A Post-Market Study Assessment of the Safety and Performance of the MitraClip G4 System
Conditions: Mitral Valve Regurgitation, Mitral Regurgitation
Sponsor: Abbott Medical Devices

 
Clinical Investigation Plan Cover Page 
 
 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the express 
written consent of Abbott. 
87173 CIP Posting Cover Page Ver C 
Template 
Page 1 of 1 
 
NCT Number: NCT04177394 
EXPAND G4 
MitraClip EXPAND G4 
Study Document No: < ABT-CIP-10320> 
Version [C] 
Date: 04-NOV2020 
 
 
Sponsor  
 
 
Abbott 
        
 
 
 
3200 Lakeside Dr 
      
  
 
 
Santa Clara, CA 
        
 
 
 
95054 
 
 
 

   
 
  
.  
Study Name: MitraClip 
EXPAND G4  
Clinical Investigation Plan 
 
 
 
Page 3 of 99 
 
• 
Use of Controlled Gripper Actuation 
• 
In-hospital MAE defined as the number of MAEs that occur prior to 
discharge from hospitalization in which MitraClip Procedure was 
performed 
 
Clinical endpoints (Discharge, 30 day, 6 month, 1, 2, 3, 4, 5 year)):  
• 
All-cause Mortality  
• 
Heart Failure Hospitalization 
• 
Occurrence of AE 
• 
Device-Related Complications  
o Mitral valve stenosis 
o Single Leaflet Device Attachment (SLDA) 
o Device Embolization 
o Myocardial perforation 
o Need for mitral valve replacement instead of repair due at 
least in part to the MitraClip procedure or the presence of 
the MitraClip device 
• 
MR Reduction to ≤1+ (Discharge, 30 day, 1 year, 5 year) 
• 
MR Reduction to ≤2+ (Discharge, 30 day, 1 year, 5 year) 
• 
New York Heart Association (NYHA) functional class improvement 
• 
Quality of Life (QOL) assessed using the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) 
• 
6 minutes walk distance (6MWD) 
 
Echocardiographic endpoints: 
(Baseline, Discharge, 30 day, 1 year, 5 year):  
• 
MR Severity Grade 
• 
Effective Regurgitant Orifice Area (EROA) as measured by PISA 
method (Baseline only) 
• 
Coaptation Measures (depth/length) (Baseline only) 
• 
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) (Baseline only) 
• 
Grasping Area Anatomy (measure cleft or scallop if significant) 
• 
Assess chordal support (Baseline only) 
• 
Regurgitant Jet(s) Position and Quantity (Baseline only) 
• 
Tricuspid Regurgitation (TR) Severity: None, Mild, Moderate or 
Severe 
Inclusion Criteria 
1. Subjects scheduled to receive the MitraClip per the current approved 
indications for use  

   
 
  
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Clinical Investigation Plan 
 
 
 
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2. Subjects who give consent for their participation 
Exclusion Criteria 
1. Subjects participating in another clinical study that could impact the 
follow-up or results of this study.   
Abbott Medical 
Expert 
 
Global Medical Affairs Director, Mitral and Tricuspid Transcatheter 
Interventions, Abbott Structural Heart 
 
 
 
CIP Author 
  
Associate Director Clinical Science, Abbott Structural Heart 

   
 
  
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Study Name: MitraClip 
EXPAND G4  
Clinical Investigation Plan 
 
 
 
Page 5 of 99 
 
 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

   
 
  
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Study Name: MitraClip 
EXPAND G4  
Clinical Investigation Plan 
 
 
 
Page 6 of 99 
 
 
 
NATIONAL COORDINATING CLINICAL INVESTIGATOR / STUDY PRINCIPAL INVESTIGATOR  
SIGNATURE PAGE 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements 
applicable in conducting this clinical investigation. 
 
 
[Coordinating Clinical Investigator / Study Principal Investigator] 
 
Printed name: 
Signature: 
Date: 
 
 

   
 
  
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Study Name: MitraClip 
EXPAND G4  
Clinical Investigation Plan 
 
 
 
Page 7 of 99 
 
TABLE OF CONTENTS 
1.0 
INTRODUCTION........................................................................................................................... 10 
1.1 
Study Design ............................................................................................................................. 11 
1.2 
Study Objective ......................................................................................................................... 11 
2.0 
BACKGROUND AND RATIONALE .............................................................................................. 11 
2.1 
Regulatory History..................................................................................................................... 11 
2.2 
MitraClip® Post-Market Clinical Studies ................................................................................... 11 
2.3 
Rationale for Conducting this Study ......................................................................................... 15 
2.4 
Summary of Device ................................................................................................................... 15 
2.4.1 
Name of the Device .............................................................................................................. 15 
2.4.2 
Indication for Use .................................................................................................................. 15 
2.4.3 
Description of the Device ...................................................................................................... 15 
3.0 
STUDY FLOW AND FOLLOW-UP SCHEDULE .......................................................................... 16 
3.1 
Number of Subjects to be Enrolled ........................................................................................... 16 
3.2 
Study Flow and Follow up Schedule ........................................................................................ 18 
3.3 
Early Termination of the Clinical Study..................................................................................... 18 
4.0 
STUDY ENDPOINTS .................................................................................................................... 18 
4.1 
Safety and Performance Measures .......................................................................................... 18 
4.2 
Acute Measures: ....................................................................................................................... 19 
4.3 
Clinical Measures ...................................................................................................................... 19 
4.4 
Functional Improvement Measures .......................................................................................... 19 
4.5 
Echocardiographic endpoints: .................................................................................................. 20 
5.0 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................. 20 
5.1 
Subject Population .................................................................................................................... 20 
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 in Analysis ........................................................................... 21 
5.5 
Total Expected Duration of the Study ....................................................................................... 22 
5.6 
Expected Duration of Each Subject’s Participation .................................................................. 22 
5.7 
Number of Subjects Required to be Included in the Study ...................................................... 22 
5.8 
Estimated Time Needed to Select this Number ....................................................................... 22 
5.9 
Subject Discontinuation ............................................................................................................ 22 
5.10 
Subject Completion ................................................................................................................... 23 
6.0 
TREATMENT AND FOLLOW UP ASSESSMENTS .................................................................... 23 
6.1 
Pre-treatment ............................................................................................................................ 23 
6.1.1 
Clinical Assessments ............................................................................................................ 23 
6.1.2 
Pre-treatment Imaging .......................................................................................................... 23 
6.2 
Index Procedure ........................................................................................................................ 24 
6.3 
Post-procedure .......................................................................................................................... 24 
6.4 
Subject Follow-up...................................................................................................................... 24 
7.0 
ADVERSE EVENTS ..................................................................................................................... 25 
7.1 
Definitions.................................................................................................................................. 25 
7.1.1 
Adverse Event ....................................................................................................................... 25 
7.1.2 
Serious Adverse Event ......................................................................................................... 26 

