subordinate hospital and 
laboratory personnel, employees of the sponsor, members of the armed forces, and persons kept in 
detention.   
 
 
 
36 Zoghbi WA, Adams D, Bonow RO, Enriquez-Sarano M, Foster E, Grayburn PA, Hahn RT, Han Y, Hung J, Lang 
RM, Little SH, Shah DJ, Shernan S, Thavendiranathan P, Thomas JD, Weissman NJ. Recommendations for 
Noninvasive Evaluation of Native Valvular Regurgitation: A Report from the American Society of Echocardiography 
Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 2017 
Apr;30(4):303-371. 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 33 of 36 
  
 
 
 
APPENDIX III - Case Report Forms 
 
Data will be collected on electronic case report forms (eCRFs).  The eCRFs will be made available before 
the study starts enrollment.   
 
 
 
 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 34 of 36 
  
 
 
APPENDIX IV - Summary of Changes  
 
Amendment History 
 
Version # 
Date of Release 
Reason for Amendment 
1.0 
12 Dec 2017 
Initial Version 
1.0 
14 Feb 2018 
BSI request for Performance Goal to be added 
2.0 
26 June 2018 
Correct inconsistencies in protocol 
 
 
Details of Change 
 
Section/pg# 
Version 1.0 
12Dec2017 
Version 1.0 07Feb2018 
Rationale 
Section 4.3, p10 
Section 9.0, p 16-18 
Primary analysis 
was based upon 
acceptance 
criteria  
Primary analysis now based upon a 
performance goal 
Request from BSI 
to update endpoint 
analysis 
Summary, p5 
Section 1.1, p6  
Introduction page 6,  
Section 3.1/3.2, p9  
and  
Section 5.0, p 10 &12 
Sample size =200 
Sample size increased to 220 
Required for 
success to 
Performance Goal 
Summary p5,  
Section 4.2 p11,  
Definitions p 30 &32 
MAE definition 
was inadvertently 
taken from a 
MitraClip tricuspid 
study 
Updated MAE definition to make 
more consistent with other MitraClip 
MR studies 
More appropriate 
to use definition 
from pervious MR 
studies 
Section/ 
page# 
Version 1.0_7 February 2018 
Version 2.0_26 June 2018 
Rationale 
Summary 
/p5 
 
5.3.1/p11 
Inclusion Criteria #2: 
Subjects eligible to receive the 
MitraClip per the current approved 
indications for use  
Inclusion Criteria #2: 
Subjects scheduled to receive the 
MitraClip per the current approved 
indications for use  
To clarify that the 
intention is for the 
treatment decision to 
be 
made 
before 
study enrollment 
Summary / 
page 5  
4.2 / page 
10 
Device Related Adverse Events 
(including 
device 
embolization, 
single leaflet device attachment 
(SLDA), bleeding, perforation, etc) 
 
Device 
Related 
Adverse 
Events 
(including mitral valve stenosis, device 
embolization, 
single 
leaflet 
device 
attachment (SLDA), Iatrogenic atrial 
septal defect, myocardial perforation, 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) 
Correct 
inconsistency of this 
definition to other 
MitraClip studies 
4.2 / p 10 
 
Added: Clinical Endpoints will be 
assessed at each study time point, 
all 
data 
reported 
at 
the 
To clarify data to be 
included in clinical 
endpoints 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 35 of 36 
  
 
 
corresponding study visit will be 
included for the study time point.      
 Table 
1/ 
page 14 
Visits at: 
30 days (30 days +14 days)  
12 months (365 days ± 30 days)  
 
Phone call or visit at: 
6 months (180 days ± 90 days) 
 
Visits at: 
30 days (30 days -14 days /+60 days)  
12 months (365 days -30 days/ +90 
days)  
 
Phone call or visit at: 
6 months (180 days -30 days/ +90 days) 
 
Windows in protocol 
inconsistent with 
standard of care. 
Increased time to 
permit visits per 
standard of care 
without deviation.    
7.1.2/ 
page 
14-
15 
Serious Adverse Event definition 
includes:   
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 
Protocol, 
without 
a 
serious 
deterioration in 
health, is 
not 
considered to be a serious adverse 
event. 
Serious Adverse Event updated to only 
to remove this text, except for the one 
sentence:   
 
A planned hospitalization for pre-existing 
condition, or a procedure required by the 
Clinical Protocol, without a serious 
deterioration in health, is not considered 
to be a serious adverse event. 
 
Definition 
inconsistent 
with 
ISO14155, corrected 
to match ISO14155 
standard definition 
7.2.1/ 
page 15 
Unanticipated (Serious Adverse) 
Device Effect [U(S)ADE] 
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 protocol 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. 
This section has been removed 
Remove 
inconsistency 
21CFR 
812 
and 
U(S)ADE/UADE 
definition 
do 
not 
apply to this protocol 

 
 
MitraClip® XTR PMCF Study 
 
 
Protocol 17-518-1: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 36 of 36 
  
 
 
Table 1 / 
p1 4 
 and 
7.3.1./ p15 
 
Added 
footnote 
to 
Table 
1 
and 
paragraph to section 7.3.1 as follows: 
Adverse Events to reported during this 
study include: cardiovascular events, 
device-related complications (as defined 
in section 4.2), and events classified as 
MAEs (as defined in section 4.2).  These 
AEs should be reported starting from the 
time that the MitraClip delivery system is 
introduced to the femoral vein through 
the 12-month follow up visit. 
To clarify 
appropriate AE 
reporting for a post-
market study 
 
9.3 / p17 
The sample size calculation was 
performed using PASS 11 (Hintze 
JL, 2002. PASS User’s Guide-II. 
NCSS). 
The 
sample 
size 
calculation 
was 
performed using PASS 15 (Hintze J, 
2017, NCSS, LLC. Kaysville, Utah). 
Software Update.  
The actual 
calculation was 
performed under 
PASS 11 and a 
duplicate output was 
confirmed under 
updated software 
(PASS 15) 
9.4.3 / p18 
 
Added section on Handling of Multiplicity 
Issues 
This section is 
added to clarify that 
the PMCF study is 
not subject to 
multiplicity issues, 
since only one 
primary endpoint will 
be tested with 
hypothesis. 
Appendix 
II 
Definitions 
/ p33 
 
Unanticipated Adverse Device Effect 
[UADE] 
UADEs 
or 
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 
protocol 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.  
All 
reported 
adverse 
events 
are 
reviewed 
by 
Sponsor 
so 
that 
UADEs/USADEs are identified and 
addressed.   
Added to specify 
that Sponsor review 
will take place to 
identify UADEs 
 
 
END OF MitraClip XTR PMCF Protocol 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 38 of 68 
  
 
 
 
 
APPENDIX II: ABBREVIATIONS AND ACRONYM  
 
 
 
 
 
 
 
 
A2-P2 
Second location on anterior and posterior leaflets 
ACCESS 
ACCESS-EU Study 
AE 
Adverse Event 
APS 
Acute Procedural Success 
ASD 
Atrial Septal Defect 
CDS 
Clip Delivery System 
CE 
Conformité Européene 
CEC 
Clinical Events Committee 
Co-PIs 
Co-Primary Investigators 
CRF 
Case Report Form 
CV 
Cardiovascular 
CVA 
Cardiovascular Accident 
DC 
Delivery Catheter 
DD 
Device Deficiency 
DM 
Device Malfunction 
DMR 
Degenerative Mitral Regurgitation 
DVT 
Deep venous thrombus 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EROA 
Effective Regurgitant Orifice Area 
EU 
European Union 
Euroscore 
European System for Cardiac Operative Risk Evaluation 
EVEREST II 
The EVEREST II Study 
EXPAND 
The MitraClip EXPAND Study 
FDA 
U.S. Food and Drug Administration 
FMR 
Functional Mitral Regurgitation 
GCP 
Good Clinical Practice 
GRASP 
The GRASP Registry 
HIPAA 
Health Insurance Portability and Accountability Act 
HRR 
High Risk Registry (part of EVEREST II) 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
IVC 
Inferior Vena Cava 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LVOT 
Left Ventricle Outflow Tract 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 39 of 68 
  
 
 
 
MAE 
Major Adverse Event 
MitraClip NT  
MitraClip NT System  
MitraClip NTR 
MitraClip NTR System (new delivery system) 
MitraClip XTR 
MitraClip XTR System (new delivery system and longer clip arms) 
MOPs 
Manual of Operations 
MR 
Mitral Regurgitation 
NYHA 
New York Heart Association 
PMCF 
Post Market Clinical Follow-Up 
QOL 
Quality of Life 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAX 
Short Axis 
SGC 
Steerable Guide Catheter 
SLDA 
Single leaflet device attachment 
TEE 
Transcatheter Esophageal Echocardiogram 
TIA 
Transient Ischemic Attack 
TR 
Tricuspid Regurgitation 
TRAMI 
Transcatheter Mitral Valve Interventions Study 
TTE 
Transcatheter Thoracic Echocardiogram 
TVT 
Transcatheter Valve Treatment Registry 
UADE 
Unanticipated Adverse Device Event 
USADE 
Unanticipated Serious Adverse Device Event 
 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 40 of 68 
  
 
 
APPENDIX III: DEFINITIONS 
 
DEATH (All Cause) 
All deaths regardless of cause.  Death is further divided into 2 categories 
 
1.  CARDIOVASCULAR DEATH (VARC) 
Per the Valve Academic Research Consortium (VARC)5 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 
 
3. NON-CARDIOVASCULAR DEATH 
Any death not covered by the VARC definitions of Cardiovascular Death, such as death caused 
by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma. 
 
 
DEVICE EMBOLIZATION 
Detachment of the deployed MitraClip from the leaflets as assessed by the study site. 
 
DEVICE THROMBOSIS 
Formation of an independently moving thrombus on any part of the MitraClip evidenced by 
echocardiography or fluoroscopy.  If the MitraClip is explanted or an autopsy is performed, this diagnosis 
should be confirmed. 
 
