Trial to Evaluate Treatment With Abbott Transcatheter Clip Repair System in Patients With Moderate or Greater Tricuspid Regurgitation (TRILUMINATE)
Phase: NA
Conditions: Tricuspid Valve Insufficiency
Sponsor: Abbott Medical Devices

 
Clinical Investigation Plan Cover Page 
 
 
 
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NCT Number: NCT03227757 
TRILUMINATE 
Trial to Evaluate Treatment with Abbott Transcatheter Clip Repair System in Patients with Moderate or 
Greater Tricuspid Regurgitation (TRILUMINATE) 
Study Document No: Protocol 16-517 
Version 2.0 
Date: 01-FEB-2018 
 
 
Sponsor  
 
 
Abbott Structural Heart 
3200 Lakeside Drive 
Santa Clara, CA 95054 
 
 
Abbott  
The Corporate Village 
Da Vincilaan 11 Box F1 
1935 Zaventem, Belgium 
 
 

 
 
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PROTOCOL #16-517 
 
Trial to Evaluate Treatment with Abbott Transcatheter Clip Repair 
System in Patients with Moderate or Greater Tricuspid 
Regurgitation (TRILUMINATE) 
 
 
Protocol Number 
#16-517 
Version Number 
Version 2.0 
Date 
01 February 2018 
Primary Investigator:                
Prof. Dr. Georg Nickenig 
Med. Klinik und Poliklinik II 
Universitätsklinikum Bonn 
Planned Number of Sites and 
Region(s) 
Up to 25 Sites in Europe, Canada and United States of America  
Abbott Medical Expert 
Ihsen Merioua, MD 
Director, Medical Affairs Structural Heart 
Abbott Vascular Inc. 
Trial Type 
A prospective single arm multi-center trial in EU, Canada and 
US sites 
Sponsor/Data Monitoring 
 
Evalve, Inc. 
A subsidiary of Abbott Vascular Inc. 
3200 Lakeside Drive Santa Clara, CA 95054, USA 
 
Acting through its legal representative in the European Union 
Abbott Vascular International BVBA  
Park Lane  
Culliganlaan 2B 1831 Diegem Belgium 
Trial Monitor 
Evalve, Inc. 
A subsidiary of Abbott Vascular Inc. 
3200 Lakeside Drive Santa Clara, CA 95054, USA 
 
Acting through its legal representative in the European Union 
Abbott Vascular International BVBA  
Park Lane  
Culliganlaan 2B 1831 Diegem Belgium 

 
 
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Electronic Data Capture 
Software 
Medidata RAVE 
Eligibility Committee 
Interventional Cardiologist:  Georg Nickenig 
Interventional Cardiologist:  Paul Sorajja  
Interventional Cardiologist:  Jorg Hausleiter  
Interventional Cardiologist:  Phillip Lurz 
Interventional Cardiologist:  Saibal Kar 
Interventional Cardiologist:  Azeem Latib 
Heart Failure Specialist:     Jean-Noël Trochu  
Heart Failure Specialist:       Michael Böhm 
Cardiac Surgeon:  
Paolo Denti  
Cardiac Surgeon:  
Gilbert Tang  
Echocardiographer:  
Christoph Hammerstingl   
Echocardiographer:  
Michael Näbauer 
Echocardiographer:             Stephan von Bardeleben 
Echocardiographer:             Michaël Nabaüer 
Echocardiographer:  
Rebecca Hahn 
Clinical Events Committee 
Clinical Research Foundation (CRF) 
1700 Broadway, 9th Floor 
New York, NY 10019, USA 
Data Safety Monitoring Board 
AXIO Research 
2601 Fourth Avenue, Suite 200 
Seattle, WA 98121 
Study Steering Committee 
Chairman  
Georg Nickenig   
Co-chairman  
Ottavio Alfieri  
Interventional Cardiologist:   Alec Vahanian 
Heart Failure Specialist:     Michelle Hamilton 
Cardiac Surgeon:  
Francesco Maisano 
*Eligibility Committee members (see above) are also part of the 
Study Steering Committee. 
Echocardiography Scientific 
Committee 
Jose Zamorano  
Rebecca Hahn 
Elyse Foster 
Christoph Hammerstingl 
Protocol Author 
Mike Hsu, Ph.D. 
Principal Clinical Research Scientist 
Abbott Vascular Inc. 
 

 
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Table of Contents 
 
Compliance Statement: .......................................................................................................................... 7 
PROTOCOL SUMMARY ....................................................................................................................... 8 
1.0 
INTRODUCTION ...................................................................................................................... 15 
1.1 
Trial Objective ...................................................................................................................... 15 
1.2 
Trial Design .......................................................................................................................... 15 
2.0 
BACKGROUND INFORMATION .............................................................................................. 15 
2.1 
Background and Rationale ................................................................................................... 15 
2.1.1 
Tricuspid Regurgitation Description and Etiology .............................................................. 15 
2.1.2 
MitraClip Experience in Treatment of Mitral Regurgitation ................................................ 15 
2.1.3 MitraClip Experience in Tricuspid Regurgitation .................................................................. 18 
2.1.4   TVRS Trial Rationale ......................................................................................................... 22 
2.2 
Summary of Investigational Device ....................................................................................... 23 
2.2.1 
Name of the Investigational Device ................................................................................... 23 
2.2.2 
Intended Indication for Use ............................................................................................... 23 
2.2.3 
Description of the Investigational Device .......................................................................... 23 
2.2.4 
Summary of Preclinical Studies ........................................................................................ 24 
3.0 
CLINICAL TRIAL/INVESTIGATION FLOW AND FOLLOW-UP SCHEDULE ............................ 24 
3.1 
Number of Subjects to be Enrolled ....................................................................................... 27 
3.2 
Measures Taken to Avoid and Minimize Bias ....................................................................... 27 
3.2.1 
Subject Recruitment ......................................................................................................... 27 
3.2.2 
Site Heart Team ............................................................................................................... 27 
3.2.3 
Administration of Assessments ......................................................................................... 27 
3.2.4 
Review of Echocardiographic Images by the Independent Echocardiographic Core Lab .. 28 
3.2.5 
Independent Eligibility Committee ..................................................................................... 28 
3.2.6 
Safety and Effectiveness Monitoring ................................................................................. 28 
3.3 
Follow-Up Compliance ......................................................................................................... 28 
3.4 
Early Termination of the Clinical Trial ................................................................................... 29 
4.0 
ENDPOINTS ............................................................................................................................ 29 
4.1 
Primary Effectiveness Endpoint ............................................................................................ 29 
4.2 
Primary Safety Endpoint ....................................................................................................... 30 
4.3  Secondary Endpoints ................................................................................................................ 30 
4.3.1  Acute Secondary Endpoints ............................................................................................... 30 
4.3.2 Clinical Composite Endpoints .............................................................................................. 31 
4.3.3 Clinical Components Endpoints ........................................................................................... 31 
4.3.4 Patient Reported Endpoints ................................................................................................. 31 
4.3.5 Device or Procedure-Related Adverse Events ..................................................................... 31 
4.3.6 Echocardiographic Endpoints .............................................................................................. 32 
4.4 Exploratory Endpoints ................................................................................................................ 32 
5.0 
SUBJECT SELECTION AND WITHDRAWAL .......................................................................... 32 
5.1 
Subject Population ............................................................................................................... 32 
5.1.1 
General Inclusion Criteria ................................................................................................. 33 
5.1.2 
Echocardiographic Inclusion Criteria ................................................................................. 34 
5.1.3 
General Exclusion Criteria ................................................................................................ 34 
5.1.4 
Echocardiographic Exclusion Criteria: .............................................................................. 35 
5.2 
Subject Screening and Informed Consent ............................................................................ 35 
5.2.1 
Subject Screening ............................................................................................................ 35 
5.2.2 
Study Informed Consent ................................................................................................... 37 
5.2.3 Enrollment of Medicare Beneficiaries (US Cohort only) ....................................................... 37 

 
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5.3 
Subject Enrollment ............................................................................................................... 37 
5.4 
Subject Discontinuation ........................................................................................................ 38 
5.5 
Total Expected Duration of the Clinical Investigation ............................................................ 39 
5.6 
Expected Duration of Each Subject’s Participation ............................................................... 39 
5.7 
Number of Subjects Required to be Included in the Clinical Investigation ............................. 39 
5.8 
Estimated Time Needed to Enroll this Number (i.e., Enrollment Period) ............................... 39 
5.9 
Trial Completion ................................................................................................................... 39 
6.0 
TREATMENT AND EVALUATION of the TVRS ....................................................................... 40 
6.1 
Baseline Clinical Assessments ............................................................................................. 40 
6.2 
Pre-Procedure Anticoagulation/Antiplatelet and Antibiotic Therapy ...................................... 40 
6.2.1 
Anticoagulation/Antiplatelet Therapy ................................................................................. 40 
6.2.2 
Antibiotic Therapy ............................................................................................................. 41 
6.2.3 
Pre-procedure/Baseline Imaging ...................................................................................... 41 
6.2.4 
Pre-Procedural ECG and Physical Exam .......................................................................... 41 
6.2.5 
Baseline Activated Clotting Time ...................................................................................... 41 
6.3 
Index Procedure ................................................................................................................... 44 
6.3.1 
Procedure Involved in the Use of the Device .................................................................... 44 
6.3.2 
Subject Preparation .......................................................................................................... 44 
6.3.3 
Anticoagulation Therapy ................................................................................................... 44 
6.3.4 
Treatment Procedure ........................................................................................................ 44 
6.4 Post-Procedure .......................................................................................................................... 45 
6.4.1 
Post-procedure Imaging and Care .................................................................................... 45 
6.4.2 
Post-Procedure Medications ............................................................................................. 45 
6.4.2.1 Antibiotic Therapy ......................................................................................................... 45 
6.4.2.2 Antiplatelet/Anticoagulation Regimen ........................................................................... 46 
6.4.2.3 Management of Hypertension ....................................................................................... 46 
6.4.3 
Procedural and Discharge Data ........................................................................................ 46 
6.5 
Follow-up for All Subjects ..................................................................................................... 47 
6.6 
Additional Follow-up Visits .................................................................................................... 48 
6.7 
Additional Interventions for TR Reduction ............................................................................. 48 
6.8 
Heart-Related Office Visits ................................................................................................... 49 
6.9 
Tricuspid/Mitral Valve Surgery .............................................................................................. 49 
6.9.1 
30-Day Post-Tricuspid and/or Post-Mitral Valve Surgery Follow-up .................................. 49 
6.10 
Explanted TVRS Clip ............................................................................................................ 50 
7.0 
Adverse Events ........................................................................................................................ 50 
7.1 
Definitions ............................................................................................................................ 50 
7.1.1 
Adverse Event .................................................................................................................. 50 
7.1.2 
Serious Adverse Event ..................................................................................................... 50 
7.1.3 
Device Deficiency/Device Malfunction .............................................................................. 51 
7.2 
Device Relationship .............................................................................................................. 51 
7.2.1 
Unanticipated (Serious Adverse) Device Effect [U(S)ADE] ............................................... 51 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting ......................................... 51 
7.3.1 
Adverse Event Reporting .................................................................................................. 51 
7.3.2 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB ................... 52 
7.3.3 
Device Deficiency/Device Malfunction Reporting .............................................................. 52 
7.3.4 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .................... 53 
7.4 
Safety Monitoring by Data Safety Monitoring Board.............................................................. 53 
8 
ADJUDICATION OF EVENTS ...................................................................................................... 53 
8.1 
The Clinical Events Committee (CEC) .................................................................................. 53 
9. 
STATISTICAL ANALYSIS ............................................................................................................ 53 
9.1 
Statistical Overview .............................................................................................................. 53 