   
 
  
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Clinical Investigation Plan 
 
 
 
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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 
STATISTICAL ANALYSIS ............................................................................................................ 27 
8.1 
Statistical Overview ................................................................................................................... 27 
8.2 
Analysis Populations ................................................................................................................. 27 
8.3 
Sample Size Calculations and Assumptions ............................................................................ 27 
8.4 
Statistical Analyses ................................................................................................................... 28 
8.4.1 
Study Endpoint Analyses ...................................................................................................... 28 
8.4.2 
Handling of Multiplicity Issues ............................................................................................... 28 
8.4.3 
Procedures for Accounting for Missing, Unused or Spurious Data ..................................... 28 
8.5 
Deviations from the Original Statistical Plan ............................................................................ 28 
9.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................... 28 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 29 
10.1 
Selection of Clinical Sites and Investigators............................................................................. 29 
10.2 
Protocol Amendments ............................................................................................................... 29 
10.3 
Training ..................................................................................................................................... 29 
10.3.1 
Site Training ...................................................................................................................... 29 
10.3.2 
Training of Sponsor’s Monitors ......................................................................................... 29 
10.4 
Monitoring.................................................................................................................................. 29 
10.5 
Deviations from Protocol ........................................................................................................... 30 
10.6 
Quality Assurance Audit............................................................................................................ 30 
10.7 
Sponsor Auditing ....................................................................................................................... 30 
11.0 
DATA HANDLING AND RECORD KEEPING .............................................................................. 31 
11.1 
Data Management/Data Analysis ............................................................................................. 31 
11.2 
Source Documentation ............................................................................................................. 31 
11.3 
Electronic Case Report Form Completion ................................................................................ 31 
11.4 
Record Retention ...................................................................................................................... 32 
12.0 
ETHICAL CONSIDERATION ........................................................................................................ 32 
12.1 
Medical Ethics Committee Review ........................................................................................... 32 
13.0 
PUBLICATION POLICY ................................................................................................................ 32 
14.0 
RISK ANALYSIS ........................................................................................................................... 33 
14.1 
Anticipated Clinical Benefits ..................................................................................................... 33 
14.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects .................................. 33 
14.3 
Residual Risks Associated with the Investigational Device ..................................................... 33 
14.4 
Risks Associated with Participation in Clinical Study ............................................................... 33 
14.5 
Possible Interactions with Protocol-Required Concomitant Medications................................. 33 
14.6 
Steps that will be Taken to Control or Mitigate the Risks......................................................... 33 
14.7 
Risk to Benefit Rationale........................................................................................................... 34 
APPENDIX I – MITRACLIP G4 CLIP SELECTION AND LEAFLET GRASPING TECHNIQUE 
RECOMMENDATIONS ............................................................................................................................. 35 
APPENDIX II – MITRACLIP G4 PMCF CLINICAL STUDY PROTOCOL ................................................ 38 
APPENDIX III - ABBREVIATIONS AND ACRONYMS ............................................................................ 76 
APPENDIX IV - DEFINITIONS ................................................................................................................. 77 
APPENDIX V - CASE REPORT FORMS ................................................................................................. 84 

   
 
  
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Clinical Investigation Plan 
 
 
 
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APPENDIX VI- LITERATURE REVIEW AND SUMMARY OF POST-MARKET TRIALS ....................... 85 
APPENDIX VII: MONITORING PLAN ...................................................................................................... 96 
APPENDIX VII:  CONTACT INFORMATION ........................................................................................... 97 
APPENDIX IX: FORESEEABLE ADVERSE EVENTS ............................................................................ 98 
APPENDIX X - SUMMARY OF CHANGES ............................................................................................. 99 
 
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) or Internal Review Boards 
(IRBs) of the respective study site and by the applicable regulatory authorities. 
 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
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1.0 
INTRODUCTION  
This clinical study protocol defines the MitraClip EXPAND G4 study being conducted to confirm the safety 
and performance of the MitraClip G4 System in a post-market setting.  This Post-market study will be 
conducted on commercial cases conducted with the approved MitraClip G4 System.   
 
The MitraClip® System received Conformité Européene approval (CE Mark) in 2008 and US Food and 
Drug administration (FDA) Approval in 2013 and 2019 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 
 patients in clinical trials and more than 
 patients 
in worldwide use to date.  Abbott is now introducing the next generation MitraClip G4 System. This new 
system has three important advancements over the previous MitraClip Systems: 
 
• 
Introduction of two new clip sizes: NTW and XTW 
• 
Incorporation of the option to grasp leaflets simultaneously or independently, i.e., controlled 
gripper actuation (CGA) 
• 
Integration of a continuous left atrial pressure (LAP) monitoring from the Steerable Guide Catheter  
 
The MitraClip EXPAND G4 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 G4 System.  The prospectively generated data in 
this study will be used to evaluate device outcomes and to evaluate the clip selection and leaflet grasping 
recommendations identified by the MitraClip G4 Advisory Board (Appendix I) in contemporary real-world 
settings.  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 G4 Study will become part of the MitraClip G4 Post Market 
Clinical Follow-up (PMCF) Study (Appendix II). Data from the MitraClip G4 PMCF Study will be used to 
fulfill the regulatory requirement for PMCF associated with the CE mark approval of the MitraClip G4 
System.  
 
The next generation MitraClip G4 system received FDA approval in July 2019 for use in the United States, 
was authorized by Health Canada in July 2019, received approval in Japan in June 2020, and received 
CE Mark in September 2020. The MitraClip EXPAND G4 Study will be conducted on commercial 
MitraClip G4 System that have received approval in the local geography as required.   
 
 
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 

   
 
  
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Study Name: MitraClip 
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Clinical Investigation Plan 
 
 
 
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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 G4 System. The study is 
designed in two phases: 
 
• 
Phase I: Clinical and echocardiographic outcomes data was collected from approximately 
 
subjects enrolled at approximately 
 sites in the United States with the goal of evaluating the 
early safety and procedural outcomes associated with the MitraClip G4. The follow up duration 
was 30 days. Phase I was completed 
. 
 
• 
Phase II: Up to 
 post-market, consented patients will be treated with a MitraClip G4 device 
according to local guidelines and IFU from the Europe, the United States, Canada and Japan will 
be included in the analysis for The MitraClip EXPAND G4 Study.  Follow-up echocardiograms will 
be collected at Discharge, 30 days and 1 year and 5 year at post-procedure visits. Additional 
clinical follow-up visits will be at 6 months (phone call), 2, 3, 4 year (office visits). Cardiovascular 
adverse events will be reported through 5 years to confirm safety of the MitraClip G4 System. 
The current protocol describes the design of the EXPAND G4 Phase II post-market study. 
 