ENDOCARDITIS 
A diagnosis of endocarditis based on the following 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) 
 
Endocarditis is based on the confirmation of either Pathological Criteria or Clinical Criteria.   
 
Diagnosis for Clinical Criteria of Endocarditis must at least meet 1 of the following combinations: 
• 
2 major criteria or 
• 
1 major plus 3 minor criteria or 
• 
5 minor criteria 
 
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 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 41 of 68 
  
 
 
 
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 
Positive echocardiogram 
Oscillating vegetation 
Abscesses 
Valve perforation 
New partial dehiscence of prosthetic valve 
New valvular regurgitation 
 
Minor Criteria 
Predisposing heart condition: 
Mitral Valve Prolapse, 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 
 
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.  
 
HEART FAILURE HOSPITALIZATION 
Defined as an event that meets the following criteria:  
 
D. Requires hospitalization with treatment in any inpatient unit or ward in the hospital for at least 
24 hours, including emergency department stay,  
 
AND 
 
E. 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 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 42 of 68 
  
 
 
 
F. 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 this protocol, overnight stays at nursing home facilities, physical rehab or 
extended care facilities, including hospice, do not meet the protocol definition of hospitalization.   
 
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. 
 
MAJOR ADVERSE EVENT (MAE) 
MAE defined as a composite of all-cause Death, MI, Stroke, or non-elective CV surgery for device related 
complications (CEC adjudicated)  
 
MAJOR BLEEDING  
Major bleeding is defined as bleeding ≥ Type 3 based on a modified Bleeding Academic Research 
Consortium (BARC)37 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 
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  
 
 
37 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. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 43 of 68 
  
 
 
 
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 
 
MAJOR VASCULAR COMPLICATION 
Any major complication, relating to, or affecting, the circulatory system as a result of the MitraClip 
procedure, including new onset of any of the following:   
• 
Hematoma at access site >6 cm.; 
• 
Retroperitoneal hematoma; 
• 
Arterio-venous fistula; 
• 
Symptomatic peripheral ischemia/ nerve injury with clinical signs or symptoms lasting >24 hours;  
• 
Vascular surgical repair at catheter access sites;  
• 
Pulmonary embolism; 
• 
Ipsilateral deep vein thrombus; or 
• 
Access site-related infection requiring intravenous antibiotics and/or extended hospitalization. 
 
MYOCARDIAL INFARCTION 
Myocardial infarction (MI) classification and criteria for diagnosis is defined as follows:  
 
Peri-procedural MI (≤ 72 hours after MitraClip procedure) 
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)  
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 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 44 of 68 
  
 
 
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. 
 
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-ELECTIVE (i.e., URGENT or EMERGENT) CARDIOVASCULAR SURGERY FOR PROCEDURE 
OR DEVICE RELATED EVENTS 
Cardiovascular surgical procedure performed for device related complication requiring surgery within 24 
hours of onset of adverse event, including events found during scheduled follow-up.  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 that may 
lead to non-elective cardiovascular surgery include, myocardial perforation, Single Leaflet Device 
Attachment (confirmed by Echo Core Lab), embolization of the MitraClip or MitraClip System 
components, iatrogenic atrial septal defect, or the need for valve replacement instead of repair due at 
least in part to the MitraClip procedure or the presence of the MitraClip. 
 
SINGLE LEAFLET DEVICE ATTACHMENT (SLDA) 
Defined as unilateral MitraClip detachment from one leaflet as assessed by the study site and confirmed by 
the ECL.  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.   
 
STROKE/CEREBROVASCULAR ACCIDENT and TIA 
Cerebrovascular Accident (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 or as undetermined 
if there is insufficient information to allow categorization as ischemic or hemorrhagic. 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 45 of 68 
  
 
 
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, 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. 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 46 of 68 
  
 
 
Undetermined – An acute episode where 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 Adverse Device Effect [UADE] 
UADEs or 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 protocol 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.  All 
reported adverse events are reviewed by Sponsor so that UADEs/USADEs are identified and addressed.   
 
VULNERABLE POPULATION (ISO14155 Definition) 
Defined as subject whose willingness to volunteer in a clinical investigation could be unduly influenced 
by the expectation, whether justified or not, of benefits associated with participation or of retaliatory 
response from senior members of a hierarchy in case of refusal to participate.  Examples of populations 
which may contain vulnerable subjects include: Individuals with lack of or loss of autonomy due to 
immaturity or through mental disability, persons in nursing homes, children, impoverished persons, 
subjects in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, and 
those incapable of giving informed consent. Other vulnerable subjects may include, for example, 
members of a group with a hierarchical structure such as university students, subordinate hospital and 
laboratory personnel, employees of the sponsor, members of the armed forces, and persons kept in 
detention.   
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 47 of 68 
  
 
 
 
APPENDIX IV: 
LITERATURE REVIEW AND SUMMARY OF PRECLINICAL TRIALS 
 
 
CINICAL TRIALS 
In the United States, the MitraClip System has been studied under an Investigational Device Exemption 
(IDE G030064). The IDE consists of the following cohorts: 
1) Phase I Feasibility Study (EVEREST I) 
1) Phase II Safety / Effectiveness Study (EVEREST II) 
a) EVEREST II Roll-In 
b) EVEREST II Randomized Controlled Trial Arm 
c) EVEREST II High Risk Registry Arm 
2) Phase II Continued Access Study (REALISM) 
a) Non-High Risk Arm 
b) High Risk Arm 
c) Emergency Use/Compassionate Use cases 
 
1) 
 EVEREST I 
 
EVEREST I38 was initiated on July 2, 2003 and enrollment concluded on February 15, 2006. A total of 
55 patients were enrolled and treated in EVEREST I.  The EVEREST I Feasibility trial was the first 
prospective, multi-center, non-randomized trial to evaluate the preliminary safety and effectiveness of 
the percutaneous MitraClip System in patients with moderate-to-severe (3+) or severe (4+) MR in surgical 
candidates.  Percutaneously-treated patients were followed at discharge, 30 days, 6, 12, 18 and 24 
months and annually thereafter through 5 years. An independent Echocardiography Core Laboratory 
(ECL) assessed MR severity and other echocardiographic parameters at baseline and follow-up. The 
last patient has completed 5-year follow-up and the study is now closed. 
 
The MitraClip device was implanted in 89% (49/55) of patients and the trial met its pre-specified safety 
acceptance criterion, demonstrating mechanistic feasibility of implant and safety of the MitraClip System 
and procedure. There were no intra-procedural deaths.  Acute procedural success was achieved in 
70.9% of patients.  A majority of patients (83.3%) implanted with a MitraClip deviced experienced 
reduction in MR severity to 2+ or less at discharge.  No MitraClip device embolizations occurred in this 
cohort.  Ten percent (10%) of the initial cohort had single leaflet device attachment (SLDA).  A majority 
of SLDAs were detected early (within 30 days post-MitraClip procedure). Patients demonstrated 
improvement in NYHA Functional Class and left ventricular measurements that were sustained through 
5 years. At 5 years, freedom from death was 86.4% and freedom from mitral valve surgery was 55.1%. 
The results of the EVEREST I trial at 5 years provide evidence of the safety and long-term durability of 
the MitraClip device in the early cohort of patients treated in the United States. 
 
 
 
 
 
 
 
 
 
 
38 IDE G030064/ P100009/A017 EVEREST I Final Clinical Report Version 1.0 - 17/Nov/2011  

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 48 of 68 
  
 
 
 
2) 
EVEREST II  
a. Randomized Clinical Trial (RCT)39 
The EVEREST II RCT40,41,42 is a prospective, multi-center, randomized controlled trial where patients 
with moderate-to-severe (3+) or severe (4+) MR were randomized in a 2:1 ratio between the Device 
group (MitraClip device) and the Control group (mitral valve surgery). Patient follow-up occurs at 
discharge, 30 days, 6, 12, 18 and 24 months and yearly thereafter through 5 years. An independent 
Echocardiography Core Laboratory (ECL) assessed MR severity and other echocardiographic 
parameters at baseline and follow-up. The trial was intended to demonstrate superiority of safety 
balanced against reduced effectiveness of the MitraClip device when compared to mitral valve surgery. 
All patients have completed 5 years of follow-up and the study is now closed. 
 
The trial enrolled 279 patients: 184 were randomized in the Device group and 95 were randomized in the 
Control group. Of these, 178 patients in the Device group underwent the MitraClip procedure and 80 
patients in the Control group underwent mitral valve surgery. The trial met both primary safety and 
effectiveness endpoints. There were no intra-procedural deaths.  Among patients who underwent the 
MitraClip procedure in the Device group (MitraClip patients), a device was implanted in 89% of patients. 
The procedure time averaged approximately 3 hours, patients were hemodynamically stable during the 
procedure, and the average length of hospital stay was 2.6 days. In comparison, the average length of 
hospital stay for patients undergoing surgery in the Control group (surgery patients) was 7.5 days. A 
large majority (94.9%) of MitraClip patients were discharged home without home healthcare. In 
comparison, only 71.3% of surgery patients were discharged home without home healthcare. Acute 
procedural success (APS) was achieved in 77% of patient treated in the Device Group.  A majority of 
patients implanted with the MitraClip device (784) experienced reduction in MR severity to 2+ or less at 
discharge, while 100% of patients undergoing mitral valve surgery in the Control group experienced 
reduction in MR severity to 2+ or less. 
 
Patients who underwent the MitraClip procedure experienced a 30-day major adverse event rate 
(composite of death, myocardial infarction (MI), 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, gastro-intestinal (GI) complication requiring surgery, new onset of 
permanent atrial fibrillation, septicemia and major bleeding complication) of 7.9% versus 50% in patients 
who underwent mitral valve surgery in the Control group. Excluding the most common event of major 
bleeding complication, MitraClip device patients still experienced a lower major adverse event rate (4.5%) 
than surgery patients (11.3%). 
 