 
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9.2 
Analysis Populations ............................................................................................................ 54 
9.3  
Sample Size Calculations and Assumptions ......................................................................... 54 
9.3.1  
Primary Effectiveness Endpoint: ................................................................................... 54 
9.4 
Statistical Analyses............................................................................................................... 55 
9.4.1 
Primary Effectiveness Endpoint Analysis .......................................................................... 55 
9.4.2 
Primary Safety Endpoint Analysis ..................................................................................... 55 
9.4.3 
Secondary & Exploratory Endpoint Analyses .................................................................... 56 
9.4.4 
Handling of Multiplicity Issues ........................................................................................... 56 
9.4.5 
Labeling Claim .................................................................................................................. 56 
9.4.6 
Procedures for Accounting for Missing, Unused or Spurious Data .................................... 56 
9.5  
Deviations from the Original Statistical Plan ......................................................................... 56 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................................ 56 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................ 56 
11.1 
Selection of Clinical Sites and Investigators.......................................................................... 56 
11.2  
Protocol Amendments .......................................................................................................... 57 
11.3 
Training ................................................................................................................................ 57 
11.3.1 
Site Training ................................................................................................................. 57 
11.3.2 
Training Required for the Use of the Device ................................................................. 57 
11.3.3 
Training of Sponsor’s Monitors ..................................................................................... 57 
11.4 
Monitoring ............................................................................................................................ 57 
11.5 
Deviations from Protocol ...................................................................................................... 58 
11.6 
Quality Assurance Audit ....................................................................................................... 59 
11.7 
Sponsor Support to Clinical Trial/Investigation Site for Regulatory Body Inspection ............. 59 
11.8 
Committees .......................................................................................................................... 59 
11.8.1 
Study Steering Committee ............................................................................................ 59 
11.8.2 Data Safety Monitoring Board (DSMB) .............................................................................. 59 
11.8.3 
Clinical Events Committee (CEC) ................................................................................. 60 
11.8.4 
Eligibility Committee ..................................................................................................... 60 
12. 
DATA HANDLING AND RECORD KEEPING ........................................................................... 60 
12.1 
Source Documentation ......................................................................................................... 60 
12.2 
Electronic Case Report Form Completion ............................................................................. 61 
12.3 
Record Retention ................................................................................................................. 61 
12.4 
Investigational Devices ......................................................................................................... 61 
12.4.1 Investigational Device Accountability ................................................................................. 61 
13. 
ETHICAL CONSIDERATION ................................................................................................... 61 
13.1 
Institutional Review Board/Medical Ethics Committee Review .............................................. 61 
14. 
PUBLICATION POLICY ........................................................................................................... 62 
15. 
RISK ANALYSIS ...................................................................................................................... 62 
15.1 
Anticipated Clinical Benefits ................................................................................................. 62 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ................................. 63 
15.3 
Residual Risks Associated with the Investigational Device, as Identified in the Risk Analysis 
Report 63 
15.4 
Risks Associated with Participation in Clinical Investigation .................................................. 63 
15.5 
Possible Interactions with Protocol-Required Concomitant Medications ............................... 63 
15.6 
Steps that will be Taken to Control or Mitigate the Risks ...................................................... 63 
15.7 
Risk to Benefit Rationale ...................................................................................................... 64 
APPENDIX I: 
Abbreviations and Acronyms .................................................................................... 66 
APPENDIX II: 
Definitions ................................................................................................................. 68 
APPENDIX III: 
Contact Information ................................................................................................... 78 
APPENDIX IV: 
Rates of Foreseeable Adverse Events ...................................................................... 79 
APPENDIX V:  
Monitoring Exposure to Ionizing Radiation ................................................................ 82 

 
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APPENDIX VI: 
6 Minute Walk Test Guidelines – American Thoracic Society .................................... 84 
APPENDIX VII: 
Monitoring Plan ..................................................................................................... 92 
APPENDIX VIII:  
Echocardiography Acquisition Guideline ............................................................... 93 
APPENDIX IX: 
 Eligibility Committee Rules ....................................................................................... 95 
 
 

 
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COMPLIANCE STATEMENT:  
 
This trial will be conducted in accordance with this Protocol/Clinical Investigational Plan, the Declaration 
of Helsinki, applicable Good Clinical Practices and regulations (e.g., 21 CFR Part 50, 21 CFR Part 56, 
21 CFR Part 812, 21 CFR Part 54, 21 CFR Part 11, 45 CFR Part 46, and OUS ISO14155) and the 
appropriate local legislation(s). The most stringent requirements, guidelines or regulations must always 
be followed. The conduct of the trial will be approved by the appropriate Institutional Review Board 
(IRB)/Ethics Committee (EC) of the respective investigational site and by the applicable regulatory 
authorities. 
  

 
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PROTOCOL SUMMARY 
Trial Name and 
Number 
TRILUMINATE 
Trial Number #16-517 
Title 
Trial to Evaluate Treatment with Abbott Transcatheter Clip Repair 
System in Patients with Moderate or Greater Tricuspid 
Regurgitation (TRILUMINATE) 
Objectives 
To evaluate performance of the Tricuspid Valve Repair System 
(TVRS) in patients with symptomatic moderate or greater 
tricuspid regurgitation who are deemed appropriate for 
percutaneous transcatheter intervention by the site heart team.  
Intended Use 
The Tricuspid Valve Repair System (TVRS) is intended for 
reconstruction of the insufficient tricuspid valve through tissue 
approximation. 
Investigational or 
Trial Device 
Tricuspid Valve Repair System (TVRS) 
Targeted number 
of subjects to 
receive study 
device 
A minimum of 85 subjects will be enrolled and undergo the TVRS 
procedure in up to 25 sites with a maximum of 21 (25%) patients 
per site in this trial.   
 
Maximum of 18 subjects will be enrolled and undergo the TVRS 
procedure in up to 5 US sites. 
Clinical 
Trial/Investigation 
Design 
Prospective, Single Arm, Multi-Center Trial.  
 
Patients will be evaluated at baseline, discharge, 30 days, 6 
months, 1 year, 2 years, and 3 years 
Primary 
Effectiveness 
Endpoint 
Echocardiographic Tricuspid Regurgitation (TR) reduction at least 
1 grade at 30 days post-procedure, to be tested against a pre-
specified performance goal. 
Primary Safety 
Endpoint 
A composite of Major Adverse Event (MAE) at 6-months, to be 
tested against a pre-specified performance goal.  
 
Major Adverse Events (MAE) occurring after femoral vein puncture.  
MAE as listed below will be adjudicated by the Clinical Events 
Committee: 
• 
Cardiovascular Mortality,  
• 
Myocardial Infarction (MI),  
• 
Stroke,  
• 
New onset renal failure,  
• 
Endocarditis requiring surgery 
• 
Non-elective Cardio-Vascular (CV) surgery for TVRS 
device-related AE post-index procedure. 
Secondary 
Endpoints  
Acute Secondary Endpoints: 
• 
Acute Procedural Success (APS):  Successful 
implantation of the TVRS Clip with resulting at least 1 
grade reduction in TR severity as determined by the 

 
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Echocardiography Core Laboratory (ECL) assessment of 
a discharge echocardiogram (30-day echocardiogram will 
be used if discharge echocardiogram is unavailable or 
uninterpretable). Subjects who die or undergo tricuspid 
valve surgery before discharge are an APS failure. 
• 
Acute Device Success:  Successful access, delivery of the 
Clip and removal of device delivery system.  Successful 
delivery of the Clip is the deployment of the device as 
planned, with no additional unplanned surgery or re-
intervention related to the device or access procedure. 
• 
Implant Success Rate: Successful delivery and 
deployment of the Clip(s) with achievement of leaflet 
approximation(s) and retrieval of the delivery catheter 
• 
Total Procedure Time: defined as the time elapsed from 
the first of any of the following: intravascular catheter 
placement or trans-esophageal echocardiogram (TEE), to 
the removal of the last catheter and TEE 
• 
Device Time: defined as the time the Steerable Guide 
Catheter is placed in the right atrium until the time the 
TVRS Delivery System is retracted into the Steerable 
Guide Catheter 
• 
Fluoroscopy Duration: defined as the duration of exposure 
to fluoroscopy during the TVRS procedure 
• 
Length of hospital stay for the index TVRS procedure 
• 
Location to which subject was discharged (home, home 
health or another facility) 
o If subject discharged to another facility, length of 
stay at facility to which subject was discharged 
 
Clinical Composite Endpoints: 
• 
MAE at discharge, 30 days,1 year, 2 years and 3 years 
 
Clinical Component Endpoints: 
Clinical Endpoints at 30 days, 6 months, 1 year, 2 years and 3 
years: 
• 
Components of MAE 
• 
All-cause mortality  
• 
NYHA Functional Class  
• 
Tricuspid valve surgery (including type of surgery) 
• 
New use of any cardiac rhythm management devices 
(Pacemakers, Implantable Cardioverter-Defibrillator (ICD), 
and Cardiac Resynchronization Therapy (CRT)), including 
reason for intervention 
• 
Additional TVRS intervention and reason for intervention 
 
 
 

 
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Additional Clinical Endpoints: 
• 
Major bleeding at 30 days 
• 
Pulmonary Thromboembolism at 30 days 
• 
New Onset Renal Failure at 30 days and 6 months 
• 
New Onset Liver Failure at 30 days and 6 months 
• 
New onset atrial fibrillation at 30 days, 6 months and 1 
year. 
• 
Change in diuretic(s) used at 30 days, 6 months, and 1 
year (as compared to baseline) 
 
Patient-reported Quality of Life (QoL) and Health Economics and 
Outcomes Research (HEOR) Endpoints: at Baseline, 30 days, 6 
months, 1 year, 2 years and 3 years*: 
• 
Distance walked in the 6-Minute Walk Test (6MWT 
distance or 6MWD)  
• 
KCCQ QoL scores  
• 
SF-36 QoL scores  
• 
Number and duration of re-hospitalizations and reason for 
re-hospitalization (i.e., heart failure, cardiovascular, non-
cardiovascular) 
*Actual rates/scores and the relative change from baseline to 
each follow-up time point. 
 
Prevalence of Device or Procedure-Related Adverse Events: 
Device or procedure-related adverse events will be broken down 
into those that occur within 30 days of the procedure and those that 
occur after 30 days of the procedure.  Examples of procedure or 
device-related adverse events are: 
• 
Myocardial perforation 
• 
Damage to tricuspid valve apparatus 
• 
Access Site bleeding requiring surgery 
• 
Non-vascular bleeding 
 
Echocardiographic Endpoints 
Echocardiographic endpoints will be assessed by the 
Echocardiography Core Laboratory (ECL) and reported at 
baseline, discharge, 30 day, 6 months, 1 year, 2 year, and 3 year 
post-implantation (unless indicated).   

 
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• 
TR Severity Grade  
• 
Effective Regurgitant Orifice Area (EROA) 
• 
Regurgitant Volume 
• 
Regurgitation Jet Area 
• 
Vena Contracta Width 
• 
Proximal Isovelocity Surface Area (PISA) Radius 
• 
Inferior Caval Vein Diameter  
• 
Tricuspid Annular Diameters (Antero-Posterior (A-P) and 
Septal-Lateral (S-P)) 
• 
Tricuspid Annular area 
• 
Tricuspid Valve Area 
• 
Tenting Area (At baseline only) 
• 
Tenting Distance (At baseline only) 
• 
Tricuspid Leaflet Tethering Distance (At baseline only) 
• 
Right Ventricular End Diastolic Dimension (RVEDD) 
• 
Right Ventricular End Systolic Dimension (RVESD) 
• 
Right Ventricular Fractional Area Change 
• 
Right Ventricular Systolic Pressure (RVSP)  
• 
Right Atrial Volume 
• 
Tricuspid Annular Plane Systolic Excursion (TAPSE) 
• 
Right Ventricular Free Wall Strain 
• 
Mean Tricuspid Valve Gradient 
• 
Cardiac Output 
• 
Forward Stroke Volume (Left Ventricle) 
• 
Left Ventricular Ejection Fraction (LVEF)  
• 
Single Leaflet Device Attachment 
• 
Embolization of the TVRS Clip or TVRS System 
components  
• 
Tricuspid Valve Stenosis 
 
Exploratory 
Endpoints 
 
Hemodynamics through Right Heart Catheterization:   
Right heart catheter measurements at: 
• 
Immediately before TVRS procedure: Measurements to 
include: right atrial a-wave/v-wave, right atrial and 
ventricular pressures, pulmonary resistance, Pulmonary 
Artery (PA) pressures and cardiac output),   
• 
Post-procedure Right Atrial Catheterization, immediately 
after TVRS procedure (right-atrial a-wave/v-wave, right 
atrial pressure) 
Subject Follow-up 
Subjects will have scheduled office visit evaluations at the 
following time points (Schedule details in Table 2): 

 
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• 
Baseline 
• 
Discharge  
• 
30 days 
• 
6 months 
• 
1 year 
• 
2 years 
• 
3 years 
Key Inclusion 
Criteria 
General Inclusion Criteria: 
1. Age ≥18 years and ≤90 years at time of consent and must 
not be a member of a vulnerable population. 
2. Subject or a legally authorized representative (where 
allowed per local regulations; refer to Section 5.1.1) must 
provide written informed consent prior to any trial related 
procedure 
3. Subject must agree not to participate in any other clinical 
trial for a period of one year following the index procedure 
4. In the judgment of the investigator at the site, subject has 
been adequately treated per applicable standards 
(including medical management), including treatment for 
coronary artery disease, mitral regurgitation and heart 
failure (e.g., with cardiac resynchronization therapy, 
revascularization, and/or optimal medical therapy as 
appropriate; see APPENDIX II: Definitions for definition of 
optimal therapy) at least 30-days prior to index procedure. 
The Eligibility Committee must concur that the subject has 
been adequately treated. 
5. New York Heart Association (NYHA) Functional Class II 
(conditional), III, or ambulatory IV 
a. Subjects with moderate TR:  Only NYHA Class III 
or IV may be considered for inclusion 
b. Subjects with severe or greater TR: NYHA II, III, or 
IV may be considered for inclusion 
6. No indication for left-sided or pulmonary valve correction 
(Left sided heart valve disease or pulmonary stenosis 
needs to be adequately treated for at least 30-days prior to 
study enrollment for TR treatment) 
7. The Site Heart Team (a minimum of one interventionalist, 
one cardiac surgeon and one echocardiographer) concur 
the benefit-risk analysis supports intervention for tricuspid 
regurgitation per current guidelines for the management of 
valvular heart disease (refer to Section 5.1.1) and that the 
subject is at high risk for tricuspid valve surgery . 
8. In the judgment of the TVRS implanting Investigator, 
femoral vein access is determined to be feasible and can 
accommodate a 25 Fr catheter.  
 