1.2 
Study Objective 
The primary objective of this study is to assess the safety and performance of the MitraClip G4 System 
within a contemporary real-world setting.  
 
2.0 
BACKGROUND and RATIONALE 
2.1 
Regulatory History 
In 2008, based upon data from the EVEREST studies, the MitraClip® received CE mark approval for 
commercial use in Europe. 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 primary MR who are at prohibitive risk for surgery.  In March 2019, FDA expanded 
the indication to treat patients with heart failure symptoms and moderate-to-severe or severe secondary 
mitral regurgitation despite being treated with optimal medical therapy, based on the landmark COAPT 
study results. The current iteration of the device: MitraClip G4, which was the subject of this clinical study, 
was approved by FDA in July 2019, approved in Canada in July 2019, approved in Japan in June 2020, 
and received CE Mark in September 2020.  
 
2.2 
MitraClip® Post-Market Clinical Studies 
In the time since these approvals, a number of post-market clinical studies have been conducted on the 
MitraClip.  All 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.   
 
 
 
 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
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Table 1.  Summary of Post-Market MitraClip® Studies 
 
Study Reference 
Study Design 
Study Population 
Study Outcome 
Franzen et al.3 
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-EU4 
(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 
QOL5 
Getting Reduction 
of Mitral 
Insufficiency by 
Percutaneous Clip 
Implantation 
GRASP Registry6 
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.  
Several TRAMI reports have 
been published 7,8 
828 prospective 
patients at 21 sites 
(from the largest 
publication9) 
70%FMR 
94% Severe MR 
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 
 
3 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. 
4 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. 
5 ACCESS-EU Phase I Study Final Clinical Report, Version 1.0, 20/Aug/2012 
6 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. 
7 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. 
8 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. 
9 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. 

   
 
  
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Clinical Investigation Plan 
 
 
 
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The Transcatheter 
Valve Treatment 
Sentinel Pilot 
Registry10 
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.11 -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) 
A Contemporary, 
Prospective Study 
Evaluating Real-
world Experience 
of Performance 
and Safety for the 
Next Generation 
of MitraClip® 
Devices 
(EXPAND)12 
Prospective, Multi-center, 
Single Arm, International, 
Post-Market, Real World, 
Observational Study 
Conducted in United States 
and Europe. 
~1000 patients   
MR ≥3+ 
Euroscore II : 
8.1 ± 8.0 (539) 
Acute procedure success rate 
92.9%  
30 day major adverse event rate 
was very low. 
MR ≤ 2+ at 30 day at 90.1% in 
primary MR patients and 96.3% 
in secondary MR patients. 
 
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.13 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) 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, 
 
10 Therapy in Contemporary Clinical Practice: Results from the German Transcatheter Mitral Valve Interventions 
Registry.  Eur Heart J.  2016; 37:703-712. 
11 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. 
12 von Bardeleben RS et al., Contemporary, real-world, clinical outcomes with the next generation MitraClip™ 
(NTR/XTR) System: Results from the 1000+ patient global EXPAND Study. Presentation, ESC 2019. 
13 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. 

   
 
  
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Page 14 of 99 
 
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.14 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).   
 
In addition, Abbott has initiated a large scale observational study (1000 patients) in US and EU 
(EXPAND) to evaluate the safety and performance of the MitraClip NTR/XTR system.  The 30 day 
study outcomes were recently reported in ESC 201915. The acute procedure success rate was 92.9% 
(962/1035) and 30 day major adverse event rate was very low.  MR ≤ 2+ at 30 day was achieved at 
90.1% in primary MR patients and 96.3% in secondary MR patients. This study also characterized the 
baseline mitral valve anatomic features (assessed by the echo core-lab) associated with NTR and XTR 
clip selection. It was identified that MitraClip XTR (compared to NTR) was more often used in Primary 
MR in subjects with larger gaps. For secondary MR patients, XTR was used when there was significant 
leaflet tethering, particularly in the P2/P3 locations. Data presented in EuroPCR 202016 showed that 
MR reduction with XTR clip size was more favorable in PMR subjects with more complex MV 
anatomies, larger prolapse, smaller ventricles and more severe MR. and thereby demonstrating the 
utility of XTR Clip in tailoring the therapy to individual’s MV anatomy. 
 
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 
 
14 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. 
15 von Bardeleben R. S. et al. Contemporary, real-world, clinical outcomes with the next generation MitraClip 
(NTR/XTR) System: Results from the 1000+ patient global EXPAND Study. European Society of Cardiology (ESC) 
Congress 2019. 
16 Maisano F. et al. Clip Selection Strategy and Outcomes with MitraClip™ (NTR/XTR): Evidence-Based 
Recommendations from the Global EXPAND Study. EuroPCR e-Congress 2020. 

   
 
  
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Clinical Investigation Plan 
 
 
 
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FIGURE 2:  Schematic for Study Inclusion and Flow 
 
3.2 
Study Flow and Follow up Schedule 
Consecutive eligible patients that present for MitraClip procedure should be consented for the MitraClip 
EXPAND G4 Study.  Patients are included in the analysis upon completion of MitraClip G4 procedure.   
 
Follow-up data on clinical assessment should be submitted at ischarge, 30-day visit, 6-month phone call, 
1 year, 2 year, 3 year, 4 year and 5 year visits.  Echocardiograms are required to be submitted for the 
baseline, discharge, 30-day and 12-month and 5 year time points. All Echocardiograms conducted by 
the site during the study period (required by protocol or not) will be submitted to the Sponsor (see Table 
2). Section 6.4 of this protocol provides more detail on follow-up visits.    
 
The first 
 subjects treated with the MitraClip G4 in the MitraClip EXPAND G4 Study in Europe with 
evaluable acute procedural success (APS) data will be included in the G4 PMCF Study as described in 
Appendix II. Subjects with evaluable echocardiograms may be selected for a more detailed assessment 
by an independent core lab.  
 
A schematic of the study flow is shown in Figure 2.   
 
 
3.3 
Early Termination of the Clinical Study 
No formal statistical rule for early termination of the MitraClip EXPAND G4 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: 
• 
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 Internal 
Review Board/Ethics Committee (IRB/EC).   
 
 
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.   
 
 
• 
Performance  
The assessment of performance measures will include all data reported at 30-day visits for this 
study.   

   
 
  
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Clinical Investigation Plan 
 
 
 
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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 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), or myocardial perforation) through 
discharge.   
• 
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. 
• 
Use of Controlled Gripper Actuation (CGA) 
• 
Use of Left Atrial Pressure (LAP) Monitoring 
• 
Number of Attempted Grasps defined as the number of attempts to stabilize leaflets by the open 
Clip 
• 
Device-Related Complications defined as the occurrence of one of 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 
‒ 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 Major Adverse Events (MAE) defined as the number of MAEs that occur prior to 
discharge from hospitalization in which MitraClip Procedure was performed. 
 