 
 
39  EVEREST II Randomized Controlled Trial (RCT) -0401– Five Year Final Report, Report Version 1.0 - 
03/Nov/2014 
40 Mauri L, Garg P, Massaro JM, Foster E, Glower D, Mehoudar P, Powell F, Komtebedde J, McDermott E, Feldman 
T.  The EVEREST II Trial: Design and Rationale for a Randomized Study of the Evalve MitraClip System Compared 
with Mitral Valve Surgery for Mitral Regurgitation.  Am Heart J.  2010; 160:23-29. 
41 Feldman T, Foster E, Glower DD, 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, Mauri L, Investigators EI.  Percutaneous Repair 
or Surgery for Mitral Regurgitation.  N Engl J Med.  2011; 364:1395-1406. 
42 Feldman T, Kar S, Elmariah S, Smart SC, Trento A, Siegel RJ, Apruzzese P, Fail P, Rinaldi MJ, Smalling RW, 
Hermiller JB, Heimansohn D, Gray WA, Grayburn PA, Mack MJ, Lim DS, Ailawadi G, Herrmann HC, Acker MA, 
Silvestry FE, Foster E, Wang A, Glower DD, Mauri L, Investigators EI.  Randomized Comparison of Percutaneous 
Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II.  J Am Coll Cardiol.  2015; 66:2844-
2854. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 49 of 68 
  
 
 
Through 30 days, MitraClip patients experienced a lower site-reported adverse event rate than surgery 
patients in the following categories: cardiac rhythm disorders (atrial arrhythmias, bradyarrhythmia, 
ventricular arrhythmia), congestive heart failure, peripheral edema, anemia, infections, neurologic events 
and respiratory events.  At 30 days, MitraClip patients experienced a higher event rate than surgery 
patients in the following categories: atrial septal defect, myocardial ischemia, residual or recurrent MR, 
single leaflet device attachment (SLDA), gastrointestinal bleed, and vascular complications such as 
hematoma, bleed or bruising.  
 
Significant and meaningful clinical benefits were observed in both MitraClip and surgery patients, which 
were sustained through 5 years: 
MR reduction to 2+ or less at 5 years was in 82.1% of MitraClip patients and 97.6% of surgery patients 
Reduction in left ventricular end diastolic volume and dimension was observed in both MitraClip and 
surgery patients, which was sustained through 5 years 
Improvement in NYHA Functional Class was demonstrated in both groups, with 91.5% of MitraClip 
patients and 97.6% of surgery patients free from NYHA Functional Class III or IV symptoms at 5 years 
 
The results of the RCT demonstrate the continued safety, durability of effectiveness and clinical benefit 
of the MitraClip device through 5 years. These results are consistent with the expectation of superior 
safety and reduced effectiveness of the MitraClip device when compared to mitral valve surgery. These 
results support an overall favorable risk to benefit profile of the MitraClip device through 5 years. 
 
Overall, the MitraClip clinical trials have shown consistently excellent safety and efficacy profile. 
Reduction of MR severity has shown improvements in symptoms, improved quality of life measurements, 
and functional improvements in patients who had significant MR.  
 
b. EVEREST II High Risk Registry (HRR)43 
The EVEREST II High Risk Registry44 is a single-arm prospective, multi-center, clinical trial designed to 
evaluate the safety and effectiveness of the MitraClip System in patients with moderate-to-severe (3+) 
or severe (4+) MR considered to be at high risk of surgical mortality.  High risk was defined as predicted 
procedural mortality risk calculated using the STS surgical risk calculator of ≥12% or in the judgment of 
the surgeon investigator the patient was considered a high risk surgical candidate due to the presence 
of specific protocol-defined criteria. 
 
The primary objective of the EVEREST II HRR was to assess procedural safety in high surgical risk 
patients.  Accordingly, the primary safety endpoint was procedural mortality at 30 days or prior to 
discharge compared to predicted surgical mortality.  Secondary effectiveness measures were similar to 
those in the EVEREST II RCT, including changes in ECL-assessed measures of left ventricular function, 
NYHA functional class and SF-36 quality of life score at 1 year compared to baseline.  Rate of 
hospitalizations for heart failure 1-year pre- and 1-year post-MitraClip was added as a descriptive 
endpoint for the EVEREST II HRR.  
 
The EVEREST II HRR study enrolled 78 patients at 25 centers.  Implant success in the EVEREST II 
HRR was high with 96.2% of patients implanted with one (59.0%) or two (37.2%) MitraClip devices.  The 
mean post-procedure ICU/CCU/PACU stay was 2.2 days and the mean hospital stay was 3.9 days with 
 
 
43 EVEREST II High Risk Registry (HRR) – 0401 - Five Year Final Report, Report Version 1.0 – 03/Nov/2014 
44 Whitlow PL, Feldman T, Pedersen WR, Lim DS, Kipperman R, Smalling R, Bajwa T, Herrmann HC, Lasala J, 
Maddux JT, Tuzcu M, Kapadia S, Trento A, Siegel RJ, Foster E, Glower D, Mauri L, Kar S, Investigators EI.  Acute 
and 12-Month Results with Catheter-Based Mitral Valve Leaflet Repair: The EVEREST II (Endovascular Valve 
Edge-to-Edge Repair) High Risk Study.  J Am Coll Cardiol.  2012; 59:130-139. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 50 of 68 
  
 
 
a median of 2 days.  Approximately 75% of patients were discharged home without the need for 
professional home healthcare.  An additional 10% were discharged home with home healthcare required, 
resulting in a total of almost 86% being discharged home after the MitraClip procedure.  At discharge, 
MR was reduced in a majority of patients (74.7%) to ≤2+ and in 40% of patients to ≤1+.   
 
The primary safety endpoint of procedural mortality (observed vs. predicted) was met.  The observed 
procedural mortality rate at 30 days was 7.7% (95.472% UCB=14.8%) and compared favorably (p=0.006) 
to the average predicted surgical mortality of 18.2%.  The observed procedural mortality rate was also 
lower when compared to the average STS mortality risk (14.2%).   
 
Among patients with paired data at baseline and 1 year, MR reduction was sustained to ≤2+ in 77.8% of 
patients and to ≤1+ in 31.5% of patients.  Significant improvement in NYHA Class was observed at 1 
year in the EVEREST II HRR.  Among patients with paired data at baseline and 1 year, the proportion of 
patients with NYHA Class III or IV reduced from 88.9% at baseline to 25.9% at 1 year.  Improvement in 
both physical and mental components of the SF-36 quality of life by 4.0 and 3.2 points respectively were 
observed at 1 year.  A significant decrease in the rate of heart failure hospitalizations (0.65 to 0.36 per 
patient-year) was observed in the year following the MitraClip procedure compared to the year prior. 
 
Adverse events occurred at rates as expected in the advanced age patient population with significant co-
morbidities.  The MAE rate at 30 days was 26.9%, with transfusions ≥2 units comprising the majority of 
events (17.9%).  There was no incidence of non-elective (urgent/emergent) cardiovascular surgery for 
adverse events or new onset of persistent atrial fibrillation in this cohort through 1 year.  
 
After the initial 30 days post-procedure, site-reported adverse events (AE) occurred at a steady low rate 
as expected for this population.  The most commonly site-reported AEs through 5 years were cardiac, 
renal and vascular.  The most commonly reported cardiac AE were congestive heart failure, atrial 
arrhythmia, peripheral edema and syncope.  The most commonly reported renal AE were renal 
insufficiency/failure and infection. The most commonly reported vascular AE was hemodynamic 
instability.  These rates are as expected for a percutaneous procedure in elderly patients with multiple 
baseline co-morbidities.   
 
Device complications were rare; the rate of single leaflet device attachment (SLDA) was 1.3% in the first 
year with no new occurrences reported thereafter.  Only 2 patients had confirmed mitral stenosis through 
5 years. 
 
Through 5 years, a total of 42 (53.8%) deaths occurred in the EVEREST II HRR.  This mortality rate is 
as expected due to the high risk nature of the patient population.  At 5 years, MR reduction was sustained 
to ≤2+ in 73.9% of surviving patients with paired data and to ≤1+ in 47.8% of surviving patients with 
paired data.  Among patients with paired data at baseline and 5 years, the proportion of surviving patients 
with NYHA Class III or IV reduced from 89.7% at baseline to 18.9%, 9.7%, and 16.7% at 3 years, 4 years 
and 5 years, respectively. LVEDV and LVESV are significantly reduced at 5 years following the MitraClip 
procedure.  These reductions are indicative of left ventricular reverse remodeling associated with MR 
reduction.   
 
These data from the EVEREST II HRR suggest a role for the MitraClip device in treating symptomatic 
patients with 3+ to 4+ MR who are at high risk of mortality with MV surgery.  MitraClip device placement 
in this selected high-risk group is feasible, effective in reducing symptoms and improving clinical status, 
and relatively safe in patients who otherwise have no safe option to reduce MR. 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 51 of 68 
  
 
 
3) 
REALISM Continued Access 
The EVEREST II REALISM study is a continued access registry designed for continued data collection 
on the use of the MitraClip System in “real world” conditions.  After the completion of enrollment in the 
pivotal EVEREST II RCT and EVEREST II HRR study, continued access to the technology was 
warranted to collect additional safety and effectiveness data on the MitraClip device.  There are two arms 
(High Risk and Non-High Risk) in the REALISM study.  Enrollment in the Non-High Risk arm of the study 
concluded on April 14, 2011, and enrollment in the High Risk arm concluded on December 19, 2013.  
Patients with serious or life-threatening conditions that did not meet REALISM High Risk or Non-High 
Risk eligibility criteria were evaluated for consideration for either Emergency Use (EU) or Compassionate 
Use (CU).   
 