 
 

 
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Echocardiographic Inclusion Criteria: 
9. Moderate or greater (≥2+) Tricuspid Regurgitation 
determined by the assessment of a qualifying transthoracic 
echocardiogram 
(TTE) 
and 
transesophageal 
echocardiogram (TEE) confirmed by the Echocardiography 
Core Lab (ECL) (refer to Appendix VIII).  Subjects with 
moderate TR will only be included in the trial if moderate TR 
is accompanied by a tricuspid annular diameter of ≥40mm 
as measured by the site heart team echocardiographer.  
Note: Additional NYHA criteria for moderate TR patients 
(see Inclusion Criteria #5).  Additional note: If any cardiac 
procedure(s) that may occur within 90-days of procedure, 
then TTE and TEE must be repeated prior to the index 
procedure. 
10. Tricuspid valve anatomy determined to be suitable for 
implantation (e.g., no severe leaflet defects preventing 
proper placement of the TVRS, Ebstein Anomaly) 
determined by the site heart team 
11. Tricuspid valve anatomy evaluable by TTE and TEE 
 
Key Exclusion 
Criteria 
General Exclusion Criteria: 
1. Subject is currently participating in another clinical trial that 
has not yet completed its primary endpoint. 
2. Pregnant or nursing subjects and those who plan 
pregnancy in the period up to 1 year following index 
procedure. Female subjects of child-bearing potential must 
have a negative pregnancy test done within 7 days prior to 
the index procedure per site standard test. 
3. Severe uncontrolled hypertension Systolic Blood Pressure 
(SBP) ≥ 180 mmHg and/or Diastolic Blood Pressure (DBP) 
≥ 110 mm Hg) 
4. Systolic Pulmonary Artery Pressure >60mmHg (echo 
determined) 
5. Prior tricuspid valve leaflet surgery or any currently 
implanted prosthetic tricuspid valve, or any prior 
transcatheter tricuspid valve procedure.  
6. Mitral Regurgitation moderate-severe or greater severity 
(≥3+)  
7. Pacemaker or ICD leads that would prevent appropriate 
placement of the TVRS Clip 
8. Active endocarditis or active rheumatic heart disease or 
leaflets 
degenerated 
from 
rheumatic 
disease 
(i.e. 
noncompliant, perforated). 
9. MI or known unstable angina within prior 30 days to 
enrollment 
10. Percutaneous coronary intervention within prior 30 days to 
enrollment 
11. Hemodynamic instability defined as systolic pressure < 90 
mmHg with or without afterload reduction, cardiogenic 

 
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shock or the need for inotropic support or intra-aortic 
balloon pump or other hemodynamic support device. 
12. Cerebrovascular Accident (CVA) within prior 3 months to 
enrollment 
13. Chronic dialysis 
14. Bleeding disorders or hypercoagulable state 
15. Active peptic ulcer or active gastrointestinal (GI) bleeding 
16. Contraindication, allergy or hypersensitivity to dual 
antiplatelet 
and 
anticoagulant 
therapy 
Note: 
Contraindication to either antiplatelet or anticoagulant 
therapy (individually not both therapies) is not an exclusion 
criterion. 
17. Active infections requiring current antibiotic therapy (if 
temporary illness, patients may enroll 4 weeks after 
discontinuation of antibiotics with no active infection). 
18. Known allergy or hypersensitivity to device materials 
19. In the judgment of the investigator, a condition that could 
limit a patient’s ability or unwillingness to participate in the 
study, comply with study required testing and/or follow-up 
visits or that could impact scientific integrity of the study 
20. Evidence of intracardiac, inferior vena cava (IVC), or 
femoral venous mass, thrombus or vegetation. 
21. Life expectancy of less than 12 months due to non-cardiac 
conditions 
 
Echocardiographic Exclusion Criteria: 
      22. Tricuspid valve stenosis 
23. Left Ventricular Ejection Fraction (LVEF) ≤20% 
24. Tricuspid valve leaflet anatomy which may preclude clip 
implantation, proper clip positioning on the leaflets or 
sufficient reduction in TR.  This may include: 
a. Evidence of calcification in the grasping area  
b. Presence of a severe coaptation defect (> 2cm) of 
the tricuspid leaflets 
Analysis 
Population 
The primary analysis population is defined as subjects who signed 
and dated Informed Consent Form and have an attempted TVRS 
procedure, upon femoral vein puncture. 
 
 
 

 
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1.0 
INTRODUCTION 
 
1.1 Trial Objective 
 
To evaluate safety and effectiveness of the Tricuspid Valve Repair System (TVRS) in patients with 
symptomatic moderate or greater tricuspid regurgitation (TR) who are deemed appropriate for 
percutaneous transcatheter intervention by the site heart team.  
 
1.2 Trial Design 
 
The TRILUMINATE Trial is a prospective, single arm, multi-center study of the TVRS for treating 
symptomatic moderate or greater TR in patients currently on medical management and who are 
deemed high risk for tricuspid valve surgery and appropriate for percutaneous transcatheter 
intervention.   
 
A minimum of 85 subjects will be prospectively enrolled and undergo the TVRS procedure in up to 25 
sites in Europe, Canada and the United States: 
• 
A clinical report will be included as part of the submission for CE Mark and other regulatory 
submissions, as appropriate. 
• 
Each site is capped at 21 (25%) analysis subjects. 
 
All subjects will have scheduled office visit evaluations at baseline, discharge, 30 days, 6 months, 1 
year, 2 years, and 3 years.   
 
2.0 
BACKGROUND INFORMATION 
 
2.1 
Background and Rationale 
 
2.1.1 Tricuspid Regurgitation Description and Etiology 
 
Similar to the etiologies of mitral regurgitation, tricuspid regurgitation (TR) results from either 
degenerative disease of the leaflets (primary or degenerative TR) or from pathologic dilation of the right 
ventricle (secondary or functional TR).  Both result in mal-coaptation of the leaflets, which allows blood 
flow back into the right atrium during systole.  Lead-induced TR (not observed in MR) is caused by either 
pacemaker or implantable cardioverter-defibrillator (ICD) lead impairment of the tricuspid valve 
preventing proper coaptation.  TR has long been an overlooked condition and not clinically understood.  
By the time TR manifests in the form of clinical symptoms, the patient is usually much sicker. 
 
Current treatment guidelines for TR indicate medical therapy to address venous congestion (e.g., 
diuretics) and/or treatment of the underlying disease to reduce TR (e.g., surgery).  Percutaneous 
treatments are currently not commercially available for treatment of TR.  
2.1.2 MitraClip Experience in Treatment of Mitral Regurgitation 
 
Extensive clinical evidence has shown the safety and efficacy of the MitraClip System in various 
worldwide trials involving over 3,500 patients to date.  This collective data supports clinical safety of this 
device, effectiveness in mitral regurgitation (MR) reduction and improvements in echocardiographic 
measures of left ventricular (LV) function, and obvious improvement in patient Quality of Life (QoL).  The 
MitraClip received CE Mark in 2008 and FDA Approval in 2013 for percutaneous treatment of mitral 

 
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regurgitation.  Success achieved with this approach and physician interest in using the clip for reducing 
TR forms the rationale for the TRILUMINATE Trial.   
 
The first human procedure using the predicate MitraClip System was performed on June 27, 2003 in 
Caracas, Venezuela. Only one procedure was performed in Venezuela. 
 
Since then, in the United States, the MitraClip System has been studied under an Investigational Device 
Exemption (IDE G030064). The IDE consisted of the following cohorts: 
 
1) Phase I Feasibility Study (EVEREST I) 
2) Phase II Safety / Effectiveness Study (EVEREST II) 
a) EVEREST II Roll-In 
b) EVEREST II Randomized Controlled Arm 
c) EVEREST II High Risk Registry Arm 
3) Phase II Continued Access Study (REALISM) 
a) Emergency Use/Compassionate Use cases   
b) Non High Risk 
c) High Risk 
 
 
EVEREST I was initiated on July 2, 2003 and concluded on February 15, 2006. A total of 55 patients 
were enrolled and treated in EVEREST I.  The EVEREST I Feasibility trial was the first prospective, multi-
center, non-randomized trial to evaluate the preliminary safety and effectiveness of the percutaneous 
MitraClip System in patients with moderate-to-severe (3+) or severe (4+) MR in surgical candidates.  
Percutaneously-treated patients were followed at discharge, 30 days, 6, 12, 18 and 24 months and 
annually thereafter through 5 years. An independent Echocardiography Core Laboratory (ECL) assessed 
MR severity and other echocardiographic parameters at baseline and follow-up. The last patient has 
completed 5-year follow-up and the study is now closed. 
 
The MitraClip device was implanted in 89% (49/55) of patients and the trial met its pre-specified safety 
acceptance criterion, demonstrating mechanistic feasibility of implant and safety of the MitraClip System 
and procedure. There were no intra-procedural deaths.  A majority of patients (70.9%) experienced 
reduction in MR severity to 2+ or less at discharge.  No MitraClip device embolizations occurred in this 
cohort.  Ten percent (10%) of the initial cohort had single leaflet device attachment (SLDA).  A majority 
of SLDAs were detected early (within 30 days post-MitraClip procedure). Patients demonstrated 
improvement in NYHA Functional Class and left ventricular measurements that were sustained through 
5 years. At 5 years, freedom from death was 86.4% and freedom from mitral valve surgery was 55.1%. 
The results of the EVEREST I trial at 5 years provide evidence of the safety and long-term durability of 
the MitraClip device in the early cohort of patients treated in the United States. 
 
The EVEREST II RCT was a prospective, multi-center, randomized controlled trial where patients with 
moderate-to-severe (3+) or severe (4+) MR were randomized in a 2:1 ratio between the Device group 
(MitraClip device) and the Control group (mitral valve surgery). Patient follow-up occurs at discharge, 30 
days, 6, 12, 18 and 24 months and yearly thereafter through 5 years. An independent Echocardiography 
Core Laboratory (ECL) assessed MR severity and other echocardiographic parameters at baseline and 
follow-up. The trial was intended to demonstrate superiority of safety balanced against reduced 
effectiveness of the MitraClip device when compared to mitral valve surgery. All patients have completed 
5 years of follow-up and the study is now closed. 
 
The trial enrolled 279 patients, 184 in the Device group and 95 in the Control group. Of these, 178 patients 
in the Device group underwent the MitraClip procedure and 80 patients in the Control group underwent 

 
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mitral valve surgery. The trial met both primary safety and effectiveness endpoints. There were no intra-
procedural deaths.  Among patients who underwent the MitraClip procedure in the Device group 
(MitraClip patients), a device was implanted in 89% of patients. The procedure time averaged 
approximately 3 hours, patients were hemodynamically stable during the procedure, and the average 
length of hospital stay was less than 3 days. In comparison, the average length of hospital stay for 
patients undergoing surgery in the Control group (surgery patients) was 7.5 days. A large majority 
(94.9%) of MitraClip patients were discharged home without home healthcare. In comparison, only 71.3% 
of surgery patients were discharged home without home healthcare. A majority of MitraClip device 
patients (77%) experienced reduction in MR severity to 2+ or less at discharge, while 100% of patients 
undergoing mitral valve surgery in the Control group experienced reduction in MR severity to 2+ or less. 
 
Patients who underwent the MitraClip procedure experienced a 30-day major adverse event rate 
(composite of death, myocardial infarction (MI), re-operation for failed surgical repair or replacement, 
non-elective cardiovascular surgery for adverse events, stroke, renal failure, deep wound infection, 
ventilation for greater than 48 hours, gastro-intestinal (GI) complication requiring surgery, new onset of 
permanent atrial fibrillation, septicemia and major bleeding complication) of 7.9% versus 50% in patients 
who underwent mitral valve surgery in the Control group. Excluding the most common event of major 
bleeding complication, MitraClip device patients still experienced a lower major adverse event rate (4.5%) 
than surgery patients (11.3%). 
 
Through 30 days, MitraClip patients experienced a lower site-reported adverse event rate than surgery 
patients in the following categories: cardiac rhythm disorders (atrial arrhythmias, bradyarrhythmia, 
ventricular arrhythmia), congestive heart failure, peripheral edema, anemia, infections, neurologic events 
and respiratory events.  At 30 days, MitraClip patients experienced a higher event rate than surgery 
patients in the following categories: atrial septal defect, myocardial ischemia, residual or recurrent MR, 
single leaflet device attachment (SLDA), gastrointestinal bleed, and vascular complications such as 
hematoma, bleed or bruising.  
 