4.3 
Clinical Measures  
(Discharge, 1, 6 and 12 months, and 2, 3, 4, 5 years): 
• 
All-cause Mortality  
• 
Heart Failure Hospitalization 
• 
MAE as defined above  
• 
Device-Related Complications defined above 
MR Reduction to ≤1+ (Discharge, 1, 12 months, and 5 years) 
• 
MR Reduction to ≤2+ (Discharge, 1, 12 months, and 5 years) 
4.4 
Functional Improvement Measures  
(Baseline, Discharge, 12 months, and 2, 3, 4, 5 years): 
• 
New York Heart Association (NYHA) functional class improvement  
• 
Quality of Life (QOL) assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
6 minutes walk distance (6MWD)  
 

   
 
  
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Clinical Investigation Plan 
 
 
 
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4.5 
Echocardiographic endpoints: 
(Baseline, Discharge, 1, 12 months, and 5 years):  
• 
MR Severity Grade 
• 
Effective Regurgitant Orifice Area (EROA) as measured by PISA method (Baseline only) 
• 
Coaptation Measures (depth/length) (Baseline only) 
‒ 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) (Baseline only) 
‒ 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) (Baseline only) 
• 
Assess chordal support (Baseline only) 
• 
Regurgitant Jet(s) Position and Quantity (Baseline only) 
• 
TR Severity: None, Mild, Moderate or Severe 
 
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This study will include an analysis of all consented subjects who satisfy the inclusion and exclusion 
criteria and who are treated with the MitraClip G4 System. The study will include approximately 
 
subjects treated with the MitraClip G4 System that have data available for assessment of APS.  
 
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 EXPAND G4 Study if they are eligible per the 
inclusion/exclusion criteria.   
 
5.2.2 Informed Consent 
Patient Information and Consent Form must receive approval of Sponsor and Ethics Committee (EC) or 
Internal Review Board (IRB) prior to beginning enrollment into the MitraClip EXPAND G4 Study.   
 

   
 
  
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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 G4 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) EC/IRB approved informed consent prior to any data is reported into this 
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. 
 
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. 
 
If approved by the EC/IRB, subjects from vulnerable populations may be enrolled in the study.  The 
ISO14155 definition of vulnerable population is as follows: individuals who are unable to fully understand 
all aspects of the investigation that are relevant to the decision to participate, or who could be manipulated 
or unduly influenced as a result of a compromised position, expectation of benefits or fear of retaliatory 
response.  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 consented subjects treated commercially with the MitraClip G4 System should be 
considered for inclusion in the study.  All subjects must meet the criteria below before being enrolled into 
the MitraClip G4 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 
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 
Per ISO 14155, the patient is considered enrolled upon signing and dating an informed consent for 
participation.  Only subjects that have an attempted MitraClip G4 procedure will be included in this 
analysis.  

   
 
  
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Clinical Investigation Plan 
 
 
 
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5.5 
Total Expected Duration of the Study 
The time to complete the MitraClip EXPAND G4 study is estimated to be approximately  years. 
 
5.6 
Expected Duration of Each Subject’s Participation 
The final required visit for subjects in the MitraClip EXPAND G4 Study is at  year post-procedure.  
Therefore, the expected duration of participation for subjects is approximately  years.  
 
5.7 
Number of Subjects Required to be Included in the Study 
Approximately 
 subjects will be included in the MitraClip EXPAND G4 Study. 
 
5.8 
Estimated Time Needed to Select this Number  
The estimated time to include 
 subjects in Phase II is about  years.   
 
5.9 
Subject Discontinuation 
Subjects that are consented and receive a MitraClip G4 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 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 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 

   
 
  
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Clinical Investigation Plan 
 
 
 
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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. 
 
5.10 
Subject 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 
• 
upon Study completion (e.g., 5 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.  If a MitraClip procedure is considered appropriate and the patient meets 
the screening criteria for the study (i.e. 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.  No data may be entered into the study unless the informed 
consent is completed. 
 
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:  demographics, medical history, 
surgical risk (STS Repair/Replacement Scores and/or EuroSCORE II), MR severity and New York Heart 
Association (NYHA) Functional Class and KCCQ.  If a 6-minute walk test is conducted as standard of 
care at baseline, these results will be collected in the G4 EXPAND Study.   
 
6.1.2 Pre-treatment Imaging 
Pre-Treatment Transthoracic Echocardiogram (TTE) and Transesophageal Echocardiogram (TEE) 
should be conducted per standard of care for a MitraClip Procedure.   
 

   
 
  
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Clinical Investigation Plan 
 
 
 
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6.2 
Index Procedure 
All Investigators must read and understand the Instructions for Use (IFU) that accompanies the Device. 
Handling and preparation of the MitraClip G4 System should be in accordance with the IFU. 
 
The MitraClip procedure should be conducted in accordance with standard of care practice and approved 
labelling.  All consented patients that have a successful or attempted procedure with the MitraClip G4 
will be entered into the study.  
 
NOTE FOR U.S. Sites:  In order to permit device reimbursement, please enter required data into the 
TVT Registry per your standard processes for all MitraClip EXPAND G4 cases.  The data collected in 
this registry does not replace the data collected by the TVT Registry (US).    
 
6.3 
Post-procedure 
Post treatment TTE, Clinical Assessments and Laboratory / Clinical Tests should be conducted prior to 
discharge per standard of care.  Some of the key post-procedure information (the discharge time point) 
to be reported for this study include:  Medical Exam and Reporting of Vitals, length of hospital stay, 
adverse events, MR severity and NYHA Functional Class. 
 
6.4 
Subject Follow-up 
Follow-up visits should be conducted per standard of care based on the follow up schedule outcomes in 
Table 2. During the follow-up period for this study (5 years) any unscheduled echocardiograms, either 
TEE or TTE, should be submitted. 
 
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, 12-
month and 2, 3, 4, 5-year visits.  Visit should be scheduled relative to the date of the MitraClip Procedure.  
If a 6-minute walk test is conducted as standard of care and was conducted at baseline; results for 6-
minute walk test at 30 day,12-months and 2, 3, 4, 5-year visits will be collected in the EXPAND G4 Study.   
 
Visits at: 
• 
30 days (-14 days / +60 days)  
• 
1, 2, 3, 4, 5 years (- 30 days / +90 days)   
 
Phone call or visit at: 
• 
6 months (- 30 days / +90 days) 
 
 
 
 
 

   
 
  
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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). 
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 be 
reported during this study include: all cardiovascular events, events classified as MAEs (as defined in 
section 4.1) and device-related complications (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 5 
year follow up visit. 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. 
 