Each arm of the REALISM study was designed with inclusion/exclusion criteria and endpoints aligned to 
maintain consistency with the EVEREST II RCT and HRR studies.  Eligibility criteria in REALISM HR are 
identical to EVEREST II HRR, with one exception: patients are excluded from REALISM HR if they had 
a concurrent medical condition resulting in a life expectancy of less than 1 year.  This criterion was added 
to exclude terminally ill patients, including those in hospice.  Safety, effectiveness and follow-up data 
collection in REALISM HR are identical to EVEREST II HRR, with enrollment and follow-up ongoing 
through 5 years. 
 
a. REALISM Non-High Risk Arm45 
A total of 271 patients have been enrolled in the non-high risk arm of REALISM.  MitraClip implant rate 
was 95.2%.  Post-procedure, the average duration of hospitalization was 2.8 days.  The mean duration 
of stay in the ICU/CCU/PACU post-procedure was 28.8 hours, and a majority of patients (91.5%) returned 
home post procedure and required no home-health care.  Two patients (0.7%) died prior to discharge of 
non-cardiac causes. 
 
At the 30-day and 12-month time points, 11.4% and 27.3% of the participants respectively experienced 
MAEs as adjudicated by the CEC.  A total of 27 deaths were reported during the 12-month follow-up 
window (410 days).  Thirteen of the 27 deaths were CEC-adjudicated to cardiac causes.  Interim Kaplan-
Meier analysis at 5 years demonstrated an event-free survival rate of 61.0%.  The incidence of SLDA 
after index procedure was reported in 11 (4.3%) of the 258 patients who received at least one MitraClip 
device in the Non-High Risk arm.  No cases of MitraClip procedure-related embolizations were reported. 
 
Reduction to MR ≤2+ was achieved in 89% of patients at 30 days and in 84% of patients at 12 months.  
A similar trend was observed at subsequent follow-ups with a majority (>75%) of patients with MR 
severity remaining consistently mild to moderate.  A reduction was observed in LV dimensions and 
volumes measured with echocardiography on analysis of matched data up to 60 months, which was 
consistent with the reduction in MR severity and indicative of LV remodeling.   
An overall improvement in cardiac status was observed, with more than 88.0% of the treated patients 
being categorized as NYHA Class I or II through follow-up visits which indicated an improvement in the 
symptomatic status and was consistent with the results of MR severity improvement and LV remodeling.  
Statistically significant improvements in SF-36 PCS quality of life scores and clinically meaningful 
improvements in SF-36 quality of life MCS scores were observed at 30 days and 12 months. 
 
The results of the non-high risk arm of the REALISM study are consistent with the findings from the 
previously conducted studies for the MitraClip Device including the pivotal EVEREST II RCT. 
 
 
45 EVEREST II REALISM– Non-High Risk   2017 Annual Report, Protocol #0401- Clinical Investigation Report Ver 
1.0  - 24/APR/2017 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 52 of 68 
  
 
 
b. REALISM High Risk Arm46 
A total of 628 patients have been enrolled in the high risk arm of REALISM.  A majority of patients had 
multiple pre-existing co-morbidities at baseline and were considered high risk for mitral valve surgery.  
The mean STS mortality risk score of this high-risk population was 11.1%, with 43.5% of patients having 
a mortality risk score ≥12%.   
 
In the high-risk cohort, the MitraClip implant rate was 96%, with 53% of the patients receiving a single 
MitraClip device and 43% of the patients receiving multiple devices.  Following the intervention, patients 
spent a mean duration of 36.5 hours in the ICU/CCU/PACU during an average hospital stay of 3.2 days.  
A majority (83.3%) of the patients returned home with no further need for assisted healthcare.  Twelve 
patients (1.9%) died before discharge.   
 
The CEC-adjudicated major adverse event (MAE) rates including transfusions were 15.6% at 30 days 
and 35.4% at 12 months.  A total of146 deaths were reported up to the 12-month follow-up window (410 
days).  Of these 146 deaths, 97 (66.4%) were adjudicated as cardiac-related and 49 (33.6%) were 
adjudicated as non-cardiac related.  There were no reports of MitraClip device embolization during the 
study.  Of the 603 patients who had at least one MitraClip device implanted, 13 cases of single leaflet 
Device attachment (SLDA) were noted.   
 
Reduction to MR ≤2+ was achieved in 90% of patients at discharge/30 days and in 85% of patients at 12 
months.  A similar trend was observed at subsequent follow-ups with a majority (>80%) of patients with 
MR severity remaining consistently mild to moderate.  A steady reduction in LV volume and dimensions 
was observed through 60 months, which indicated that a reverse LV remodeling occurred following 
implantation of the MitraClip device.  There was a significant improvement from baseline of 35.2 meters 
in mean distance walked in 6-minute walk test (6MWT) at 12 months.  There were statistically significant 
improvements in the physical component score (PCS) and mental component score (MCS) domains of 
the SF-36 QoL scores at both 30 days and 12 months. 
 
There was a reduction in the proportion of patients hospitalized and events leading to hospitalization for 
CHF from the pre-enrollment time-point (36.6% and 402, respectively) to the 12-month follow-up (17.8% 
and 174, respectively). 
 
Safety and Device efficacy data from the high-risk arm of the REALISM study show that the MitraClip is 
a viable option for treatment of degenerative and functional MR in high-risk individuals who carry a 30-
day STS-calculated or surgeon-assessed mortality risk ≥12%.  Follow-up through 5 years demonstrates 
that the MitraClip procedure and device have an acceptable safety profile and that outcomes are durable.  
Long-term survival of this high-risk cohort is as expected considering their baseline incidence of multiple 
major co-morbidities.  
 
 
 Commercial Experience 
 
The MitraClip System received approval for commercialization in Europe in March 2008, and is indicated 
for reconstruction of the insufficient mitral valve through tissue approximation.  This broad indication has 
allowed early commercial use to depart from patients traditionally treated in the EVEREST II RCT clinical 
trial, which was limited to surgical candidates, mainly with preserved LV function and degenerative valve 
 
 
46 EVEREST II REALISM– High Risk 2017 Annual Report, Protocol #0401- Clinical Investigation Report Ver 1.0   
24/Apr/2017 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 53 of 68 
  
 
 
disease, and move towards increasingly higher surgical risk patients featuring more complex mitral valve 
anatomies.   
 
One such early example of the expanded use of the MitraClip therapy in contemporary clinical practice 
was published by Franzen et al.47 who sought to evaluate the outcomes of the MitraClip device in a cohort 
of high surgical risk patients without applying any of the rigid EVEREST II exclusion criteria.  Of 51 
consecutive patients treated with the MitraClip device at the Hamburg University Heart Centre between 
September 2008 and July 2009, 35 (69%) had LV characteristics and/or a mitral valve morphology that 
would have excluded them from enrolment in the EVEREST I and II trials.  The positive acute outcomes 
achieved in these patients paved the way for larger contemporary commercial registries, the most 
prominent of which are summarized below: 
 
ACCESS-EU Phase I 
ACCESS-EU48 was a two-phase prospective, single-arm, multicenter post-approval observational study 
of the MitraClip in Europe for the treatment of MR sponsored by Abbott Vascular.  The primary objective 
of the ACCESS-EU study was to gain information with respect to health economics and clinical care, and 
to provide further evidence of safety and effectiveness. Five hundred sixty-seven (567) patients were 
treated with the MitraClip in Europe.  One-year clinical follow-up was available in 487 patients. The study 
is now closed.   
 
Patients in ACCESS-EU had a mean age of 73.7 years and were predominantly males (63.8%).  A 
majority (77.1%) had functional MR.  At baseline, 84.9% were in NYHA functional class III or IV, and the 
mean LVEF was 35%.  The mean logistic EuroScore was 23.0% with approximately half of patients 
having a logistic EuroScore of 20% or greater.  Despite the broad indication for the MitraClip in Europe, 
the patients treated in the ACCESS-EU study were representative of the higher end of the surgical risk 
spectrum.  
 
Patients enrolled in ACCESS-EU represent a population with significant, symptomatic MR, a high rate of 
multiple serious comorbidities.  Considering the high MitraClip device implant rate (99.6%, 565/567), the 
high rate of meaningful MR reduction (78.9%, 258/327 MR<2+), and the resulting improvements in 6-
minute walk (59.5 m difference, p<0.0001), Minnesota Living with Heart Failure Questionnaire quality of 
life score (13.5 point improvement, p<0.0001) and NYHA Functional Class (71.5% NYHA Class I or II, 
p<0.0001), at 1 year, it is concluded that the MitraClip device provides an important therapeutic option 
for patients with significant mitral regurgitation, and is an especially important option for patients who 
may be considered high surgical risk. 
 
Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation (GRASP) 
The GRASP registry is a single-center, prospective, observational study of consecutive high surgical risk 
patients with moderate-to-severe or severe MR undergoing percutaneous mitral valve repair with the 
MitraClip System at Ferrarotto Hospital (Catania, Italy).  The study does not have specific exclusion 
criteria; and the indication for MitraClip therapy is established by a multidisciplinary Heart Team.  The 
 
 
47 Franzen O, Baldus S, Rudolph V, Meyer S, Knap M, Koschyk D, Treede H, Barmeyer A, Schofer J, Costard-
Jackle A, Schluter M, Reichenspurner H, Meinertz T.  Acute Outcomes of MitraClip Therapy for Mitral Regurgitation 
in High-Surgical-Risk Patients: Emphasis on Adverse Valve Morphology and Severe Left Ventricular Dysfunction.  
Eur Heart J.  2010; 31:1373-1381. 
48 Maisano F, Franzen O, Baldus S, Schafer 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 1-Year Results 
from the ACCESS-EU, a Prospective, Multicenter, Nonrandomized Post-Approval Study of the MitraClip Therapy 
in Europe.  J Am Coll Cardiol.  2013; 62:1052-1061. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 54 of 68 
  
 
 
degree of preprocedural MR is quantified according to current guidelines by two expert 
echocardiographers. 
 
A total of 117 consecutive patients underwent MitraClip implantation between August 2008 and October 
2012 as part of the ongoing GRASP registry49.  Mean age was 72±10 years and 67% were male.  The 
mean logistic EuroSCORE was 12±14%, and a majority (76%) of patients had functional MR.  MR grade 
3+ or 4+ was present in 98% of patients, and NYHA functional class symptoms in 80% of patients.  At 
baseline, 63% of patients met the EVEREST leaflet anatomic criteria (i.e., coaptation depth <11 mm, 
coaptation length >2 mm). 
 