Significant and meaningful clinical benefits were observed in both MitraClip and surgery patients, which 
were sustained through 5 years: 
• 
MR reduction to 2+ or less at 5 years was in 82.1% of MitraClip patients and 97.6% of surgery 
patients 
• 
Reduction in left ventricular end diastolic volume and dimension was observed in both MitraClip 
and surgery patients, which was sustained through 5 years 
• 
Improvement in NYHA Functional Class was demonstrated in both groups, with 91.5% of 
MitraClip patients and 97.6% of surgery patients free from NYHA Functional Class III or IV 
symptoms at 5 years 
 
The results of the RCT demonstrate the continued safety, durability of effectiveness and clinical benefit 
of the MitraClip device through 5 years. These results are consistent with the expectation of superior 
safety and reduced effectiveness of the MitraClip device when compared to mitral valve surgery. These 
results support an overall favorable risk to benefit profile of the MitraClip device through 5 years. 
 
Overall, the MitraClip clinical trials have shown consistently excellent safety and efficacy profile. 
Reduction of MR severity has shown improvements in symptoms, improved QoL measurements, and 
functional improvements in patients who had significant MR.  
 
 
 

 
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2.1.3 MitraClip Experience in Tricuspid Regurgitation 
 
As of March 2017, there have been at least 13 published manuscripts representing 95 patients who 
received off-label/compassionate use of the MitraClip device in the tricuspid valve (Table 1). All patients 
were described to have high grade, moderate to severe, or severe tricuspid regurgitation with 
symptomatic heart failure (NYHA III or IV).  All patients had at least 1 co-morbidity reported; 94 of the 
patients were also deemed to be high risk for surgical intervention by a heart team (1 patient refused 
surgery).   
 
Depending on the severity of the coaptation gap, 1 to 3 clips have been used per case.  All patients 
received at least 1 MitraClip device resulting in reduction in TR grade which persisted from post-
procedure up to 6 months post-implant.   Some reports have indicated that reduction in 
echocardiographic measurements of vena contracta area and width, EROA, annular diameter, and TR 
volume, with unchanged left heart function and volumes.  There were no reports of adverse events or 
device-related complications in any of the reported cases to date. 
 

 
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Two key publications, Hausleiter (n=18) and Nickenig (n=64) have reported outcomes on a larger cohort 
of patients.  Hausleiter et al1 reported an 18-patient cohort who received the MitraClip device for either 
only the tricuspid valve (isolated TR; n=6) or both mitral and tricuspid valve (combined MR and TR; n=12).  
At baseline, all patients had either NYHA functional class III or IV symptoms, with 17 of the patients 
having renal impairment.  Baseline mean LVEF was 43% and RVEF was 38%.  An average of 2.3 clips 
were used per patient for the treatment of TR.  At 30-day post-implant, all subjects had at least 1 grade 
TR improvement and ~70% subjects had NYHA I/II. There was 1 stroke event, 1 repeat intervention, and 
no reported mortality at 30-day follow-up for this cohort of subjects.  Thirty-day mean LVEF and RVEF 
was 46% and 30%, respectively. 
 
Nickenig et al2 has reported the largest multi-centered cohort data to date.  He reported a 64-patient 
cohort across 10 international centers.  All patients had symptomatic moderate to massive TR on optimal 
medical treatment and were considered unsuitable for surgery.  The MitraClip device was used for either 
only the tricuspid valve (isolated TR; n=42) or both mitral and tricuspid valve (combined MR and TR; 
n=22) treatment.  At baseline, 93% of patients were NYHA III/IV, 82% had LVEF <50%, and 95% 
experienced dyspnea.  Ninety-seven percent (97%) of the patients had 1 or more clip deployed at the 
tricuspid valve.  At post-procedure, 91% of the patients had at least 1 grade reduction in TR.  No 
intraprocedural death, cardiac tamponade, emergency surgery, stroke, myocardial infarction or major 
vascular complications occurred. There were 3 (5%) in-hospital deaths. 
 
Overall, the cases presented to date have shown either reduction in TR severity or other 
echocardiographic parameter(s) (i.e. vena contracta width, vena contracta area, etc.), improvement in 
symptoms, and/or improvement in quality of life measurements.  Additionally, based on the minimal 
number of adverse events (total n=2 events) and few deaths reported in the abovementioned reports, 
the procedure appears to be safe. 
 
Table 1: Summary of Literature Using MitraClip in TR  
 
 
 
1 Jörg Hausleiter, Daniel Braun, Mathias Orban, Julinda Mehilli, Steffen Massberg, Michael Näbauer.  Transcatheter 
treatment of severe tricuspid regurgitation using the MitraClip system.  Presentation at TCT 2016 Conference.  
October 31, 2016. 
3 Kowalski M, Franz N, Ritter F, Hofmann S, Stabel-Mahassine C, Warnecke H, Thale J. Simultaneous 
transfemoral transcatheter mitral and tricuspid valve edge-to-edge repair (using MitraClip system) completed by 
atrial septal defect occlusion in a surgically inoperable patient. First-in-human report. Kardiochir Torakochirurgia 
Pol. 2015 Dec;12(4):295-7. 
4 Kowalski M, Franz N, Hofmann S, Ritter F, Thale J, Warnecke H. Transapical transcatheter aortic valve 
implantation followed by transfemoral transcatheter edge-to-edge repair of the tricuspid valve using the MitraClip 
 
First Author 
Case Background 
Procedure Info 
Result 
Kowalski3 
84yo Female, Severe TR, 
Severe MR, NYHA III, 
edema, bilateral pleural 
effusions, and Stage III 
Chronic Kidney Disease 
(CKD) 
Treated both MR (2nd 
clip to prior 
treatment) and TR (1 
clip) 
Tricuspid regurgitation (vena 
contracta area at baseline 1.03 
cm², after procedure 0.66 cm²) 
Kowalski4 
81yo Male, Severe TR, 
aortic stenosis, mild MR, 
NYHA III, edema, ascites, 
Transapical TAVI, 
then 1 clip 
vena contracta 1.22 to 0.48 cm², 
vena contracta width 10 to 5 mm 
post-procedure; 

 
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system - a new treatment concept for an inoperable patient with significant aortic stenosis and  severe tricuspid 
valve regurgitation. Postepy Kardiol Interwencyjnej. 2016;12(3):262-6. 
4 Kowalski M, Franz N, Hofmann S, Ritter F, Thale J, Warnecke H. Transapical transcatheter aortic valve 
implantation followed by transfemoral transcatheter edge-to-edge repair of the tricuspid valve using the MitraClip 
system - a new treatment concept for an inoperable patient with significant aortic stenosis and  severe tricuspid 
valve regurgitation. Postepy Kardiol Interwencyjnej. 2016;12(3):262-6. 
5 Hammerstingl C, Schueler R, Malasa M, Werner N, Nickenig G. Transcatheter treatment of severe tricuspid 
regurgitation with the MitraClip system. Eur Heart  J. 2016 Mar 7;37(10):849-53. 
6 Schofer J, Tiburtius C, Hammerstingl C, Dickhaut PO, Witt J, Hansen L, Riess FC, Bijuklic K. Transfemoral 
Tricuspid Valve Repair Using a Percutaneous Mitral Valve Repair System. J Am Coll Cardiol. 2016 Feb 
23;67(7):889-90. 
7 van Melle JP, Schurer R, Willemsen M, Hoendermis ES, van den Heuvel AF. Percutaneous tricuspid valve 
repair using MitraClip® for the treatment of severe  tricuspid valve regurgitation in a patient with congenitally 
corrected transposition of the great arteries. Neth Heart J. 2016 Nov;24(11):696-697. 
8 Franzen O, von Samson P, Dodge-Khatami A, Geffert G, Baldus S. Percutaneous edge-to-edge repair of 
tricuspid regurgitation in congenitally corrected transposition of the great arteries. Congenit Heart Dis. 2011 Jan-
Feb;6(1):57-9. 
9 Lesevic H, Frangieh AH, Kasel AM, Ott I. Successful percutaneous edge-to-edge  repair in degenerative 
tricuspid valve regurgitation using the MitraClip system.  Eur Heart J. 2016 Oct 2. pii: ehw410. 
pleural effusions, and Stage 
III CKD.  LVEF 35%.  RVEF 
35%.  Heart team 
determined inoperable. 
transfemoral TR 8 
days later 
Mean gradient 1mmHg; 
NYHA II-III @ 6mo; 
LVEF @ 38% and RVEF @ 43% 
@ 6mo 
Hammerstin
gl5 
3 consecutive cases (79 to 
89 yo), TR grade 3-4 to 4, 
NYHA III-IV, EuroScore 
23.8% to 26.2% 
Treated TR (1 to 3 
clips) 
Echocardiography showed acute 
reduction of TR in all patients (∆-
EROA, 0.4+0.4 cm2), which was 
confirmed with TTE before 
discharge. Along with other TR 
defining measures, internal vena 
cava (IVC) width (∆-IVC width, 
3.5+2.1 mm) and TV annular 
diameters (∆-TV annular diameters, 
14.3+8.9 mm) were reduced. 
Measures on left heart function and 
volumes remained unchanged.   
Schofer6 
77yo female, Severe TR, 
NYHA III, Severe COPD, 
and A-fib. 
Treated TR (1 Clip) 
Mild TR @ post-procedure 
 
van Melle7 
56yo female with ccTGA 
and dextrocardia, moderate 
to severe TR, recurrent 
heart failure. 
Treated TR (1 Clip) 
TR mild @ 6 mo. 
Reduction in HF symptoms 
Franzen8 
62yo female, ‘high grade’ 
TR, NYHA III, recurrent left 
sided heart failure, and 
patient refuse surgery 
Treated TR (1 clip) 
Residual TR @ post-procedure; 
Minimal TR @ 3mo. 
NYHA I @ 3 mo 
Lesevic9 
84yo female, Severe DTR, 
too fragile for surgery. 
Treated TR (1 clip) 
Reduced to grade ‘1’ at post-
procedure 

 
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10 Hauslieter J, Braun D, Orban M, Mehilli J, Massberg S, Nabauer M. TCT 87: Transcatheter Treatment of Severe 
Tricuspid Regurgitation Using the MitraClip® System: 30-day Clinical Results in 13 Consecutive Patients.  TCT 
2016 Conference.  October 31, 2016 Presentation. 
11 Braun D, Nabauer M, Orban M, Orban M, Gross L, Englmaier A, Rösler D, Mehilli J, Bauer A, Hagl C, Massberg 
S, Hausleiter J. Transcatheter treatment of severe tricuspid regurgitation using the edge-to-edge repair technique. 
EuroIntervention. 2017 Feb 3;12(15):e1837-e1844. 
12 Picard F, Tadros VX, Millan X, Asgar A.  CASE 2: Tricuspid Clipping: MitraClip Device for a Congentially 
Corrected Transposition of Great Arteries on a Systemic Tricuspid Valve.  TCT 2015 Conference.  October 11, 
2015 Presentation. 
13 Tang GH, Kaple R, Cohen M, Dutta T, Undemir C, Ahmad H, Poniros A, Bennett J, Feng C, Lansman S. First 
percutaneous Micra leadless pacemaker implantation and tricuspid valve repair with MitraClip NT for lead-
associated severe tricuspid regurgitation. EuroIntervention. 2017 Feb 3;12(15):e1845-e1848. 
14 Nickenig G, Kowalski M, Hausleiter J, Braun D, Schofer J, Yzeiraj E, Rudolph V, Friedrichs K, Maisano F, 
Taramasso M, Fam NP, Bianchi G, Bedogni F, Denti P, Alfieri O, Latib A, Colombo A, Hammerstingl C, Schueler 
R. Transcatheter Treatment of Severe Tricuspid Regurgitation with the Edge-to-Edge: MitraClip Technique. 
Circulation. 2017 Mar 23. 
15 Latib A, Mangieri A, Agricola E, Denti P, Regazzoli D, Giannini F, Ancona MB, Monaco F, Alfieri O, Colombo A. 
Percutaneous bicuspidalization of the tricuspid 
valve using the MitraClip system. Int J Cardiovasc Imaging. 2017 Feb;33(2):227-228. 
Hausleiter10
11 
18 cases, avg 78yo, 95% 
TR 3+/4+, NYHA III or IV,  
Treated TR avg 2.3 
clips per patient 
All had at least 1 grade reduction in 
TR;  
1 stroke and 1 additional 
intervention at 30 day; 
~70%  with NYHA I/II @ 30d 
Picard12 
67yo Male, Severe TR, CC-
TGA, CAD, previous PCI, 
Severe aorto-iliac vascular 
disease; 
Heart team determined high 
surgical risk 
Treated TR (1 Clip) 
TR 4/4 to 2/4 post-procedure; TV 
2mmHg mean gradient @ post 
procedure; NYHA II; 
No admission for HF after 1 year 
follow-up 
Tang13 
71yo Female, Severe TR, 
chronic A-fib, mod-sev MR, 
NYHA III/IV 
Treat both MR (2 
clips) and TR (2 
clips); laser lead 
extraction and 
percutaneous 
transfemoral Micra 
leadless pacemaker 
implant 
Moderate TR at 30-days 
Mild MR at 30-days 
Nickenig14 
64 patient multi-center 
registry study, mean age 
76.6yo, 88% w/ TR, 
severe/massive, 93% w/ 
NYHA III/IV 
N=42 TR only 
treatment 
N=22 TR and MR 
treatment 
91% had at least 1 grade 
improvement in TR, Improved 
6MWT, 63% w/ NYHA III/IV 
Latib15 
84yo male, Severe TR, 
cardiac senile amyloidosis, 
NYHA III,  
Treated TR (2 clips),  
Mild-moderate TR @ 1mo, NYHA II 

 
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2.1.4   TVRS Trial Rationale 
 
Tricuspid regurgitation occurs when the tricuspid valve fails to close properly, causing blood to flow 
backwards into the right atrium. If left untreated, TR can lead to right heart enlargement and right heart 
failure. In the US alone, there is an estimated 1.6 million patients suffering from TR17.  Additionally, an 
estimated 50% of patients with mitral regurgitation have moderate to severe tricuspid regurgitation18. TR 
is currently undertreated by surgery. In the US, surgeons treat only 5,500 patients per year, most of them 
in conjunction with left heart surgeries. When treating the valves, surgeons choose repair 90% of the 
time versus replacement (10%)19. 
 