   
 
  
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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. 
 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 
Selection of Clinical Sites and Investigators 
Sponsor will select investigators qualified by training and experience, to participate in the study of the 
MitraClip G4 System. 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.  Sites will be 
required to perform some cases with the MitraClip G4 System before participating the MitraClip EXPAND 
G4 Study.     
10.2 
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 of the 
Protocol amendment (administrative changes) or obtaining EC’s/IRB’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/IRB 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. 
 
10.3 
Training 
10.3.1 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; 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.  
 
10.3.2 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. 
 
10.4 
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.  

   
 
  
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Clinical Investigation Plan 
 
 
 
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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. 
10.5 
Deviations from Protocol 
The Investigator will not deviate from this 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.   
 
10.6 
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. 
10.7 
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/IRB 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. 
 
 

   
 
  
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11.0 DATA HANDLING AND RECORD KEEPING 
11.1 
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 
IRB/EC and clinical study monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the clinical study. 
 
11.2 
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 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 
11.3 
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.  
 

   
 
  
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11.4 
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. 
 
 
12.0 ETHICAL CONSIDERATION  
12.1 
Medical Ethics Committee Review  
Ethics Committee (EC) or Internal Review Board (IRB) 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 IRB/EC, the 
Sponsor, and/or the regulatory agencies as needed.  
 
Until the clinical study is completed, the Investigator will advise his/her EC/IRB of the progress of this 
clinical study, per requirements.  
 
 
13.0 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. 
 

   
 
  
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14.0 RISK ANALYSIS 
14.1 
Anticipated Clinical Benefits 
Treatment with the MitraClip has been shown to effectively reduce Mitral Regurgitation in several clinical 
studies (Table 1 of this protocol).  Treatment with the MitraClip G4 System within this study is anticipated 
to offer this same established benefit.  The changes to the MitraClip G4 System were designed to have 
the same clinical impact with added ease in grasping of the mitral leaflets during the implant procedure.  
Design validation study indicates that users also responded favorably to the simplified Clip deployment 
procedure, stating that it is significantly better to the MitraClip NTR/XTR deployment procedure. Users 
rated leaflet grasping and capture with MitraClip G4 as better than leaflet grasping and capture with 
MitraClip NTR/XTR.  Data from this study may help to further identify benefits of the MitraClip G4 device 
in improving mitral leaflet grasping and improve clinical outcomes. 
 
14.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Please refer to the approved Instruction for Use for possible adverse events of the MitraClip™ G4 
procedure.  
 
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 G4 device as part of this study is identical to treatment with the MitraClip 
G4 device outside of this study.  Participation in the study will not impact the MitraClip G4 procedure or 
use of the MitraClip G4 System in any way, therefore there is no added procedural risk by participating 
in this study.   
 
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 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 
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.  
 

   
 
  
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In the study, the device is required to be used in accordance with the MitraClip® System IFU 
Contraindications, warnings and precautions will be provided with all devices to be used during this study 
per the IFU.  
 
14.7 
Risk to Benefit Rationale  
Subjects participating in this study will be receiving the latest technology in MitraClip. MitraClip has been 
be safe and effective in over 
 patients in clinical trials and more than 
 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 G4 implant within this study are identical 
to the risks of receiving a MitraClip G4 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 the enrollment of patients treated with the MitraClip G4 System into this 
study.   
 

   
 
  
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17 Nishimura RA, Otto CM, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A 
Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines J Am Coll 
Cardiol 2014:0735-1097 

   
 
  
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APPENDIX II – MITRACLIP G4 PMCF CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

   
 
  
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10320-1: MitraClip G4 PMCF Study 
(sub-analysis of the first 
 European subjects in EXPAND G4 Study) 
 
A Post-Market Clinical Follow-up Assessment of the Safety and 
Performance the MitraClip G4 System 
 
 
Version Number 
 
Date 
November 4, 2020 
Planned Number of Sites and 
Region(s) 
 
 
Protocol Author  
  
Associate Director Clinical Science 
Abbott Structural Heart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

   
 
  
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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION........................................................................................................................... 43 
1.1 
Study Design ............................................................................................................................. 43 
1.2 
Study Objective ......................................................................................................................... 43 
2.0 
BACKGROUND AND RATIONALE .............................................................................................. 43 
2.1 
Literature Review ...................................................................................................................... 43 
2.2 
Rationale for Conducting this Study ......................................................................................... 45 
2.3 
Summary of Device ................................................................................................................... 45 
2.3.1 
Name of the Device .............................................................................................................. 45 
2.3.2 
Indication for Use .................................................................................................................. 46 
2.3.3 
Description of the Device ...................................................................................................... 46 
3.0 
STUDY FLOW AND FOLLOW-UP SCHEDULE .......................................................................... 47 
3.1 
Number of Subjects to be Enrolled ........................................................................................... 47 
3.2 
Early Termination of the Clinical Study..................................................................................... 48 
4.0 
STUDY ENDPOINTS .................................................................................................................... 49 
4.1 
Primary Endpoint....................................................................................................................... 49 
4.2 
Clinical Endpoints:..................................................................................................................... 49 
4.3 
Success Criteria: ....................................................................................................................... 49 
5.0 
SUBJECT SELECTION AND WITHDRAWAL ............................................................................. 49 
5.1 
Subject Population .................................................................................................................... 49 
5.2 
Subject Screening and Informed Consent ................................................................................ 51 
5.2.1 
Subject Screening ................................................................................................................. 50 
5.2.2 
Informed Consent.................................................................................................................. 50 
5.3 
Eligibility Criteria ........................................................................................................................ 50 
5.3.1 
Inclusion Criteria ................................................................................................................... 50 
5.3.2 
Exclusion Criteria .................................................................................................................. 50 
5.4 
Subject Enrollment and Inclusion in Analysis ........................................................................... 50 
5.5 
Total Expected Duration of the Study ....................................................................................... 51 
5.6 
Expected Duration of Each Subject’s Participation .................................................................. 51 
5.7 
Number of Subjects Required to be Included in the Study ...................................................... 51 
5.8 
Estimated Time Needed to Select this Number ....................................................................... 51 
5.9 
Subject Discontinuation ............................................................................................................ 51 
6.0 
TREATMENT AND FOLLOW UP ASSESSMENTS .................................................................... 51 
6.1 
Pre-treatment ............................................................................................................................ 51 
6.1.1 
Clinical Assessments ............................................................................................................ 51 
6.1.2 
Pre-treatment Imaging .......................................................................................................... 51 
6.2 
Index Procedure ........................................................................................................................ 52 
6.3 
Post-procedure .......................................................................................................................... 52 
6.4 
Subject Follow-up...................................................................................................................... 52 
7.0 
ADVERSE EVENTS ..................................................................................................................... 53 
7.1 
Definitions.................................................................................................................................. 53 
7.1.1 
Adverse Event ....................................................................................................................... 53 
7.1.2 
Serious Adverse Event ......................................................................................................... 53 
7.1.3 
Device Deficiency/Device Malfunction.................................................................................. 53 
7.2 
Device Relationship .................................................................................................................. 54 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting ........................................... 54 