Acute procedural success was achieved in all patients.  MR was reduced to 1+ and 2+ post-procedure 
in 63% and 37% of patients, respectively.   
 
The primary safety end point was the rate of major adverse events (MAEs) at 30 days, defined as the 
composite of death, myocardial infarction, reoperation for failed mitral valve surgery, nonelective 
cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, mechanical 
ventilation for >48 hours, gastrointestinal complication requiring surgery, new-onset permanent atrial 
fibrillation, septicemia, and transfusion of ≥2 units of blood.  The primary efficacy end point was freedom 
from death, surgery for mitral valve dysfunction, or grade ≥3+ MR at 30 days and 1 year after clip 
implantation. 
 
MAEs occurred in 4 patients (4.3%) at 30 days.  One patient died from gastrointestinal bleeding within 
30 days.  Ten additional patients died within 1 year for a total of 11 deaths.  Another 8 patients died 
between 1- and 3-years post-procedure.   
 
Deterioration to MR ≥3+ was recorded in 25% of patients with degenerative MR and 7% of those with 
functional MR at 1 year.  No surgery for mitral valve dysfunction was needed within the first year after 
clip implantation.  No cases of clip detachment or embolization were observed.  Kaplan-Meier estimates 
of freedom from the primary efficacy endpoint was 96.4% at 30 days and 75.8% at 1 year.  No survival 
difference was noted based on MR etiology.  
 
Results from the GRASP registry support the safety and efficacy of the MitraClip device in a real-world 
setting.  
 
 
GRASP Registry:  EVERESTON versus EVERESTOFF Criteria 
Attizzani et al.50 analyzed the outcomes of GRASP patients according to baseline echocardiographic 
criteria.  Patients who did not meet the EVEREST echocardiographic criteria were assigned to the 
investigational group (EVERESTOFF; N=93), whereas those meeting the EVEREST echocardiographic 
 
 
49 Grasso C, Capodanno D, Scandura S, Cannata S, Imme S, Mangiafico S, Pistritto A, Ministeri M, Barbanti M, 
Caggegi A, Chiaranda M, Dipasqua F, Giaquinta S, Occhipinti M, Ussia G, Tamburino C.  One- and Twelve-Month 
Safety and Efficacy Outcomes of Patients Undergoing Edge-to-Edge Percutaneous Mitral Valve Repair (from the 
GRASP Registry).  Am J Cardiol.  2013; 111:1482-1487. 
50 Attizzani GF, Ohno Y, Capodanno D, Cannata S, Dipasqua F, Imme S, Mangiafico S, Barbanti M, Ministeri M, 
Cageggi A, Pistritto AM, Giaquinta S, Farruggio S, Chiaranda M, Ronsivalle G, Schnell A, Scandura S, Tamburino 
C, Capranzano P, Grasso C.  Extended Use of Percutaneous Edge-to-Edge Mitral Valve Repair Beyond EVEREST 
(Endovascular Valve Edge-to-Edge Repair) Criteria: 30-Day and 12-Month Clinical and Echocardiographic 
Outcomes from the GRASP (Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation) Registry.  
JACC Cardiovasc Interv.  2015; 8:74-82. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 55 of 68 
  
 
 
criteria were assigned to the control group (EVERESTON; N=78).  Among the 93 patients included in the 
EVERESTOFF group, 35 patients had LVEF ≤25%, 28 patients had LV end systolic diameter >55 mm, 34 
patients had coaptation depth ≥11 mm, and 10 patients had the flail width ≥15 mm.  Otherwise, baseline 
characteristics were comparable between the two groups. 
 
High rates of acute procedural success were achieved in both groups (97.8% and 100% for EVERESTOFF 
and EVERESTON, respectively). At 30-days, the rate of MAEs (i.e. primary safety endpoint) was 
comparable between groups (2.6% vs. 6.5%, respectively, p=0.204).  Freedom from death, surgery for 
mitral valve dysfunction, or grade ≥3+ MR (i.e. primary effectiveness endpoint) was 90.1% and 93.5%, 
respectively (p=0.427).  Reduction in MR severity, symptomatic improvements, and re-hospitalizations 
for heart failure were comparable between the two groups. 
 
At 1 year, Kaplan-Meier freedom from the primary efficacy endpoint was demonstrated in 71.4% and 
76.2%, respectively, in the EVERESTOFF and EVERESTON groups.  Approximately 90% of surviving 
patients in both groups had sustained MR reduction to ≤2+, and approximately 78% of patients from both 
groups had NYHA functional class I or II at 1 year. 
 
A sub-group analysis of the EVERESTOFF patients evaluated the impact of different characteristics of 
enrollment based on 1) valve geometry, 2) ventricle function/geometry, and 3) a combination of the two.  
Although the combined group revealed numerically lower efficacy (primary efficacy endpoint 76.2%, 75%, 
and 62.5%, respectively, p=0.521), higher rates of MR ≥3+ (14.5%, 12.5%, and 20.8%, p=0.710), as well 
as higher death rates (9.5%, 12.5%, and 25%, respectively, p=0.312), these differences did not reach 
statistical significance.   
 
This analysis of the GRASP Registry suggests that MitraClip implantation in patients with expanded 
baseline echocardiographic features was associated with similar rates of safety and efficacy through 12-
month follow-up when compared with patients meeting the EVEREST anatomical criteria. 
 
The German Transcatheter Mitral Valve Interventions (TRAMI) 
The German transcatheter mitral valve interventions (TRAMI) registry was initiated in August 2010 to 
collect data from clinical centers in Germany involved in transcatheter therapies for mitral valve disease.  
The registry comprises a retrospective part, including patients who have been treated at individual sites 
prior to study initiation, and a prospective part after study site initiation.  Follow-up for the retrospective 
part was not defined in the study protocol and was performed according to institutional practice.  Follow-
up for the prospective part was scheduled at 30 days and then at 1, 3, and 5 years.  Enrollment in TRAMI 
is ongoing. 
Several reports on TRAMI have been published over the years51,52.  The largest prospective cohort was 
described by Puls et al.53.  A total of 828 patients were prospectively enrolled at 21 German sites between 
2010 and 2013.  One-year follow-up was available in 749 patients.   
 
 
51 Baldus S, Schillinger W, Franzen O, Bekeredjian R, Sievert H, Schofer J, Kuck KH, Konorza T, Mollmann H, 
Hehrlein C, Ouarrak T, Senges J, Meinertz T, investigators GTMVI.  MitraClip Therapy in Daily Clinical Practice: 
Initial Results from the German Transcatheter Mitral Valve Interventions (TRAMI) Registry.  Eur J Heart Fail.  2012; 
14:1050-1055. 
52 Schillinger W, Hunlich M, Baldus S, Ouarrak T, Boekstegers P, Hink U, Butter C, Bekeredjian R, Plicht B, Sievert 
H, Schofer J, Senges J, Meinertz T, Hasenfuss G.  Acute Outcomes after MitraClip Therapy in Highly Aged Patients: 
Results from the German Transcatheter Mitral Valve Interventions (TRAMI) Registry.  EuroIntervention.  2013; 9:84-
90. 
53 Puls M, Lubos E, Boekstegers P, von Bardeleben RS, Ouarrak T, Butter C, Zuern CS, Bekeredjian R, Sievert H, 
Nickenig G, Eggebrecht H, Senges J, Schillinger W.  One-Year Outcomes and Predictors of Mortality after MitraClip 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 56 of 68 
  
 
 
 
Patients had an average age of 76 years and a majority (89%) were symptomatic with NYHA functional 
class III or IV.  Median STS mortality risk score was 6.0%.  Approximately 70% of patients underwent the 
MitraClip procedure for functional MR.  The MitraClip implant rate in this cohort was 97%, with an average 
of 1.4±0.6 clips implanted per procedure.  Mean procedure time and fluoroscopy duration were 102.8 
±54.1 minutes and 28.8±57.9 minutes, respectively.  Mitral regurgitation was reduced from severe (94%) 
at baseline to none or mild in 85.2% of patients post procedure. 
 
One patient died intra-operatively and in-hospital mortality was 2.4% (n=18).  No emergent cardiac 
surgery was required.  The rate of in-hospital Major adverse cardiac and cerebrovascular events 
(MACCE) was 3.1%. Other in-hospital major complications occurred in 12.8% of patients and were mainly 
associated with major bleeding complications.  Five (0.7%) cases of SLDA were reported in this cohort.  
The median length of hospital stay was 9 days, and a majority of patients (89.3%) were discharged to 
their normal social environment. 
 
Thirty-day and 1-year mortality were 4.5% and 20.3%, respectively.  The rates of transient ischemic 
attack (TIA; 3.8%), stroke (2.1%), and myocardial infarction (0.9%) at 1-year were low.  A total of 8.5% 
of patients underwent a subsequent mitral valve surgery (2.3%) or second MitraClip device intervention 
(5.2%), respectively, to correct recurring MR.  A majority (63.3%) of patients were in NYHA functional 
class I or II at 1-year and significant improvement in quality of life was observed using the EuroQuol 
visual analogue scale (EQ-5D). 
 
Predictors of 1-year mortality included NYHA class IV, anemia, previous aortic valve intervention, serum 
creatinine ≥1.5 mg/dL, peripheral artery disease, LVEF 30%, severe tricuspid regurgitation, and 
procedural failure (defined as operator-reported failure, conversion to surgery, failure of clip placement, 
or residual post-procedural severe mitral regurgitation). 
 
These results demonstrate that treatment of significant MR with the MitraClip device is efficacious and 
results in significant clinical improvements in a high proportion of TRAMI patients after 12 months.  In 
this cohort, failure to achieve procedural success had the highest hazard ratio for predicting 1-year 
mortality. 
 