Per the ESC guidelines for surgical and interventional treatment of tricuspid regurgitation (2017 
ESC/EACTS Guidelines for the Management of Valvular Heart Disease20), surgery is indicated (Class I) 
in patients with either: 1) severe TR undergoing left-sided valve surgery or, 2) symptomatic with severe 
isolated primary TR without severe right ventricular (RV) dysfunction.  Surgery should be considered 
(Class IIA) in patients with moderate tricuspid regurgitation undergoing left-sided valve surgery.  Similarly, 
the 2017 AHA/ACC Guidelines (2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the 
management of patients with valvular heart disease21) indicate: 1) surgery for patients with severe TR 
undergoing left-sided surgery (Class I), or 2) surgery can be beneficial for mild or greater FTR at the time 
of left-sided surgery with either tricuspid annular dilatation or prior evidence of right HF (Class IIa), or 3) 
surgery can be beneficial for severe primary TR who are unresponsive to medical therapy (Class IIa).  
Although surgery is a Class I recommendation for severe TR patients undergoing tricuspid valve (TV) 
surgery carry a high risk of surgical mortality rate of approximately 8% - 18%22,23,24   and a higher rate of 
 
 
 
16 Avenatti E, Barker CM, Little SH. Tricuspid regurgitation repair with a MitraClip device: the pivotal role of 3D 
transoesophageal echocardiography. Eur Heart J Cardiovasc Imaging. 2017 Mar 1;18(3):380. 
17 Stuge O., Liddicoat J., et al. JTCS 2006;132:1258-61 
18 Argarwal et al. Circ Cardiovasc Interv 2009;2:565-573 
19 Rogers JH.Circulation2009:119: 2718-25 
20 Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez 
Muñoz D, Rosenhek R, Sjögren J, Tornos Mas P,  Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL; 
ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur 
Heart J. 2017 Sep 21;38(36):2739-2791. 
21 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, 
O'Gara PT, Rigolin VH, Sundt TM 3rd, Thompson A. 2017 AHA/ACC Focused Update of the 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. Circulation. 2017 Jun 
20;135(25):e1159-e1195. 
22 Ratnatunga CP, Edwards MB, Dore CJ, Taylor KM. Tricuspid valve replacement: UK Heart Valve Registry mid-
term results comparing mechanical and biological prostheses. Ann Thorac Surg. 1998 Dec;66(6):1940-7. 
23 Moraca RJ, Moon MR, Lawton JS, Guthrie TJ, Aubuchon KA, Moazami N, Pasque MK,  Damiano RJ Jr. 
Outcomes of tricuspid valve repair and replacement: a propensity analysis. Ann Thorac Surg. 2009 Jan;87(1):83-8 
24 McCarthy PM, Bhudia SK, Rajeswaran J, Hoercher KJ, Lytle BW, Cosgrove DM, Blackstone EH. Tricuspid valve 
repair: durability and risk factors for failure. J Thorac Cardiovasc Surg. 2004 Mar;127(3):674-85. 
Avenatti16 
77yo male, severe TR, 
NYHA IV,  
Treated TR (1 clip) 
Moderate TR at discharge 
NYHA II at 3mo 

 
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35% for repeat tricuspid valve surgery25.   Additionally, many patients are refractory to medical therapy 
and continue with high morbidity and mortality rates associated with TR.  There is an unmet need for 
patients who are refractory to medical therapy whose only current option is surgery which is associated 
with high risks and may not be appropriate for a subset of these patients.  With no other currently available 
options, TR will persist and gradually increase in severity; thus, having increased morbidity and mortality 
rates as the condition progresses26.  A percutaneous approach that is effective and safe is thus an 
appealing alternative. 
 
Abbott proposes to initiate a clinical trial to evaluate the performance of a modified version of the MitraClip 
NY system, called the Tricuspid Valve Repair System, for percutaneous treatment of TR. 
 
2.2 
Summary of Investigational Device 
 
2.2.1 Name of the Investigational Device 
 
The investigational device to be used in this trial is the Tricuspid Valve Repair System (TVRS).  
 
2.2.2 Intended Indication for Use 
 
The Tricuspid Valve Repair System (TVRS) is intended for reconstruction of the insufficient tricuspid 
valve through tissue approximation. 
 
2.2.3 Description of the Investigational Device 
 
The TVRS configuration consists of two parts: 1) a Clip Delivery System, which includes an implantable 
Clip (MitraClip® NT device), a Steerable Sleeve and a Delivery Catheter; and 2) a Steerable Guide 
Catheter which includes a dilator (Figure 1). 
 
The Clip Delivery System is used to advance and manipulate the implantable TVRS Clip for proper 
positioning and placement on the tricuspid valve leaflets. The Clip Delivery System is designed to deploy 
the implant in a way that requires multiple steps to ensure safe delivery of the device. The Steerable 
Guide Catheter provides a conduit to access the tricuspid valve and with the addition of Steerable Sleeve 
to position the Clip relative to the valve. The Delivery Catheter is designed to deliver and deploy the Clip. 
The Steerable Guide and Clip Delivery System are steered and actuated by the use of control knobs, 
levers and fasteners (Figure 1). 
 
The implantable Clip is fabricated with metal alloys and polyester fabric that are commonly used in 
cardiovascular implants. The Clip can be repeatedly opened, closed and inverted by deliberate 
manipulations of the Delivery Catheter Handle. The Clip positions are designed to allow the Clip to grasp 
and approximate the leaflets of the tricuspid valve.  
 
 
 
25 Bernal JM, Morales D, Revuelta C, Llorca J, Gutiérrez-Morlote J, Revuelta JM. Reoperations after tricuspid valve 
repair. J Thorac Cardiovasc Surg. 2005 Aug;130(2):498-503. 
 
26 Bruce CJ, Connolly HM. Right-sided valve disease deserves a little more respect. Circulation. 2009 May 
26;119(20):2726-34. 
 

 
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Figure 1:  TVRS Configuration 
 
 
2.2.4 Summary of Preclinical Studies 
 
Two non-GLP studies were performed with the MitraClip NT device to evaluate injury and healing in the 
healthy, porcine tricuspid valve and surrounding structures.  
 
An acute study was conducted to assess the ability to coapt two tricuspid leaflets and evaluate injury and 
trauma to the tricuspid valve and surrounding structures post deployment. One MitraClip was implanted 
in one animal, successfully coapting two tricuspid leaflets. Upon gross examination of the tricuspid valve 
and surrounding tissues, significant injury was not observed.  
 
A four week chronic study was conducted to assess the healing profile in the porcine tricuspid valve and 
evaluate the long term hemodynamic response after implantation with the MitraClip device in one animal. 
The animal was implanted with two MitraClip devices in the tricuspid valve and survived to the 4 week 
time point without any adverse events. Prior to termination, right sided hemodynamics were assessed 
and it was determined that there were no relevant hemodynamic changes. Gross pathology and 
histological evaluation of the implanted tricuspid valve showed that both clips were appropriately 
encapsulated in fibrous tissue. Tissue bridging between the coapted leaflets was also observed grossly 
and histologically. Overall, healing was appropriate for the four week time point and was similar to the 
healing observed at four weeks in the chronic GLP porcine mitral valve safety study. 
 
3.0 
CLINICAL TRIAL/INVESTIGATION FLOW AND FOLLOW-UP SCHEDULE 
 
For screening, each subject must undergo clinical assessments and echocardiography; both 
transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE) are acquired. Figure 
2 shows the overall flow of the trial.   
 

 
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Subjects will be screened for study eligibility by the Investigator as well as the Site Heart Team per the 
inclusion and exclusion criteria.  A cardiac surgeon and an echo specialist will assess subjects for 
eligibility criteria for surgical appropriateness and echocardiography, respectively. 
 
The TTE and TEE will be submitted to the Echocardiography Core Laboratory (ECL) for assessment of 
TR severity.  Once the subject is deemed by the ECL to meet TR severity and the subject meets all 
inclusion and none of the exclusion criteria, an Independent Eligibility Committee that includes a cardiac 
surgeon, interventionalist, and echocardiographer will review pertinent medical history to make the final 
determination regarding eligibility of prospective subjects, including eligibility of tricuspid valve anatomy 
(see APPENDIX IX).  Once the Eligibility Committee confirms that the subject is eligible for the TVRS 
procedure in the trial, the subject may be scheduled for the TVRS procedure.   
 
A baseline visit is strongly recommended to be completed 14 days prior to the TVRS procedure (see 
Section 6: Treatment and Evaluation of the TVRS).  Subjects will be considered enrolled upon signed 
and dated study informed consent. 
 
Enrolled subjects will undergo clinical evaluations at baseline, discharge, 30 days, 6 months, 1 year, 2 
years, and 3 years following the TVRS procedure (see Table 2 for Clinical Evaluation Schedule).   
 
 
 

 
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Figure 2:  Overall Flow of the Trial 
 
 
 

 
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3.1 
Number of Subjects to be Enrolled  
 
 
Eligible subjects who have signed and dated study informed consent are considered enrolled in the 
TVRS TRILUMINATE Trial.  Subjects will be eligible for analysis upon femoral vein puncture for TVRS 
procedure attempt.   
 
A minimum of 85 subjects will be enrolled and undergo the TVRS procedure at up to 25 investigational 
sites.  A maximum of eighteen (n=18) patients will be from US sites. 
 
3.2 
Measures Taken to Avoid and Minimize Bias 
 
The following steps will be taken to minimize bias in the conduct of the trial and analyses of clinical 
data. 
 
3.2.1 Subject Recruitment 
 
Investigational sites will attempt to recruit subjects who meet trial eligibility criteria. 
• 
Candidates will be considered for the trial after they have been informed of trial requirements 
and have signed and dated the informed consent form. See Section 5.2 Subject Screening and 
Informed Consent for additional details on subject screening and informed consent process. 
• 
Transthoracic and transesophageal echocardiographic criteria for trial eligibility will be 
confirmed by an independent Echocardiography Core Laboratory. 
• 
All baseline tests and assessments must be completed prior to the procedure. 
• 
Subjects will be eligible for the procedure only after the sites’ clinical personnel have confirmed 
and documented that the subject has met all eligibility criteria, the ECL has confirmed the TR 
severity and tricuspid valve anatomy eligibility criteria, and the Eligibility Committee has 
confirmed that the subject is on optimal medical therapy, high-risk for tricuspid valve surgery, 
determine eligibility of tricuspid valve anatomy, and the benefit-risk analysis supports utilization 
of percutaneous transcatheter intervention. 
 
3.2.2 Site Heart Team 
 
The site heart team includes the interventionalist, a cardiac surgeon and an echocardiographer.  The site 
heart team will assess subject eligibility based on the subject being at high risk for tricuspid valve surgery, 
the benefit-risk analysis supports intervention for tricuspid regurgitation per current guidelines (see 
Section 5.1.1) and anatomic suitability for the percutaneous TVRS procedure based on clinical and 
echocardiographic criteria. 
 
3.2.3 Administration of Assessments 
 
A standardized script will be used when administering the assessments (NYHA Functional Class, 
6MWT, and QoL questionnaires).  To minimize bias and undue influence, the QoL questionnaires must 
be completed by the subject or his/her legal representative (where allowed per local regulations).  In 
the latter case, a note to file must be completed to document the inability of subject to complete the 
questionnaire. 
 