   
 
  
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7.3.1 
Adverse Event Reporting ...................................................................................................... 54 
7.3.2 
Device Deficiency/Device Malfunction Reporting ................................................................. 54 
7.3.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor ..................... 55 
8.0 
ADJUDICATION OF EVENTS ...................................................................................................... 55 
8.1 
The Clinical Events Committee (CEC) ..................................................................................... 55 
9.0 
STATISTICAL ANALYSIS ............................................................................................................ 55 
9.1 
Statistical Overview ................................................................................................................... 55 
9.2 
Analysis Populations ................................................................................................................. 55 
9.3 
Sample Size Calculations and Assumptions ............................................................................ 55 
9.4 
Statistical Analyses ................................................................................................................... 56 
9.4.1 
Study Endpoint Analyses ...................................................................................................... 56 
9.4.2 
Clinical Endpoint Analysis ..................................................................................................... 57 
9.4.3 
Timing of Analysis ................................................................................................................. 57 
9.4.4 
Handling of Multiplicity Issues ............................................................................................... 57 
9.4.5 
Procedures for Accounting for Missing, Unused or Spurious Data ..................................... 57 
9.5 
Planned Interim Analysis .......................................................................................................... 57 
9.6 
Success Criteria ........................................................................................................................ 58 
9.7 
Deviations from the Original Statistical Plan ............................................................................ 58 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................... 58 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 58 
11.1 
Selection of Clinical Sites and Investigators............................................................................. 58 
11.2 
Protocol Amendments ............................................................................................................... 58 
11.3 
Training ..................................................................................................................................... 59 
11.3.1 
Site Training ...................................................................................................................... 59 
11.3.2 
Training of Sponsor’s Monitors ......................................................................................... 59 
11.4 
Monitoring.................................................................................................................................. 59 
11.5 
Deviations from Protocol ........................................................................................................... 59 
11.6 
Quality Assurance Audit............................................................................................................ 60 
11.7 
Sponsor Auditing ....................................................................................................................... 60 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................................. 60 
12.1 
Data Management/Data Analysis ............................................................................................. 60 
12.2 
Source Documentation ............................................................................................................. 60 
12.3 
Electronic Case Report Form Completion ................................................................................ 60 
12.4 
Record Retention ...................................................................................................................... 61 
13.0 
ETHICAL CONSIDERATION ........................................................................................................ 61 
13.1 
Medical Ethics Committee Review ........................................................................................... 61 
14.0 
RISK ANALYSIS ........................................................................................................................... 61 
14.1 
Anticipated Clinical Benefits ..................................................................................................... 61 
14.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects .................................. 62 
14.3 
Residual Risks Associated with the Investigational Device ..................................................... 62 
14.4 
Risks Associated with Participation in Clinical Study ............................................................... 62 
14.5 
Possible Interactions with Protocol-Required Concomitant Medications................................. 62 
14.6 
Steps that will be Taken to Control or Mitigate the Risks......................................................... 62 
14.7 
Risk to Benefit Rationale........................................................................................................... 63 
ANNEX I – ABBREVIATIONS AND ACRONYMS ................................................................................... 64 
ANNEX II - DEFINITIONS ........................................................................................................................ 65 
ANNEX III- CASE REPORT FORMS ....................................................................................................... 72 
ANNEX VI- SUMMARY OF CHANGES…………………………………………………………………...73 

   
 
  
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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

   
 
  
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PROTOCOL SUMMARY FOR MITRACLIP G4 PMCF STUDY  
Protocol 
Name
and Number 
: MitraClip G4 PMCF Study 
 
Title 
Post-Market Clinical Follow up Assessment of the Safety and 
Performance of the MitraClip G4 System 
Objectives 
The primary objective of this study to evaluate the safety and 
performance of the MitraClip G4 System in a post-market setting. 
Devices 
MitraClip G4 NT System 
MitraClip G4 XT System 
MitraClip G4 NTW System 
MitraClip G4 XTW System  
Targeted Number 
of subjects  
A minimum of 
 subjects treated in Europe  
 
Subject Visit 
Schedule 
Clinical Visits:  Baseline, Discharge, 30 days, 1, 2, 3, 4, 5 years 
Phone Call:  6 Months 
Primary Endpoint 
Safety and Effectiveness  
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 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 
• 
MR Severity (evaluated at Discharge, 30 days, 1 year and 5 years) 
• 
Device Related Adverse Events (including Mitral valve stenosis, 
device embolization, Single Leaflet Device Attachment (SLDA), 
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 
• 
Quality of Life (QOL) assessed using the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) 
• 
6 minute walk distance (6MWD)  
Inclusion Criteria 
1. Subjects scheduled to receive the MitraClip per the current approved 
indications for use  
2. Subjects who give consent for their participation 

   
 
  
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Exclusion Criteria 
1. Subjects participating in another clinical study that could impact the 
follow-up or results of this study.   

   
 
  
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1.0 
INTRODUCTION  
 
This clinical study protocol defines the MitraClip G4 post-market clinical follow-up (PMCF) study being 
conducted to confirm the safety and performance of the MitraClip G4 in a post-market setting. The 
MitraClip G4 System introduces three important advancements over the previous MitraClip System by (i) 
two new clip sizes: NTW and XTW, (ii) the option to grasp leaflets simultaneously or independently, i.e., 
controlled gripper actuation (CGA), and (iii) continuous left atrial pressure (LAP) monitoring integrated 
into the Steerable Guide Catheter. These advancements are intended to assist physician during the 
procedure to achieve improved leaflet grasping.  The MitraClip System has been implanted over 
 
subjects world-wide and shown safe and effective for the treatment of patients with significant mitral 
regurgitation (MR) through extensive published clinical evidence (see section 2.1). MitraClip G4 PMCF 
study aims to generate further clinical evidence to continue to support safety and performance of the 
MitraClip G4 System.  
 
This PMCF study will be conducted on commercial MitraClip G4 devices following the CE Mark approval 
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 G4 System by comparing the rate of acute procedural 
success after treatment with the MitraClip G4 to an expected rate based on historical MitraClip data.  
 
A minimum of 
 post-market, consecutive, consented, patients treated with the MitraClip G4 device in 
the EU will be included for analysis into the MitraClip G4 PMCF study.  Clinical follow-up visits will be 
requested at Discharge, 30 days, 1, 2, 3 4, 5 years post-procedure. An additional clinical follow-up phone 
call will be at 6 months.  Reported adverse events through 5 years 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 G4 System 
in a post-market setting. This study will be conducted in accordance with post market clinical follow-up 
requirements.  
 