Transcatheter Valve Treatment Sentinel Pilot Registry 
The Transcatheter Valve Treatment Sentinel Pilot Registry is part of the European Society of Cardiology 
EuroObservational Research Programme and reports acute and 12-month follow-up results of 628 
consecutive patients treated between January 2011 and December 2012 in 25 centers in 8 European 
countries. 
 
Mean age of the patients entered in the registry was 74.2±9.7 years, 63.1% were male, and 72.0% had 
functional MR.  A majority (85.5%) of patients were in NYHA functional class III or IV at baseline.  Mean 
logistic EuroSCORE was 20.4±16.7%, indicative of population of patients at high risk for surgical mortality. 
 
Acute procedural success was high (95.4%) with no difference between FMR and DMR patients.  Overall, 
in-hospital mortality was 2.9%.  MR reduction to ≤2+ was achieved in 98.2% of patients post-procedure 
with no difference between MR etiologies.  At 1-year, MR was reduced to ≤2+ in 94.0% of patients and 
 
 
Therapy in Contemporary Clinical Practice: Results from the German Transcatheter Mitral Valve Interventions 
Registry.  Eur Heart J.  2016; 37:703-712. 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 57 of 68 
  
 
 
58.6% had mild or no MR, with comparable results obtained for FMR and DMR.  A majority (74.2%) of 
patients were in NYHA functional class I or II at 1-year. 
 
At 1-year, mortality was 15.3%, without significant differences between groups (FMR 15.0% vs. DMR 
16.2%, p[log-rank]=0.650).  The estimated 1-year rate of heart failure re-hospitalization was 22.8% and 
was significantly higher in the FMR group compared to the DMR group (25.8% vs. 12%, p[log-
rank]=0.009).  Freedom from the composite endpoint of death or re-hospitalization for heart failure was 
69.0%, with no difference between FMR and DMR (p[log rank]=0.103).  Multivariate analysis showed 
that EuroSCORE and successful deployment of the MitraClip device were independently associated with 
the composite endpoint at 1 year. 
 
Re-intervention for recurring MR was infrequent with 2.9% of patients requiring a second MitraClip 
intervention and 0.9% requiring mitral valve surgery. 
 
The results of the pilot European Sentinel Registry demonstrated that procedural and late mortality was 
low and lower than expected in such a high-risk cohort, without differences between FMR and DMR.  
These results confirm long-term benefits previously reported in other real-world registries. 
 
MitraClip Asia-Pacific Registry (MARS) 
MitraClip in the Asia-Pacific Registry (MARS) 54 is a multicenter retrospective registry that includes 
patients treated at 8 centers in Australia, China, Indonesia, Malaysia and Singapore.  The study did not 
mandate specific anatomic requirements beyond the technical feasibility of grasping the mitral leaflets 
and patients who did not present with central mitral regurgitation involving A2/P2 segments were deemed 
eligible for enrollment. 
 
A total of 145 patients underwent the MitraClip procedure between February 2011 to October 2013.  
Patients were predominantly male (64%) with a mean age was 71.4±11.9 years.  At baseline, all patients 
had MR severity 3+ (19%) or 4+ (81%).  Functional MR etiology was present in 53.5%.  A majority (68.3%) 
of patients were symptomatic with NYHA functional class III or IV at baseline.  Mean STS score for the 
cohort was 7.4±8.1%. 
 
The MitraClip implant rate was 97.9% and the average procedure time was 130±98 minutes.  Acute 
procedural success was achieved in 93.7% (133/142).  One MitraClip device was implanted in 70 (49.3%) 
patients, whereas 72 (50.7%) patients received ≥2 devices.  There were no device embolization and 6 
(4.2%) patients experienced an SLDA.  The mean length of hospital stay post-procedure was 6.0±7.8 
days. 
 
The 30-day mortality rate was 5.6% (n=8), while the 30-day MAE rate, defined as a composite of stroke, 
myocardial infarction, bleeding requiring transfusions >1 unit of blood, septicemia, reoperation for failed 
mitral valve procedure, non-elective cardiac surgery for adverse events, renal failure, gastrointestinal 
complications requiring surgery, ventilation for >48 hours, and new onset of atrial fibrillation was 12.7% 
(18/142).   
 
At 30 days, 76.8% of patients had MR ≤2+, with no significant differences observed between the FMR 
and DMR sub-groups.  There was significant improvement in NYHA functional class with 82.1% of 
patients in class I or II at 30 days compared to 31.7% at baseline.  At 30 days, there was a significant 
 
 
54 Yeo KK, Yap J, Yamen E, Muda N, Tay E, Walters DL, Santoso T, Liu X, Jansz P, Yip J, Zambahari R, Passage 
J, Koh TH, Wang J, Scalia G, Kuntjoro I, Soesanto AM, Muller D.  Percutaneous Mitral Valve Repair with the 
MitraClip: Early Results from the MitraClip Asia-Pacific Registry (MARS).  EuroIntervention.  2014; 10:620-625. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 58 of 68 
  
 
 
reduction in LVEF, LVEDD, LVESD, LA indexed volume and calculated pulmonary artery systolic 
pressure compared to baseline.  
 
In a separate analysis, Tay et al.55 described and compared the use of the MitraClip therapy in patients 
with FMR and DMR treated as part of the MARS registry.  The authors reported similar rates of acute 
procedural success for FMR (95.5%, n=84) and DMR (92%, n=69) (p=0.515).   
 
The 30-day mortality rate for FMR and DMR was similar at 4.5% and 6.7% respectively (p=0.555). Thirty-
day MAE rate was 9.2% for FMR and 14.7% for DMR (p=0.281). Both FMR and DMR patients achieved 
significant improvements in MR severity and NYHA class after 30 days.  However, a significantly greater 
reduction in left ventricular end-diastolic diameter and end systolic diameter was observed in DMR 
compared to FMR. 
 
Overall, results from the MARS registry demonstrate that the MitraClip therapy is effective in reducing 
mitral regurgitation and has favorable short-term safety outcomes in both FMR and DMR patients. 
 
TVT Registry 
The Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve 
Therapy (TVT) Registry is a joint initiative of the STS and the ACC.  The goals of the registry are to serve 
as a platform for: 1) device and procedural surveillance; 2) quality assurance and improvement initiatives; 
and 3) efficient conduct of studies that will speed United States access to new devices and support the 
expansion of device labeling through evidence development. 
 
Centers that participate in the TVT Registry collect data on demographics, morbidities, functional status, 
quality of life, hemodynamic status, procedural details, and outcomes (post-operative, 30-day, and 1-
year).  The ACC National Cardiovascular Data Registry data warehouse and the Duke Clinical Research 
Institute Data Analysis Center both implement data quality checks, including feedback reports and checks 
on data range and consistency. 
 
Initial Experience (Nov 2013 – Aug 2014) 
The initial experience with commercial transcatheter mitral valve repair in the United States was first 
published by Sorajja et al.56 in 2016.  A total of 564 patients were entered into the transcatheter mitral 
leaflet clip (TMC) module of the TVT registry between November 2013 to August 2014.  Approximately 
70% of patients were enrolled at centers with pre-commercial experience.  Median age of the patients 
was 83 years, 56% were male.  NYHA functional class was III or IV in 86.0%; 292 patients (60.5%) had 
been hospitalized for heart failure in the year prior to the MitraClip procedure.  The median STS-PROM 
scores for MV repair and MV replacement were 7.9% (IQR: 4.7% to 12.2%) and 10.0% (IQR: 6.3% to 
14.5%), respectively. 
 
Consistent with the commercial indication for the MitraClip System, the vast majority (85.5%) of patients 
had degenerative MR, 9.2% had functional MR, and 5.1% had mixed etiology.  However, contrary to the 
EVEREST studies, implanting physicians were given greater discretion in the treatment of mitral valve 
 
 
55 Tay E, Muda N, Yap J, Muller DW, Santoso T, Walters DL, Liu X, Yamen E, Jansz P, Yip J, Zambahari R, 
Passage J, Ding ZP, Wang J, Scalia G, Soesanto AM, Yeo KK.  The MitraClip Asia-Pacific Registry: Differences in 
Outcomes between Functional and Degenerative Mitral Regurgitation.  Catheter Cardiovasc Interv.  2016; 87:E275-
281. 
56 Sorajja P, Mack M, Vemulapalli S, Holmes DR, Jr., Stebbins A, Kar S, Lim DS, Thourani V, McCarthy P, Kapadia 
S, Grayburn P, Pedersen WA, Ailawadi G.  Initial Experience with Commercial Transcatheter Mitral Valve Repair 
in the United States.  J Am Coll Cardiol.  2016; 67:1129-1140. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 59 of 68 
  
 
 
pathologies.  As such, an important proportion (37.8%) of patients had significant left ventricular dilation 
(end-systolic dimension ≥40 mm), baseline mean mitral gradient ≥5 mm Hg (8.0%), and MV area was <4 
cm2 (19.7%).  Moderate and severe tricuspid regurgitation was present in 35.1% and 15.1% of patients 
at baseline, respectively. 
 
The MitraClip implant rate was 96.8% with most devices implanted in the A2-P2 region (78.4%).  MR 
reduction to ≤2+ was achieved in 93.0% of patients, while MR grade ≤1+ occurred in 63.7%.  Three 
patients (0.5%) required conversion to open cardiac surgery, and 13 (2.3%) in-hospital deaths were 
observed. The incidence of in-hospital stroke was 1.2%, while major bleeding (VARC-2 criteria) occurred 
in 3.9%.  Six (1.1%) patients had a single leaflet device attachment (SLDA), and 2 (0.4%) patients had a 
device embolization.  Overall, procedural success, defined as a reduction to moderate or less MR in the 
absence of cardiac surgery or in-hospital mortality, occurred in 90.6% of patients.  The median length of 
hospital stay post-procedure was 3 days and a majority (84%) of patients were discharged home. 
 