 

 
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3.2.4 Review of Echocardiographic Images by the Independent Echocardiographic Core Lab 
 
The ECL will confirm subject’s screening echocardiography images for TR severity eligibility criteria are 
met per the 2017 ASE guideline for TR grading27, and defined in Appendix VIII.  Subjects failing the 
criteria will be considered a screen failure and not allowed into the trial.  Additionally, the ECL will be 
responsible for assessing TR severity and echocardiographic analyses at all visits (baseline and follow-
ups) and operate according to the ECL Manual of Operations. 
 
3.2.5 Independent Eligibility Committee  
  
This Committee will comprise of, at a minimum, representatives from the following specialties: heart 
failure specialist, cardiac surgery (with expertise in tricuspid valve surgery), interventional cardiology and 
echocardiography.  Their role is to review determinations made by both the Site Heart Team and ECL 
regarding trial eligibility of the patient under consideration.  Review will be performed via teleconference 
with presentation (i.e. Webex) at a regular basis (i.e. weekly) between the Eligibility Committee, ECL 
representative, and a study site(s) representative(s) of the proposed subject(s).  Study site 
representative(s) and ECL will present eligibility data to the Eligibility Committee.   If the Eligibility 
Committee deemed the proposed subject is currently not on optimal or guideline-directed medical therapy, 
tricuspid anatomy ineligible  for transcatheter intervention, and/or not high-risk for tricuspid valve surgery, 
they can further consult with the Site Heart Team and/or ECL as appropriate before accepting or rejecting 
the patient into the trial.  The composition, guiding policies, and operating procedures governing the 
Eligibility Committee are described in a separate Manual of Operations. 
Note:  Members of the Eligibility Committee are also members of the Steering Committee. 
 
3.2.6 Safety and Effectiveness Monitoring 
 
• 
All adverse events will be reviewed by Abbott/Novella Safety Monitoring group.  
• 
Adverse events requiring adjudication will be submitted to an independent Clinical Events 
Committee (CEC; Section 11.8.3).  
• 
A Data Safety Monitoring Board (DSMB) will review accumulating safety data as described in 
Section 11.8.2 
 
3.3 
Follow-Up Compliance 
 
The Sponsor will work with investigational sites to maintain a high follow-up compliance as follows: 
1. Sponsor will emphasize to the site the importance of subject follow-up during site initiation visits 
and subsequent communications. Site should communicate the importance to each subject. 
2. Sites will be informed to promptly reschedule any missed subject visits, and to reinforce the 
necessity of a follow-up visit. 
 
 
 
27 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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3. Site is advised to involve Sponsor when needed.  Example:  Arrange alternate transportation if 
a scheduled visit is missed due transportation/travel issues, or due to subject illness 
4. Sites should document reasons for any subject withdrawals from the trial, and request 
agreement for a follow-up call from the investigator at the end of the trial. 
5. Sites should monitor follow-up rates closely to promptly identify and address any issues. 
 
Additionally, investigational sites will be educated on the importance of maintaining low rates of 
withdrawals, and will be expected to make all effort to maintain low withdrawals during trial conduct. 
Withdrawals from the trial will require discussion between investigator and the Sponsor. 
 
3.4 
Early Termination of the Clinical Trial 
 
No formal statistical rule for early termination of the trial for insufficient effectiveness of the investigational 
device is defined. However, the Sponsor reserves the right to discontinue the clinical trial/investigation 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: 
 
• 
Occurrence of Unanticipated Adverse Device Effect (UADE) that presents an unreasonable 
risk to the participating subjects. 
• 
Recommendation from any oversight committee (e.g., Steering Committee, DSMB) to stop 
or terminate the trial for reasons such as higher frequency of anticipated adverse device 
effects. 
• 
Cancellation of further product development. 
 
Sponsor reserves the right to terminate a site’s participation in the trial for reasons of repeated non-
compliance with the Study Protocol; or, any other conditions of the study may result in further escalation 
in accordance with the Sponsor’s written procedures including securing compliance.  In the event of 
repeated non-compliance as determined by the Sponsor, a Sponsor’s monitor, or company 
representative will attempt to secure compliance by one or more of the following (and not limited to): 
• 
Visiting the investigator 
• 
Telephoning to the investigator 
• 
Corresponding with the investigator 
 
Should the clinical trial or site 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. 
 
The investigator shall then return all clinical trial/investigation materials (including devices) to the Sponsor, 
and provide a written statement as to why the premature termination has taken place to the IRB/EC and 
other required regulatory bodies (if applicable). All applicable Trial documents shall be subject to the 
same retention policy as detailed in Section 12 of the Protocol entitled, ‘Data Handling and Record 
Keeping’.  
 
4.0 
ENDPOINTS 
4.1 
Primary Effectiveness Endpoint  
 
The primary effectiveness endpoint is echocardiographic TR reduction at least 1 grade at 30 
days post-procedure, to be tested against a pre-specified performance goal. 

 
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4.2 
Primary Safety Endpoint  
The primary safety endpoint is a composite of Major Adverse Event (MAE) at 6-months to be 
evaluated against a pre-specified performance goal.  
 
MAE is defined as a composite of:  
• 
Cardiovascular Mortality,  
• 
MI,  
• 
Stroke,  
• 
New onset renal failure,  
• 
Endocarditis requiring surgery, and  
• 
Non-elective CV surgery for TVRS device-related AE post-procedure. 
 
 
4.3  Secondary Endpoints 
4.3.1  Acute Secondary Endpoints 
 
• 
Acute Procedural Success (APS):  Successful implantation of the Clip with resulting at least 1 
grade reduction in TR severity as determined by the Echocardiography Core Laboratory (ECL) 
assessment of a discharge echocardiogram (30-day echocardiogram will be used if discharge 
echocardiogram is unavailable or uninterpretable). Subjects who die or undergo tricuspid valve 
surgery before discharge are an APS failure. 
 
• 
Acute Device Success:  Successful access, delivery of the Clip and removal of device delivery 
system.  Successful delivery of the Clip is the deployment of the device as planned, with no 
additional unplanned surgery or re-intervention related to the device or access procedure. 
 
• 
Implant Success Rate: Successful delivery and deployment of the Clip(s) with achievement of 
leaflet approximation(s) and retrieval of the delivery catheter. 
 
• 
Total Procedure Time: Total Procedure Time is defined as the time elapsed from the first of any 
of the following: intravascular catheter placement or trans-esophageal echocardiogram (TEE), 
to the removal of the last catheter and TEE. 
 
• 
Device Time: Device time is defined as the time the Steerable Guide Catheter is placed in the 
right atrium until the time the TVRS Delivery System is retracted into the Steerable Guide 
Catheter. 
 
• 
Fluoroscopy Duration:  Fluoroscopy duration is defined as the duration of exposure to 
fluoroscopy during the TVRS procedure. 
 
• 
Length of hospital stay for the index TVRS procedure 
 
• 
Location to which subject was discharged (home, home health or another facility) 
o If subject discharged to another facility, length of stay at facility to which subject was 
discharged 
 

 
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4.3.2 Clinical Composite Endpoints 
 
• 
MAE at discharge, 30 days,1 year, 2 years and 3 years 
 
4.3.3 Clinical Components Endpoints 
 
• 
Clinical Endpoints will be assessed at 30 days, 6 months, 1 year, 2 years and 3 years: 
o Components of MAE 
o All-cause mortality  
o NYHA Functional Class  
o Tricuspid valve surgery (including type of surgery), 
o New use of any cardiac rhythm management devices (Pacemakers, ICDs, and CRT), 
including reason for intervention 
o Additional TVRS intervention and reason for intervention 
 
• 
Additional Clinical Endpoints: 
o Major bleeding at 30 days 
o Pulmonary Thromboembolism at 30 days 
o New Onset Renal Failure at 30 days and 6 months 
o New Onset Liver Failure at 30 days and 6 months 
o New onset atrial fibrillation at 30 days, 6 months and 1 year. 
o Change in diuretic(s) used at 30 days, 6 months, and 1 year (as compared to baseline) 
 
4.3.4 Patient Reported Endpoints 
Patient-reported Quality of Life (QoL) and Health Economics and Outcomes Research (HEOR) 
Endpoints: at baseline, 30 days, 6 months, 1 year, 2 years and 3 years*: 
o Distance walked in the 6-Minute Walk Test (6MWT distance or 6MWD)  
o KCCQ QoL scores  
o SF-36 QoL scores  
o Number and duration of re-hospitalizations and reason for re-hospitalization (i.e., heart 
failure, cardiovascular, non-cardiovascular) 
*Actual rates/scores and the relative change from baseline to each follow-up time point. 
Note: As applicable to patients in the US trial sites, it is anticipated that the patients enrolled 
in the TRILUMINATE trial will be U.S. Medicare beneficiaries age 65 and over. 
 
 
4.3.5 Device or Procedure-Related Adverse Events 
Prevalence of Device or Procedure-Related Adverse Events 
Device or procedure-related adverse events will be broken down into those that occur within 30 
days of the procedure and those that occur after 30 days of the procedure.  Examples of device-
related adverse events are: 
o Myocardial perforation 
o Damage to tricuspid valve apparatus 
o Access Site bleeding requiring surgery 
o Non-vascular bleeding 
 

 
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4.3.6 Echocardiographic Endpoints 
Echocardiographic endpoints will be assessed by the Echocardiography Core Laboratory (ECL) 
and reported at baseline, discharge, 30 day, 6 months, 1 year, 2 year, and 3 year post-
implantation (unless indicated).   
o TR Severity Grade  
o Effective Regurgitant Orifice Area (EROA) 
o Regurgitant Volume 
o Regurgitation Jet Area 
o Vena Contracta Width 
o PISA Radius 
o Inferior Caval Vein Diameter  
o Tricuspid Annular Diameters (A-P and S-L) 
o Tricuspid Annular area 
o Tricuspid Valve Area 
o Tenting Area (At baseline only) 
o Tenting Distance (At baseline only) 
o Tricuspid Leaflet Tethering Distance (At baseline only) 
o Right Ventricular End Diastolic Dimension (RVEDD) 
o Right Ventricular End Systolic Dimension (RVESD) 
o Right Ventricular Fractional Area Change 
o Right Ventricular Systolic Pressure (RVSP)  
o Right Atrial Volume 
o Tricuspid Annular Plane Systolic Excursion (TAPSE) 
o Right Ventricular Free Wall Strain 
o Mean Tricuspid Valve Gradient 
o Cardiac Output 
o Forward Stroke Volume (Left Ventricle) 
o Left Ventricular Ejection Fraction (LVEF)  
o Single Leaflet Device Attachment 
o Embolization of the TVRS Clip or TVRS System components 
o Tricuspid Valve Stenosis 
 
4.4 Exploratory Endpoints 
 
Right Heart Catheterization: Right heart catheter measurements at: 
o Immediately before TVRS procedure: Measurements to include: right atrial a-wave/v-
wave, right atrial and ventricular pressures, pulmonary resistance, PA pressures and 
cardiac output),   
o Post-procedure Right Atrial Catheterization, immediately after TVRS procedure (right-
atrial a-wave/v-wave, right atrial pressure) 
 
5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
 
The trial will enroll a minimum of 85 subjects who will undergo the TVRS procedure. This trial will enroll 
male and female subjects from the heart failure population who have at least moderate grade TR, and 
satisfy the general and echocardiographic inclusion and exclusion criteria. Subjects must sign and date 
the informed consent prior to conducting any trial-specific procedures not considered standard of care.  

 
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Any patient data transmitted from their institution to the ECL or Sponsor must have prior signed and 
dated informed consent.   
 
Assessment for general eligibility criteria is based on medical records of the site and interview with a 
candidate subject. If some of the clinical and laboratory tests are not included in site standard tests, they 
must be done, but after signed and dated informed consent is obtained.  Subjects must meet ALL of the 
inclusion criteria to be considered for the clinical evaluation. If ANY of the exclusion criteria are met, the 
subject is excluded from the clinical evaluation and will not qualify for the TVRS procedure. 
 