2.0 
BACKGROUND AND RATIONALE 
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.   
 

   
 
  
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ACCESS-EU18 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 
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 registry19.  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 years20,21.  The largest prospective cohort was described by Puls 
 
18 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. 
19 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. 
20 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. 
21 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. 

   
 
  
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et al.22.  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 
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. 
 
In addition, Abbott has initiated a large scale observational study (
 patients) in US and EU (EXPAND) 
to evaluate the safety and performance of the MitraClip NTR/XTR system.  The 30 day study outcomes 
were recently reported in EuroPCR. The acute procedure success rate was 92.9% (962/1035) and 30 
day major adverse event rate was very low.  MR ≤ 2+ at 30 day was achieved at 90.1% in primary MR 
patients and 96.3% in secondary MR patients. This study also characterized the baseline mitral valve 
anatomic features (assessed by the echo core-lab) associated with NTR and XTR clip selection. It was 
identified that MitraClip XTR (compared to NTR) was more often used in Primary MR in subjects with 
larger gaps. For secondary MR patients, XTR was used when there was significant leaflet tethering, 
particularly in the P2/P3 locations. 
 
The totality of post-market clinical evidence supports the use of the MitraClip System for the treatment of 
MR.  The MitraClip G4 PMCF Study will assess the safety and performance of the next generation 
MitraClip G4 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 G4 System.  The primary analysis will be conducted using the endpoint of Acute Procedural 
 
22 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. 
 

   
 
  
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4.0 
STUDY 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 All-cause Death, Myocardial Infarction, 
Stroke, or non-elective CV surgery for device related complications 
• 
MR Severity (evaluated at discharge, 30 days, 1 year and 5 years) 
• 
Device Related Adverse Events (including mitral valve stenosis, device embolization, single 
leaflet device attachment (SLDA), 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 
• 
Quality of Life (QOL) assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
New York Heart Association (NYHA) functional class improvement 
• 
6 minute walk distance (6MWD) (per standard of care) 
4.3 
Success Criteria: 
The MitraClip G4 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 
.      
 
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 G4 
System. The study will include a minimum of 
 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 G4 PMCF Study if they are eligible per the 
inclusion/exclusion criteria.   

   
 
  
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5.2.2 
Informed Consent 
Patient Information and Consent Form must receive approval of Sponsor and Ethics Committee (EC) or 
Institutional Review Board (IRB) prior to beginning enrollment into the MitraClip G4 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 G4 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) EC/IRB approved informed consent prior to any data is reported into this 
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/IRB, subjects from vulnerable populations may be enrolled in the study.  The 
ISO14155 definition of vulnerable population is as follows: A 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 consented subjects treated commercially with the MitraClip G4 System will be considered.  
All subjects must meet the criteria below before being enrolled into the MitraClip G4 PMCF 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 
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 
Per ISO 14155, the patient is considered enrolled upon signing and dating an informed consent for 
participation.   
 

   
 
  
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another study) the site shall obtain consent from the patient.  The consent will permit information about 
the patient to be submitted to the study.  No data may be entered into the study unless the informed 
consent is completed. 
 
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, MR severity, 
KCCQ Score and New York Heart Association (NYHA) Functional Class.  If a 6-minute walk test is 
conducted as standard of care at baseline, these results will be collected in the G4 PMCF Study.   
 
6.1.2 
Pre-treatment Imaging 
Pre-Treatment Transthoracic Echocardiogram (TTE) and Transesophageal Echocardiogram (TEE) 
should be conducted per standard of care for a MitraClip Procedure.   
 
6.2 
Index Procedure 
All Investigators must read and understand the Instructions for Use (IFU) that accompanies the Device. 
Handling and preparation of the MitraClip G4 System should be in accordance with the IFU. The MitraClip 
procedure should be conducted in accordance with standard of care practice and approved labelling.   
 
6.3 
Post-procedure 
Post treatment TTE, Clinical Assessments and Laboratory / Clinical Tests should be conducted prior to 
discharge per standard of care.  Post-procedure information (the discharge time point) to be reported for 
this study include at minimum:  Medical Exam and Reporting of Vitals, adverse events, MR severity, 
KCCQ Score and NYHA Functional Class. 
 
6.4 
Subject Follow-up 
Follow-up is conducted per standard of care at 30 days and annually through 5 years 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. 
 
 
 
 
 
 
 
 

   
 
  
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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. DD information on the MitraClip accessories will also be collecting during G4 PMCF 
study. 
 
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 clinical investigation 
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 in section 7 per AE and SAE definitions. Adverse Events to be 
reported during this study include: all cardiovascular events, events classified as MAEs (as defined in 
section 4.2) and device-related complications (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 5 
year follow up visit. 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. 
 
A SAE Notification Form will be made available to allow the investigator to report required SAEs in the 
event the entry cannot be made in the Electronic Data Capture (EDC) System. 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 IRB/EC reporting 
requirements. 

   
 
  
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9.4.5 
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 
Planned Interim Analysis 
No formal interim analyses are planned for this study. Interim study reports with descriptive analysis may 
be produced for regulatory or reimbursement purposes. 
 
9.6 
Success Criteria 
The primary endpoint for the PMCF study must be met for the study to be considered successful. 
9.7 
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 as required 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 the study of the 
MitraClip G4 System. 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. 
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 of the 
Protocol amendment (administrative changes) or obtaining EC’s/IRB’s approval of the Protocol 
amendment (changes in subject care or safety), according to the instructions provided by the Sponsor 
with the Protocol amendment. 
 

   
 
  
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Acknowledgement/approval by the EC/IRB 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; 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. 
11.5 
Deviations from Protocol 
The Investigator will not deviate from this 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 

   
 
  
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Clinical Investigation Plan 
 
 
 
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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/IRB 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 
IRB/EC and clinical study monitor/Sponsor, adverse event reports, and information regarding subject 
discontinuation or completion of the clinical study. 
 

   
 
  
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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 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) or Institutional  Review Board (IRB) 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 IRB/EC, 
the Sponsor, and/or the regulatory agencies as needed.  
 
Until the clinical study is completed, the Investigator will advise his/her EC/IRB of the progress of this 
clinical study, per requirements.  
 