The 30-day mortality rate in the TVT Registry was 5.8%.  Stroke at 30 days occurred in a total of 8 
patients (1.8%). The 30-day incidence of life-threatening or disabling bleeding (VARC-2 criteria) was 
2.6%.  A total of 13 (3.1%) patients were re-hospitalized for heart failure within 30 days post-procedure.   
 
Variables with univariate association for reduction in MR ≤2+ were end-diastolic dimension, baseline MR 
severity, A2-P2 location of clip implantation, and institutional case volume.  MitraClip device implantation 
at A2-P2 remained significant in multivariate models. 
 
Reduction to MR grade ≤2+ was similar at sites with and without precommercial experience (93.8% vs. 
91.1%, p=0.26), though reduction to MR grade ≤1+ was more common at pre-commercial sites (66.5% 
vs. 57.4%, p=0.04). 
 
Preliminary outcomes from the TVT Registry show that the MitraClip devices is predominantly used in a 
population of patients at prohibitive surgical risk with symptomatic severe MR due to degenerative 
disease.  Safety and efficacy outcomes of the MitraClip in a commercial setting in the United States 
were comparable with pre-approval research studies and other commercial registries. 
 
 
1-Year Outcomes (Nov 2013 – Sep 2015) 
In a subsequent report, Sorajja et al.57 updated previously published data on acute procedural success 
and extended the evaluation of these patients to 1-year follow-up.  This expanded cohort includes all 
patients who underwent commercial therapy with the MitraClip System since initial U.S. Food and Drug 
Administration approval and who were enrolled in the TVT registry through September 1, 2015. 
 
Procedural and in-hospital outcomes were determined from data in the TVT Registry.  For clinical events 
after hospital discharge (i.e.,30-day and 1-year outcomes), data from CMS administrative claims were 
used via linkage of the clinical records of the TVT registry to Medicare administrative claims data using 
direct patient identifiers. 
 
Primary outcomes were death, re-hospitalization for heart failure, and the combined endpoint of death or 
heart failure re-hospitalization within 1 year. 
 
 
 
57 Sorajja P, Vemulapalli S, Feldman T, Mack M, Holmes DR Jr, Stebbins A, Kar S, Thourani V, Ailawadi G.  
Outcomes With Transcatheter Mitral Valve Repair in the United States: An STS/ACC TVT Registry Report.  J Am 
Coll Cardiol. 2017;70(19):2315-2327. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 60 of 68 
  
 
 
A total of 2,952 patients were enrolled between November 2013 and September 2015 at 145 clinical sites 
in the U.S.  Patients were elderly with a median age of 82 year; 56% were male.  At baseline, 85% were 
symptomatic with NYHA functional class III or IV.  Overall, the median (IQR) STS-predicted risks of 
mortality for MV repair and MV replacement were 6.1% (3.7% to 9.9%) and 9.2% (6.0% to 14.1%), 
respectively. 
 
Degenerative MR etiology was present in a majority (85.9%) of patients, whereas functional MR was 
noted in 17.5% (FMR only 8.6%; mixed etiology 8.9%).  Ninety-three percent (93%) of patients presented 
with 3+ or 4+ MR at baseline.  Significant left ventricular dilation (end-systolic dimension ≥40 mm) was 
present in 32.2%.  The median LVEF was 55% and 35.4% of the patients had an LVEF <50%.  Baseline 
mean mitral gradient was ≥5 mm Hg in 9.2%, and the MV area was <4 cm2 in 20.5%.  Severe tricuspid 
regurgitation was present in 16.0% of the patients. 
 
The MitraClip was predominantly implanted in the A2-P2 region (82.8% of cases).  MR reduction to ≤2+ 
was achieved in 93.0% of patients, while MR grade ≤1+ was achieved in 61.8%.  Single-leaflet device 
attachment occurred in 1.5% of treated patients.  There were 4 reported cases of device embolization 
(0.1%).  Major or life-threatening bleeding (VARC-2 criteria) occurred in 3.9%.  The rates of stroke (0.4%) 
and myocardial infarction (0.1%) were both low.  Twenty patients (0.7%) had in-hospital conversion to 
open cardiac surgery.  Overall in-hospital mortality was 2.7%.  The median length of hospital stay was 2 
days and a majority (85.9%) of the treated patients were discharged directly home. 
 
A total of 1,867 patients (63.2%) from 139 hospitals had records that could be linked to CMS 
administrative claims.  Patients with linked CMS claims data tended to be older, had a lower rate of co-
morbidities such as diabetes and prior myocardial infarction, and were less likely to have functional MR.  
However; the STS-predicted risks of operative mortality for MV repair and MV replacement were higher 
in patients with linked CMS claims data compared to those without linked CMS claims data. 
 
In this cohort, 30-day mortality, including in-hospital events, was 5.2% and the rate of re-hospitalization 
for heart failure was 4.9%.  A majority (95.5%) of patients were discharged from hospital with MR ≤2+, 
alive and free from MV surgery at 30 days. 
 
One-year mortality in patients with linked CMS claims data was 25.8% and the rate of re-hospitalization 
for heart failure at 1 year was 20.2%.  The combined endpoint of death or heart failure re-hospitalizations 
at 1 year occurred in 37.9% of the patients.  These endpoints were lower for patients who had 
degenerative MR etiology (24.7%, 20.5%, and 35.7%, respectively) compared to those who had 
functional MR etiology (31.2%, 32.6%, and 49.0%, respectively). 
 
The subgroup of patients with severe tricuspid regurgitation also had significantly worse outcomes, with 
1-year cumulative incidences of 38.5%, 31.5%, and 54.3% for death, heart failure re-hospitalization, and 
the combined endpoint of death and heart failure re-hospitalization, respectively. 
 
Similarly, a graded effect was noted when comparing cumulative incidence of death and the combined 
endpoint of death or heart failure re-hospitalization at 1 year by discharge MR.  As expected, better 
outcomes were observed in patients discharged with MR ≤1+ (21.7% and 35.7%, respectively) compared 
to those discharged with MR 2+ (29.2% and 39.2%, respectively), and MR ≥3+ (48.9% and 54.4, 
respectively). 
 
At 1 year, 6.2% of patients with linked CMS claims data required a second MitraClip procedure.  The 
cumulative rate of stroke was 2.7%. 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 61 of 68 
  
 
 
Variables associated with mortality or re-hospitalization for heart failure after multivariate adjustment 
were increasing age, lower baseline LVEF, worse post-procedural mitral regurgitation, moderate or 
severe lung disease, dialysis, and severe tricuspid regurgitation. 
 
Based on these data, the authors conclude that the MitraClip procedure is being performed effectively 
and safely for severely symptomatic patients with MR and prohibitive surgical risk in the United States 
and contend that the observed mortality and re-hospitalizations for heart failure are related to age and 
associated with decreased LVEF, functional MR, severe tricuspid regurgitation, moderate or severe lung 
disease, and post-procedural residual MR. 
 
 
Non-EVEREST Criteria 
Patients treated with the MitraClip device as part of the EVEREST program had to meet specific anatomic 
inclusion criteria.  These criteria, included a regurgitant jet origin associated with the A2 to P2 segments 
of the mitral valve and, for patients with functional MR, a coaptation length of at least 2 mm, a coaptation 
depth of no more than 11 mm, and for patients with leaflet flail, a flail gap <10 mm and a flail width <15 
mm.  In addition, leaflet anatomy which may preclude device implantation, proper MitraClip device 
positioning on the leaflets or sufficient reduction in MR were excluded.  This may include: 
Evidence of calcification in the grasping area of the A2 and/or P2 scallops 
Presence of a significant cleft of A2 or P2 scallops 
More than one anatomic criteria dimensionally near the exclusion limits 
Bileaflet flail or severe bileaflet prolapse 
Lack of both primary and secondary chordal support 
 
In a real-world clinical setting, experienced implanters have started treating more complex mitral valve 
anatomies, often falling outside of the traditional EVEREST criteria.  In a recent publication, Lesevic et 
al. 58 analyzed patients treated with the MitraClip device according to the presence or absence of 
EVEREST inclusion criteria and compared the procedural success and long-term outcomes, repair 
durability, and prognostic factors. 
 
Consecutive patients treated with the MitraClip device at the German Heart Center in Munich between 
September 2009 to July 2012 were included.  All patients underwent 2D transthoracic and 2D and 3D 
transesophageal echocardiography before intervention to assess valve morphology, MR severity, and 
suitability for the MitraClip procedure.  Patients were assigned to the EVEREST (N=59) or non-EVEREST 
(N=75) groups depending on whether they would have met the eligibility criteria for the EVEREST II trial.  
 
In this study, key reasons for not meeting the EVEREST criteria included LVEF <25 % and/or LVESD 
>55 mm in 24% of patients, coaptation length <2 mm in 19%, main pathology in P1- and/or A1-segment 
(prolapse +/- flail) in 15%, main pathology in P3- and/or A3-segment (prolapse +/- flail) in 12%, flail gap 
>10 mm in 8%, and flail width >15 mm in 4%. 
 
Baseline characteristics were comparable between the two groups.  Functional MR etiology was present 
in 39% and 41% of EVEREST and non-EVEREST groups, respectively.  Both groups were high risk for 
surgery with STS mortality scores of 10.7% and 10.1% for EVEREST and non-EVEREST patients, 
respectively. 
 
 
 
58 Lesevic H, Karl M, Braun D, Barthel P, Orban M, Pache J, Hadamitzky M, Mehilli J, Stecher L, Massberg S, Ott 
I, Schunkert H, Kastrati A, Sonne C, Hausleiter J.  Long-Term Outcomes after MitraClip Implantation According to 
the Presence or Absence of EVEREST Inclusion Criteria.  Am J Cardiol.  2017; 119:1255-1261. 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 62 of 68 
  
 
 
One hundred and thirty-four (134) patients were treated with the MitraClip device.  Acute procedural 
success was achieved in 95.5% of patients with no difference between EVEREST (97%) and non-
EVEREST (95%) patients.  There was no statistical difference in the number of device implanted between 
the two groups.  A similar mean acute MR reduction was achieved in both groups (-2.3±0.9 vs -2.2±1, 
respectively; p=0.497).   
 