5.1.1 General Inclusion Criteria 
 
Subjects must meet all of the following inclusion criteria to participate in the trial: 
 
1. Subject must be ≥18 years and ≤90 years at time of consent and must not be a member of a 
vulnerable population. 
2. Subject or a legally authorized representative* (where allowed per local regulations) must provide 
written informed consent prior to any trial related procedure. 
3. Subject must agree not to participate in any other clinical trial for a period of one year following 
the index procedure. 
4. In the judgment of the investigator at the site, the subject has been adequately treated per 
applicable standards (including medical management), including for coronary artery disease, 
mitral regurgitation and heart failure (e.g., with cardiac resynchronization therapy, 
revascularization, and/or optimal medical therapy as appropriate; see APPENDIX II: Definitions 
for definition of optimal therapy) at least 30-days prior to index procedure. The Eligibility 
Committee must concur that the subject has been adequately treated. 
5. New York Heart Association (NYHA) Functional Class II (conditional), III, or ambulatory IV 
a. Subjects with moderate TR: Only NYHA Class III or IV may be considered  
b.  Subjects with severe or greater TR: NYHA II, III, or IV may be considered for inclusion 
6. No indication for left-sided or pulmonary valve correction (Left sided heart valve disease or 
pulmonary stenosis needs to be adequately treated for at least 30-days prior to study enrollment 
for TR treatment).   
7. The Site Heart Team (a minimum of one interventionalist, one cardiac surgeon and one 
echocardiographer) concur benefit-risk analysis supports intervention for tricuspid regurgitation 
per current guidelines for the management of valvular heart disease28, 29 and that the subject is 
at high risk for tricuspid valve surgery. 
 
 
 
*  For Switzerland Only: Subject must provide written informed consent prior to any trial related procedure.  A legally 
authorized representative will not be allowed to provide informed consent for a patient. 
28 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Fleisher LA, Jneid H, Mack MJ, McLeod CJ, 
O'Gara PT, Rigolin VH, Sundt TM 3rd, Thompson A. 2017 AHA/ACC Focused Update of the 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. 2017 Jul 
11;70(2):252-289. 
29 Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez 
Muñoz D, Rosenhek R, Sjögren J, Tornos Mas P,  Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL; 
 

 
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8. In the judgment of the TVRS implanting Investigator, femoral vein access is determined to be 
feasible and can accommodate a 25 Fr catheter.  
 
5.1.2 Echocardiographic Inclusion Criteria 
 
 
9. Moderate or greater (≥2+) Tricuspid Regurgitation determined by the assessment of a qualifying 
transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) confirmed by 
the Echocardiography Core Lab (ECL) (Refer to Appendix VIII).  Subjects with moderate TR will 
only be included in the trial if moderate TR is accompanied by a tricuspid annular diameter of 
≥40mm as measured by the site heart team Echocardiographer.  Note: Additional NYHA criteria 
for moderate TR patients (see Inclusion Criteria #5).  Additional note: If any cardiac procedure(s) 
that may occur within 90-days of procedure, then TTE and TEE must be repeated prior to the 
index procedure. 
10. Tricuspid valve anatomy determined to be suitable for implantation (e.g., no severe leaflet defects 
preventing proper placement of the TVRS, Ebstein Anomaly) determined by the site heart team 
11. Tricuspid valve anatomy evaluable by TTE and TEE 
 
5.1.3 General Exclusion Criteria 
 
Subjects who meet any of the following exclusion criteria may not participate in the trial: 
 
1. 
Subject is currently participating in another clinical trial that has not yet completed its primary 
endpoint. 
2. 
Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year following 
index procedure. Female subjects of child-bearing potential must have a negative pregnancy test 
done within 7 days prior to the index procedure per site standard test. 
Note: Female patients of childbearing potential should be instructed to use safe 
contraception (e.g., intrauterine devices, hormonal contraceptives: contraceptive pills, 
implants, transdermal patches hormonal vaginal devices, injections with prolonged 
release.) It is accepted, in certain cases, to include subjects having a sterilised regular 
partner or subjects using a double barrier contraceptive method. However, this should be 
explicitly justified in special circumstances arising from the study design, product 
characteristics and/or study population.  
 
3. Severe uncontrolled hypertension (SBP ≥ 180 mmHg and/or DBP ≥ 110 mm Hg) 
4. Systolic Pulmonary Artery Pressure >60mmHg (echo determined) 
5. Prior tricuspid valve leaflet surgery or any currently implanted prosthetic tricuspid valve, or any 
prior transcatheter tricuspid valve procedure.  
6. Mitral Regurgitation moderate-severe or greater severity (≥3+)  
7. Pacemaker or ICD leads that would prevent appropriate placement of TVRS Clip 
8. Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic 
disease (i.e. noncompliant, perforated). 
9. MI or known unstable angina within prior 30 days prior to enrollment 
10. Percutaneous coronary intervention within prior 30 days prior to enrollment 
 
 
 
ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur 
Heart J. 2017 Sep 21;38(36):2739-2791. 

 
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11. Hemodynamic instability defined as systolic pressure < 90 mmHg with or without afterload 
reduction, cardiogenic shock or the need for inotropic support or intra-aortic balloon pump or other 
hemodynamic support device. 
12. Cerebrovascular Accident (CVA) within prior 3 months prior to enrollment 
13. Chronic dialysis 
14. Bleeding disorders or hypercoagulable state 
15. Active peptic ulcer or active gastrointestinal (GI) bleeding 
16. Contraindication, allergy or hypersensitivity to dual antiplatelet and anticoagulant therapy.   
Note: Contraindication to either antiplatelet or anticoagulant therapy (individually not both 
therapies) is not an exclusion criterion. 
17. Active infections requiring current antibiotic therapy (if temporary illness, patients may enroll 4 
weeks after discontinuation of antibiotics with no active infection). 
18. Known allergy or hypersensitivity to device materials 
19. In the judgment of the investigator a condition that could limits a patient’s ability or unwillingness 
to participate in the study, comply with study required testing and/or follow-up visits or that could 
impact scientific integrity of the study.  
20. Evidence of intracardiac, inferior vena cava (IVC), or femoral venous mass, thrombus or 
vegetation. 
21. Life expectancy of less than 12 months due to non-cardiac conditions 
 
5.1.4 Echocardiographic Exclusion Criteria: 
 
22. Tricuspid Stenosis 
23. Left Ventricular Ejection Fraction (LVEF) ≤20% 
24. Tricuspid valve leaflet anatomy which may preclude clip implantation, proper clip positioning on 
the leaflets or sufficient reduction in TR.  This may include: 
a. Evidence of calcification in the grasping area  
b. Presence of a severe coaptation defect (> 2cm) of the tricuspid leaflets 
 
5.2 
Subject Screening and Informed Consent 
5.2.1 Subject Screening 
 
Subjects admitted for a procedure must be screened for clinical trial eligibility by a member of the clinical 
trial/investigation team (physician and/or research coordinator) previously trained to the clinical trial 
Protocol, and if applicable will be entered into a site specific screening log. 
 
Subjects meeting the general inclusion and exclusion criteria will be asked to sign and date an informed 
consent. These patients will then be entered into the screening log (as applicable, also the reason for 
screen failure as well as supporting data will be entered into the log). 
 
Screening imaging will be used for the final assessment of subject eligibility. Subjects who do not satisfy 
echocardiographic inclusion and exclusion criteria (screen failure) will not undergo the TVRS procedure 
in this clinical trial/investigation.  These subjects will be followed for 30 days after consent for adverse 
events, then withdrawn from the study.     
 
Patient data will be collected following enrollment into the trial. 
 
Screening of a subject for possible inclusion in the trial may commence once a subject has been identified 
as symptomatic, having moderate or greater grade tricuspid regurgitation. Subject’s general medical 

 
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eligibility must be assessed by the sites through subject’s interview and subject’s medical record review 
prior to the TVRS procedure and within the time windows stipulated (see Table 2 for more details).  
Relevant standard of care tests performed prior to obtaining informed consent can be used to determine 
eligibility if those tests were within the screening time window.  Signed and dated informed consent must 
be obtained prior to any test/evaluation that is not standard of care.  Additionally, signed and dated 
informed consent is required prior to any transmission of patient data to the ECL or Sponsor. 
 
Site Heart Team will evaluate the following assessments within 90 days prior to the index procedure: 
 
• 
Subject meets all general and echocardiographic inclusion criteria 
 
• 
Subject does not meet any of the general and echocardiographic exclusion criteria 
 
• 
Subject is evaluated by the Site Heart Team to confirm that they are adequately treated per 
applicable standards, including treatment for coronary artery disease, right ventricular dysfunction, 
mitral regurgitation, tricuspid regurgitation, and heart failure. Subjects with current or prior 
symptoms of heart failure and reduced LVEF should be on stable optimally up-titrated medical 
therapy recommended according to current guidelines as standard of care for heart failure therapy 
in the United States and Europe. See ‘APPENDIX II: Definitions’ for definition of optimal therapy. 
Additionally, the Site Heart Team must confirm that the subject is appropriate for percutaneous 
transcatheter intervention. 
 
• 
Clinical, physical, and labs exams must be performed: 
o Medical history 
o Weight, temperature, blood pressure and heart rate 
o Modified Rankin Scale assessment 
o Perform a pregnancy test, as appropriate 
o Measure BNP or NT-proBNP level  
o Measure AST or ALT level 
 
• 
Screening Transesophageal and transthoracic echocardiographic (TEE and TTE) images must 
be obtained within 90 days of review by the independent Eligibility Committee.   
 
• 
If Site Heart Team deems this subject is at high risk for tricuspid valve surgery and an appropriate 
candidate for TVRS, their TEE and TTE images will be submitted to the independent ECL. 
o If the subject has undergone a recent cardiac procedure(s) (within the last 90 days prior 
to the TVRS procedure), TTE and TEE must be performed after this (these) procedure(s).  
o Site must review the TTE and TEE images and confirm that subject has TR and suitable 
tricuspid valve anatomic criteria, without intracardiac mass, thrombus or vegetation. 
Trained Abbott personnel may provide support to sites in reviewing TTE/TEE images. 
 
• 
After the ECL has confirmed subject eligibility, sites will be notified by the Sponsor to compile and 
submit the following information for Eligibility Committee review: 
o Obtain and review Subject’s medical records and history.  
o Complete a physical exam, including an assessment of subject’s cardiac status and vital 
signs measures (e.g. height, weight, heart rate, blood pressure and temperature)  
o Assess subject’s NYHA Functional Class and Modified Rankin Scale 
o Have the subject examined by the investigator to assess optimization level of his/her 
medications, and appropriateness for TVRS. 
 

 
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• 
If patient does not meet any of the screening requirements, then the subject is considered a 
screen failure. 
 
5.2.2 Study Informed Consent 
 
The Investigator or designee, who has been trained on the protocol, will explain the nature and scope of 
the trial, potential risks and benefits of participation, and answer questions for the subjects. All subjects, 
or their legally authorized representatives* (where allowed per local regulations), must sign and date the 
Institutional Review Board (IRB)/Ethics Committee (EC) approved informed consent form prior to any 
clinical trial/investigation-specific procedures. The ICF must also be signed by the investigator or 
designate (if allowed per country specific regulations). The completed ICF must be kept in the subject’s 
medical records. The whole consenting process, date, and provisioning of a copy to the subject must be 
documented in the subject’s medical records. 
 
Subjects who belong in the Vulnerable Population (definition in Appendix II) will not be allowed into this 
trial. 
 
For US subjects: In addition, 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. 
 
5.2.3 Enrollment of Medicare Beneficiaries (US Cohort only) 
 
Early use of the TVRS system indicates that patients that are candidates for the therapy are an older 
patient population typically managed under Medicare. Investigator-driven studies showed mean ages of 
78 +/- 7 years (N=18, Braun et al)30  and 76.6 +/- 10 years (N=64, Nickenig et al)31. It is expected that 
enrolled patients in the TRILUMINATE study will be within this age range, with the demographic 
characteristics and cardiovascular risk factors representative of the Medicare patient population as part 
of the overall cohort. These criteria are not expected to have a negative effect on the recruitment or 
retention of underrepresented populations. Section 15 describes how all enrolled subjects, including 
Medicare beneficiaries, may be affected by the device under investigation. 
 
5.3 
Subject Enrollment 
 
Subjects are enrolled in the TRILUMINATE Trial upon signing and dating the informed consent form.  
Subjects who undergo femoral vein puncture for TVRS procedure attempt will be included in analyses of 
endpoints. 
 
 
 
 
*  For Switzerland Only:  A legally authorized representative will not be allowed to provide informed consent for a 
patient. 
30 Braun D, Nabauer M, Orban M, Orban M, Gross L, Englmaier A, Rösler D, Mehilli J, Bauer A, Hagl C, Massberg 
S, Hausleiter J. Transcatheter treatment of severe tricuspid regurgitation using the edge-to-edge repair technique. 
EuroIntervention. 2017 Feb 3;12(15):e1837-e1844. 
31 Nickenig G, Kowalski M, Hausleiter J, Braun D, Schofer J, Yzeiraj E, Rudolph V, Friedrichs K, Maisano F, 
Taramasso M, Fam NP, Bianchi G, Bedogni F, Denti P, Alfieri O, Latib A, Colombo A, Hammerstingl C, Schueler 
R. Transcatheter Treatment of Severe Tricuspid Regurgitation with the Edge-to-Edge: MitraClip Technique. 
Circulation. 2017 Mar 23. 

 
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Subjects who have provided an informed consent and are screened for eligibility, but do not undergo a 
femoral vein puncture for the TVRS procedure within 30 days of consent are considered “enrolled but 
not attempted”, and will not be included in analysis of endpoints.  Such subjects will be followed for 30 
days after consent for adverse events, then withdrawn from the study.     
 