 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
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14.0 
RISK ANALYSIS 
14.1 
Anticipated Clinical Benefits 
Treatment with the MitraClip has been shown to effectively reduce Mitral Regurgitation in several clinical 
studies (Table 1 of this protocol).  Treatment with the MitraClip G4 System within this study is anticipated 
to offer this same established benefit.  The changes to the MitraClip G4 System were designed to have 
the same clinical impact with added ease in grasping of the mitral leaflets during the implant procedure.  
Design validation study indicates that users also responded favorably to the simplified Clip deployment 
procedure, stating that it is significantly better to the MitraClip NTR/XTR deployment procedure. Users 
rated leaflet grasping and capture with MitraClip G4 as better than leaflet grasping and capture with 
MitraClip NTR/XTR.  Data from this study may help to further identify benefits of the MitraClip G4 device 
in improving mitral leaflet grasping and improve clinical outcomes. 
 
14.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects 
Please refer to the approved Instruction for Use for possible adverse events of the MitraClip G4 
procedure.  
 
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 G4 device as part of this study is identical to treatment with the MitraClip 
G4 device outside of this study.  Participation in the study will not impact the MitraClip G4 procedure or 
use of the MitraClip G4 System in any way, therefore there is no added procedural risk by participating 
in this study.   
 
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 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 
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.  
 

   
 
  
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In the study, the device is required to be used in accordance with the MitraClip G4 System IFU.    
Contraindications, warnings and precautions will be provided with all devices to be used during this study 
per the IFU.  
 
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 
 patients in clinical trials or registries, and more than 
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 G4 implant 
within this study are identical to the risks of receiving a MitraClip G4 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 the enrollment of patients treated with the MitraClip G4 System into this 
study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

   
 
  
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ANNEX 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 Getting Reduction of Mitral Insufficiency by Percutaneous Clip 
Implantation (GRASP) Registry 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
IVC 
Inferior Vena Cava 
MAE 
Major Adverse Event 
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 
 
 
 

   
 
  
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ANNEX 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 and section 7.1 of this protocol.   
 
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 Disease23 
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 
 
23 JACC, Vol 32, No.5,November 1, 1998:pg1541, Table 21 

   
 
  
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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 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,  sler'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 
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. 

   
 
  
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MAJOR ADVERSE EVENT (MAE) 
MAE is a 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)24 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  
 Perioperative intracranial bleeding within 48 h 
 Reoperation after closure of sternotomy for the purpose of controlling bleeding 
 Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
 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; 
 
24 Mehrana R, Rao SV, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report 
from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. 

   
 
  
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• 
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 ≥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 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:  
• ECG changes indicative of new ischemia [new ST-T changes or new left bundle branch block (LBBB)] 
• New pathological Q waves in at least two contiguous leads 
• Imaging evidence of new loss of viable myocardium or new wall motion abnormality 
• 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 

   
 
  
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Page 71 of 99 
 
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, 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.  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. 
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, 

   
 
  
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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. 
 
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)25:  Rating will be: none, mild, 
moderate, or severe.   
 
25 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 
 

   
 
  
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Page 73 of 99 
 
 
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.   
 
 
Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 2017 
Apr;30(4):303-371. 

   
 
  
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ANNEX 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.   
 
 
 

   
 
  
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ANNEX IV - SUMMARY OF CHANGES  
 
 
Details of Change  
 
The sample size calculation is revised to incorporate contemporary clinical evidence in evaluation of the 
primary endpoint. Please see Section 9.3 for details.  
 
Follow up duration is revised to 5 years (product lifetime) as described in 6.4. 
 
 
 
  
 
END OF MitraClip G4 PMCF Study Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

   
 
  
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APPENDIX III - 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 
IRB 
Internal Review Board 
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 
 
 
 

   
 
  
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APPENDIX IV - 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 and section 7.1 of this protocol.   
 
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 Disease26 
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 
 
26 JACC, Vol 32, No.5,November 1, 1998:pg1541, Table 21 

   
 
  
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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 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,  sler'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 
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. 

   
 
  
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MAJOR ADVERSE EVENT (MAE) 
MAE is a 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)27 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  
 Perioperative intracranial bleeding within 48 h 
 Reoperation after closure of sternotomy for the purpose of controlling bleeding 
 Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
 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; 
 
27 Mehrana R, Rao SV, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report 
from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. 

   
 
  
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Page 80 of 99 
 
• 
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 ≥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 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:  
• ECG changes indicative of new ischemia [new ST-T changes or new left bundle branch block (LBBB)] 
• New pathological Q waves in at least two contiguous leads 
• Imaging evidence of new loss of viable myocardium or new wall motion abnormality 
• 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 

   
 
  
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Page 81 of 99 
 
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.  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. 
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, 

   
 
  
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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. 
 
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)28:  Rating will be: none, mild, 
moderate, or severe.   
 
 
28 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. 

   
 
  
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Study Name: MitraClip 
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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.   
 

   
 
  
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APPENDIX V - Case Report Forms 
 
Data will be collected on electronic case report forms (eCRFs).  The eCRFs will be made available before 
the study starts enrollment.   
 
 
 
 

   
 
  
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Appendix VI- LITERATURE REVIEW AND SUMMARY OF post-market TRIALS 
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 
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.29 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-EU30 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 
 
29 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. 
30 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. 

   
 
  
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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 
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 registry31.  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 
 
31 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. 

   
 
  
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Attizzani et al.32 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 
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. 
 
32 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. 

   
 
  
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Several reports on TRAMI have been published over the years33,34.  The largest prospective cohort was 
described by Puls et al.35.  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.   
 
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. 
 
 
33 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. 
34 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. 
35 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. 
 

   
 
  
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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 
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)36 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%. 
 
36 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. 

   
 
  
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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 
reduction in LVEF, LVEDD, LVESD, LA indexed volume and calculated pulmonary artery systolic 
pressure compared to baseline.  
 
In a separate analysis, Tay et al.37 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. 
 
37 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. 

   
 
  
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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.38 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 
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. 
 
38 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. 

   
 
  
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1-Year Outcomes (Nov 2013 – Sep 2015) 
In a subsequent report, Sorajja et al.39 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. 
 
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. 
 
 
39 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. 

   
 
  
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Clinical Investigation Plan 
 
 
 
Page 93 of 99 
 
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%. 
 
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 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
Page 94 of 99 
 
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.40 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. 
 
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 
 
40 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. 

   
 
  
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Study Name: MitraClip 
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Clinical Investigation Plan 
 
 
 
Page 95 of 99 
 
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.   
 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
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APPENDIX VII: MONITORING PLAN 
 
A copy of the Monitoring Plan can be obtained upon request from the Clinical Project Manager for the 
study. 
 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
Page 97 of 99 
 
 
APPENDIX VII:  CONTACT INFORMATION 
A list of site contacts can be obtained upon request from the Clinical Project Manager for the study. 
 
 
 

   
 
  
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Clinical Investigation Plan 
 
 
 
Page 98 of 99 
 
APPENDIX IX: FORESEEABLE ADVERSE EVENTS 
Please see device instructions for use regarding potential adverse events.