During a mean follow-up of 3.5 years, 32 deaths were reported, including 5 occurring during the hospital 
stay post-index procedure.  Survival rates were similar between EVEREST and non-EVEREST patients 
(p=0.656).  Recurring MR ≥3+ was more frequent in non-EVEREST patients than in EVEREST patients 
(28% vs 45%; p=0.066).  Re-interventions for recurring MR were more frequently required in non-
EVEREST patients than in EVEREST patients, including second MitraClip device interventions (2% vs 
13%; p=0.085) and mitral valve surgeries (9% vs 28%; p=0.047).  Of the 21 patients requiring re-
intervention in both groups, 17 (81%) had degenerative MR.  Flail width was found to be an independent 
predictor for re-intervention, whereas flail gap ≥10 mm displayed a strong trend (flail width: adjusted HR 
11.2, 95% CI 2.6 to 48.3; p=0.001; flail gap: adjusted HR 3.1, 95% CI 0.9 to 11.5; p=0.077).  When 
entering the variables into logistic regression analyses for identifying independent factors associated with 
MR ≥3+ at follow-up, only flail gap ≥10 mm displayed a trend (p=0.082). 
 
At last available follow-up (median of 381 days), both groups achieved significant reduction in MR 
severity over baseline.  Similarly, NYHA functional class improved in both EVEREST and non-EVEREST 
patients from baseline to longest available follow-up (median of 652 days).  Finally, both groups 
experienced clinically and statistically significant improvements in 6-minute walk distance from baseline 
to the latest follow-up visit, with no difference between EVEREST and non-EVEREST groups. 
 
This data show that significant reduction of MR severity can be achieved in patients who do not meet the 
EVEREST II trial criteria.  Nevertheless, non-EVEREST patients were significantly more likely to require 
re-intervention for recurring MR due in part to more complex mitral valve pathologies including flail width 
>15 mm and flail gap ≥10mm.  These results also support the assumption of previous studies that 
selected patients, especially with secondary MR, can benefit from percutaneous treatment with the 
MitraClip device.  
 
In contemporary clinical practice, a small, but non-negligible proportion of patients with severe MR 
present complex mitral valve pathologies which would normally be excluded based on a strict application 
of EVEREST II anatomical criteria.  Success achieved with the MitraClip device in these patients and 
physician interest in using the clip for treating complex valve anatomies forms the rationale for the 
MitraClip® EXPAND Study.   
 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 63 of 68 
  
 
 
 
APPENDIX V: 
MONITORING PLAN 
 
A copy of the Monitoring Plan can be obtained upon request from the Clinical Project Manager for the 
study. 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 64 of 68 
  
 
 
 
APPENDIX VI: 
CONTACT INFORMATION 
 
A list of site contacts can be obtained upon request from the Clinical Project Manager for the study. 
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 65 of 68 
  
 
 
APPENDIX VII: 
FORESEEABLE ADVERSE EVENTS  
 
 
Please see device instructions for use regarding potential adverse events.   
 
 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 66 of 68 
  
 
 
APPENDIX VIII: 
SUMMARY OF CHANGES 
 
Amendment History 
 
Version # 
Date of Release 
Reason for Amendment 
1.0 
14 Feb 2018 
Original Protocol  
2.0 
26 June 2018 
Correct inconsistencies in the protocol 
 
 
Details of Change 
Section/ 
page# 
Version 1.0_14 February 2018 
Version 2.0_26 June 2018 
Rationale 
Summary 
/p6 
5.3.1/p21 
Inclusion Criteria #2: 
Subjects 
eligible 
to 
receive 
the 
MitraClip per the current approved 
indications for use  
Inclusion Criteria #2: 
Subjects 
scheduled 
to 
receive 
the 
MitraClip 
per 
the 
current 
approved 
indications for use  
To clarify that the 
intention is for the 
treatment decision 
to be made before 
study enrollment 
3.1 / p 15 
A procedure is considered attempted 
when the MitraClip delivery system is 
introduced.   
A procedure is considered attempted 
when the MitraClip delivery system is 
introduced into the femoral vein.   
To clarify at what 
point a procedure 
is considered 
attempted 
3.4 / p17 
The Steering Committee makes a 
recommendation to stop or terminate 
the study (such as higher frequency of 
anticipated adverse device effects). 
The 
Steering 
Committee 
makes 
a 
recommendation to stop or terminate the 
study 
Clarification on 
the role of the 
steering 
committee 
4.1 / p17 
 
Added sentences as follows:   
The assessment of safety will include all 
occurrences 
through 
30 
days 
post 
procedure.  
The assessment of performance measures 
will include all data reported at 30-day 
visits for this study.   
To clarify data to 
be included in 
analyses 
4.2 / p18 
Device 
Related 
Adverse 
Events 
(including device embolization, single 
leaflet device attachment (SLDA), 
bleeding, perforation, etc) 
 
Device Related Adverse Events (including 
mitral valve stenosis, device embolization, 
single leaflet device attachment (SLDA), 
Iatrogenic atrial septal defect, myocardial 
perforation, 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) 
Correct 
inconsistency with 
this definition to 
other MitraClip 
studies 
6.4 / p 24 
 
 Table 2/ 
p 25 
Visits at: 
• 30 days (30 days +14 days)  
• 12 months (365 days ± 30 days)  
 
Phone call or visit at: 
• 6 months (180 days ± 90 days) 
 
Visits at: 
• 30 days (30 days -14 days/+60)  
• 12 months (365 days -30 days/+ 90 days) 
 
Phone call or visit at: 
• 6 months (180 days -30 days/+ 90 days) 
 
Windows in 
protocol 
inconsistent with 
standard of care. 
Increased time to 
permit visits per 
standard of care 
without deviation.    
Table 2/   
p 25 
Foot note 1 reads: 
Adverse Events include: all device-
related complications, device 
deficiencies, device malfunctions, 
concurrent procedures and all 
hospitalizations 
Footnote 1 updated to read: 
Adverse Events to collected in this study 
include: cardiovascular events, device-
related complications (as defined in 
section 4.2), and events classified as 
MAEs (as defined in section 4.1) 
To clarify 
appropriate AE 
reporting for a 
post-market study 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 67 of 68 
  
 
 
Section/ 
page# 
Version 1.0_14 February 2018 
Version 2.0_26 June 2018 
Rationale 
 
Table indicates that Treatment TTE 
and Treatment TEE are required 
 
 
Footnote 2 added to say that TTE / TEE 
during treatment should be submitted for 
the study only if capturing TTE / TTE 
echoes is part of standard of care. 
To be consistent 
with standard of 
care 
7.1.2/ 
page 26 
Serious Adverse Event definition 
includes:   
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 Protocol, 
without a serious deterioration in 
health, is not considered to be a 
serious adverse event. 
Serious Adverse Event updated to only 
to remove this text, except for the one 
sentence:   
 
A planned hospitalization for pre-existing 
condition, or a procedure required by the 
Clinical 
Protocol, 
without 
a 
serious 
deterioration in health, is not considered to 
be a serious adverse event. 
 
Definition 
inconsistent with 
ISO14155, 
corrected to 
match ISO14155 
standard definition 
7.2.1/ 
page 27 
Unanticipated (Serious Adverse) 
Device Effect [U(S)ADE] 
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 protocol 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. 
This section has been removed 
Remove 
inconsistency 
21CFR 812 and 
U(S)ADE/UADE 
definition do not 
apply to this 
protocol 
7.3.1/ 
page 27 
 
Added paragraph as follows: 
Adverse Events to be reported during this 
study include: all cardiovascular events, 
device-related complications (as defined in 
section 4.2), and events classified as 
MAEs (as defined in section 4.1).  These 
AEs should be reported starting from the 
To clarify 
appropriate AE 
reporting for a 
post-market study 
 

 
 
MitraClip® EXPAND Study 
 
 
Protocol 17-518: Version 2.0 
26 June 2018 
  
 
 
 
 
Page 68 of 68 
  
 
 
Section/ 
page# 
Version 1.0_14 February 2018 
Version 2.0_26 June 2018 
Rationale 
time that the MitraClip delivery system is 
introduced to the femoral vein through the 
12-month follow up visit in cases with a 
MitraClip implant.  In cases with an 
attempted MitraClip Procedure, but no 
implant, AEs are only collected through 30 
days post attempted procedure.   
7.3.2/ 
page 26 
Unanticipated Serious Adverse Device 
Effect Reporting 
Abbott requires the Investigator to 
report any 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.  
This section has been removed 
Remove 
inconsistency 
21CFR 812 and 
U(S)ADE/UADE 
definition do not 
apply to this 
protocol 
9.4.3/ p29 
No hypothesis will be tested in this 
study,therefore, there is no adjustment 
for multiple testing. 
Details will be defined in the Statistical 
Analysis Plan (SAP).   
Statistical 
Analysis Plan is 
now in draft and 
addresses this 
15.6/ page 
36 
Risks associated with the use of the 
device during this clinical study are 
minimized through device design, 
investigator selection and training, 
pre-specified patient eligibility 
requirements, study monitoring to 
ensure adherence to the protocol and 
the use of a DSMB. Stopping rules 
will be discussed with the DSMB and 
applied for subject safety through 
enrollment.  
Risks associated with the use of the 
device during this clinical study are 
minimized through device design, 
investigator selection and training, pre-
specified patient eligibility requirements, 
study monitoring to ensure adherence to 
the protocol.    
Remove 
inconsistency 
since the safety 
team has decided 
that a DSMB is 
not needed for 
this study 
Appendix 
II 
Definitions 
/ p46 
 
Unanticipated Adverse Device Effect 
[UADE] 
UADEs or 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 protocol 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.  All reported 
adverse events are reviewed by Sponsor 
so that UADEs/USADEs are identified and 
addressed.   
Added to specify 
that Sponsor 
review will take 
place to identify 
UADEs