5.4 
Subject Discontinuation 
 
Withdrawal: 
 
Each enrolled subject shall remain in the trial until completion of the required follow-up period; however, 
a subject’s participation in any clinical trial is voluntary and the subject has the right to withdraw at any 
time without penalty or loss of benefit. Conceivable reasons for discontinuation may include, but not be 
limited to, the following: 
 
• 
Subject death 
• 
Subject voluntary withdrawal  
• 
Subject withdrawal by physician as clinically-indicated 
• 
Subject lost-to follow-up as described below  
 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will provide this 
information to the Sponsor. Investigators must also report this to their respective IRB/EC as defined by 
their institution’s procedure(s).  
 
No additional follow–up will be required or data recorded from subjects once withdrawn from the trial, 
except for the status (deceased/alive). 
 
However, if a subject withdraws from the study due to problems related to the investigational device 
safety or performance, the investigator shall ask for the subject's permission to follow his/her 
status/condition outside of the clinical investigation. 
 
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. 
 
 
For all countries, except Switzerland: 
• 
A minimum of 3 telephone calls over a period of 10 days to contact the subject or his/her 
relative/caregiver (where allowed per local regulations) should be recorded in the source 
documentation, including date, time, and name of site personnel trying to make contact. 
• 
If these attempts are unsuccessful, a certified or registered letter with confirmed receipt should 
be sent to the subject. The registered letter will request the subject to contact the site. 
• 
If the above attempts are unsuccessful, the patient’s general practitioner shall be contacted to 
investigate about the subject’s whereabouts and his/her health status (where allowed per local 
regulations). 
 
For Switzerland Only: 
• 
In the event that the 3 phone calls made over a 10-day period to reach the patient are 
unsuccessful, the patient’s general practitioner shall be contacted regarding the patient’s health 
status at the same time that the registered letter is sent to the subject.  This modification 

 
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corresponds to the quick measures for capturing the whereabouts and state of health of subjects 
by the Swiss Competent Authority and permitted by regional regulations.  
• 
In case of a subject not being able to be located, the monitor will verify that adequate measures 
have been undertaken to contact the subject’s treating General Practitioner and exchange data 
about the whereabouts and health status of the subject. 
 
If a subject misses one or more non-consecutive follow-up contact time points, it will be considered 
a missed visit.  The subject may then return for subsequent visits.  If the subject misses two 
consecutive follow-up time points the subject will be considered lost-to-follow-up.   
 
However, if a subject withdraws from the study due to problems related to the investigational device 
safety or performance, the investigator shall ask for the subject's permission to follow his/her 
status/condition outside of the clinical investigation. 
 
5.5 
Total Expected Duration of the Clinical Investigation 
 
Approximately Four (4) years, including enrollment and follow-up. 
 
5.6 
Expected Duration of Each Subject’s Participation 
 
Three (3) Years  
 
5.7 
Number of Subjects Required to be Included in the Clinical Investigation 
 
At least 85 subjects will be enrolled and undergo the TVRS procedure to obtain 85 analysis subjects (i.e., 
subjects who will be included in the analysis of endpoints). 
 
5.8 
Estimated Time Needed to Enroll this Number (i.e., Enrollment Period) 
 
Approximately 16 months 
 
5.9 
Trial Completion 
 
A Trial Completion eCRF must be completed for each patient when: 
• 
the subject is considered lost to follow-up per the above definition or  
• 
the subject withdraws from the Trial or 
• 
the subject is withdrawn due to screen failure or 
• 
the investigator withdraws the subject from the trial or 
• 
the subject dies or 
• 
the subject completes the Trial (e.g., 3 year follow-up time point has been reached) or 
• 
the sponsor terminates the Trial. 
 
Sponsor must be notified of the reason for subject discontinuation. The site will provide this information 
on the eCRF. Investigators must also report this to their EC/IRB as defined by their institution’s 
procedure. Subjects will not be replaced. 
 

 
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6.0 
TREATMENT AND EVALUATION OF THE TVRS 
 
After patients successfully completed screening, the subsequent visits will be performed in the following 
order: Baseline, Index Procedure, Discharge, 30 day, 6 months, 1 year, 2 years and 3 years visits.  Details 
are provided below. 
 
6.1 
Baseline Clinical Assessments 
 
Within 14 days prior to the TVRS procedure, a baseline visit must be completed (may occur on the day 
of, but prior to the TVRS procedure).  Per Table 2: Clinical Evaluation Schedule, clinical assessments 
at baseline include medical history, weight, temperature, heart rate, blood pressure, the Short Form 
Health Survey (SF-36) Quality of Life (QoL) questionnaire, Kansas City Cardiomyopathy Questionnaire 
(KCCQ), New York Heart Association (NYHA) Functional Class, Six Minute Walk Test (6MWT) distance, 
blood test (includes BNP or NT-ProBNP, CK or CK-MB, blood urea nitrogen, serum creatinine, and AST 
or ALT) and medical history assessments.  History of heart failure hospitalizations in the prior 1-year will 
be collected as part of the medical history at the baseline visit. Concomitant cardiovascular medications, 
including dosage, will also be collected at this visit.   
 
A 12-lead ECG must be performed within 24 hours prior to the TVRS procedure to rule out an acute 
myocardial infarction (Table 2: Clinical Evaluation Schedule). 
 
6.2 
Pre-Procedure Anticoagulation/Antiplatelet and Antibiotic Therapy 
6.2.1 Anticoagulation/Antiplatelet Therapy 
 
Discontinue the use of warfarin for at least three (3) days prior, or per institution standard of care, to the 
scheduled TVRS procedure and it is suggested that the international normalized ratio (INR) is ≤1.7 prior 
to the TVRS procedure.  Similarly, discontinue dabigatran or factor Xa inhibitors for a sufficient duration 
to ensure restoration of normal coagulation, or per institution standard of care.  Subjects may be treated 
with heparin during this period at the treating physician’s discretion.  If heparin is used, it should be 
discontinued ≥8 hours prior to the TVRS procedure for subcutaneous low molecular weight heparin 
(LMWH) and ≥4 hours prior to the TVRS procedure for intravenous unfractionated heparin (UFH).  
 
 
Clopidogrel 
 
A loading dose of clopidogrel (≥300 mg) is recommended within 24 hours prior to the procedure (6-24 
hours prior if possible) or immediately following the procedure.   
Note: A loading dose of clopidogrel may be considered even if the patient is taking clopidogrel on a daily 
basis either at home or in the hospital, as long as no other clopidogrel loading dose has been given within 
24 hours.  However, clopidogrel use is optional and its use is left to the discretion of the investigator.   
Aspirin may also be used at operator discretion. If aspirin is to be used, a loading dose of 325 mg 
acetylsalicylic acid (ASA) may be administered either pre- or immediately post-TVRS procedure. 
 
 

 
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6.2.2 Antibiotic Therapy 
 
It is recommended to administer a single dose of intravenous broad spectrum antibiotics approximately 
one hour prior to initiation of the procedure. The type and dosage of antibiotic is at the Investigator’s 
discretion or institution’s standard of care. 
 
6.2.3 Pre-procedure/Baseline Imaging 
 
Subjects are required to complete an additional TTE study within 14 calendar days prior to the procedure, 
and TEE study within 3 calendar days prior to the procedure to rule out the presence of intracardiac mass, 
thrombus or vegetation.  Both TTE and TEE may be performed within 3 calendar days, which may be 
performed immediately preceding initiation of the TVRS procedure.  Pre-procedure/Baseline imaging 
must be submitted to the ECL.  Prior to the TVRS procedure, subjects must be re-assessed to ensure 
there is no significant change in subject’s overall condition that would preclude treatment. If the subject 
has experienced any significant change that would preclude treatment, the subject must be treated and 
rescheduled for the TVRS procedure as soon as possible. If an intracardiac mass, thrombus or vegetation 
or other change in echocardiographic eligibility is identified in the TTE or TEE performed immediately 
preceding the procedure, the device may not be implanted and the subject is considered a screen failure.  
 
The use of transesophageal echocardiography (TEE) requires conscious sedation or general anesthesia, 
depending on hospital standard practice.  If complications arise during the procedure, it may be 
necessary to convert to an open surgical procedure. Emergency surgical back-up should be available as 
per the institution’s standard procedures.  The Sponsor will be available to provide technical support to 
answer questions regarding the function and operation of the TVRS System. 
 
6.2.4 Pre-Procedural ECG and Physical Exam 
 
A 12-lead ECG and physical exam should be performed within 24 hours prior to the procedure. 
 
6.2.5 Baseline Activated Clotting Time 
 
Baseline activated clotting time (ACT), prior to intravenous heparin, will be determined after achieving 
transcatheter access, but before TVRS procedure. ACT and heparin administration (or alternative 
anticoagulation therapy, e.g., bivalirudin) should be recorded in the eCRF. 
 
 

 
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Table 2:  Clinical Evaluation Schedule 
Assessments 
 
Screen-
ing 
BL 
DIS 
30-D 
6-M 
1-Y 
2-Y 
3-Y 
+14 
days 
± 28 
days 
± 28 
days 
± 28 
days 
± 28 
days 
Signed and Dated Informed Consent 
X 
X0 
 
 
 
 
 
 
Medical history 
X 
X1 
 
 
 
 
 
 
Evaluation by Site Heart Team 
X 
 
 
 
 
 
 
 
Evaluation by Independent Eligibility Committee 
X 
 
 
 
 
 
 
 
Weight, temperature, blood pressure and heart rate 
X 
X1, 2 
X 
X 
X 
X 
X 
X 
Concomitant cardiovascular medications including 
dose  
 
X1 
X 
X 
X 
X 
X 
X 
Modified Rankin Scale 
X 
 
X 
X 
X 
X 
X 
X 
Complete Blood Count (CBC) with differentials and 
platelet count 
 
X1 
X 
X 
X 
X 
X 
X 
Serum Creatinine 
 
X1 
X6 
X6 
X6 
X6 
X6 
X6 
Blood Urea Nitrogen (BUN) 
 
X1 
X 
X 
X 
X 
X 
X 
CK and/or CK-MB 
 
X1, 8 
X8 
X 
X 
X 
X 
X 
BNP or NT-proBNP 
X 
Optional 
X 
X 
X 
X 
X 
X 
AST or ALT 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy test 
X 
X1 
 
 
 
 
 
 
12-lead ECG 
 
X2 
X 
X 
X 
X 
X 
X 
Transesophageal Echocardiography (TEE) 
X3 
X4 
 
X 
 
 
 
 
Transthoracic Echocardiography (TTE) 
X3 
X1 
X 
X 
X 
X 
X 
X 
NYHA Classification 
X 
X1 
 
X 
X 
X 
X 
X 
Right Heart Catheterization 
 
X5 
 
 
 
 
 
 
Six Minute Walk Test (6MWT) distance 
 
X1 
 
 
X 
X 
X 
X 
KCCQ and SF-367 
 
X1 
 
X 
X 
X 
X 
X 
Adverse events, device deficiencies, hospitalizations, 
tricuspid valve surgery, additional TVRS intervention 
 
X1 
X 
X 
X 
X 
X 
X 
BL:Baseline, DIS:Discharge, 30-D:30 days, 1-Y:1 year, 2-Y:2 years, 3-Y:3 years,  
0: Study Informed Consent prior to or start of baseline visit. 
1:  Within 14 days prior to TVRS procedure 
2:  Performed within 24 hours prior to TVRS procedure 
3:  Within 90 days prior to Eligibility Committee review;  
4:  Additional TEE within 3 days prior to the TVRS procedure, which may be performed immediately prior to the TVRS procedure 
5 Performed immediately prior to and after index TVRS procedure.  Post-procedure measure must only be performed in the atrial. 

 
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6:  If serum creatinine is elevated by at least 0.5 mg/dl on any visit compared to the prior visit or to baseline, an additional serum creatinine must be obtained between 30 and 45 
days later to determine whether the increase is persistent 
7:  To minimize bias and undue influence, the QoL questionnaires will be completed by the subject, unless the subject is unable to complete the questionnaire on their own (a 
note to file must be completed to document the inability of subject to complete the questionnaire) 
8  If troponin is collected at baseline and/or discharge, this should also be documented in the electronic case report forms. 
  

 
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6.3 
Index Procedure 
6.3.1 Procedure Involved in the Use of the Device 
 
 
Please refer to Instructions for Use (IFU) for instructions on handling and preparation of the TVRS. All 
Investigators must read and understand the Instructions for Use (IFU) that accompanies the Device. 
6.3.2 Subject Preparation 
 
Subjects must be prepared for the procedure as per the institution’s standard practice for a percutaneous 
procedure, general anesthesia, and TEE.   
 
Note: All Investigators must have documented training by the Sponsor on the TVRS and the 
Clinical Investigation Plan/Protocol.  
 
6.3.3 Anticoagulation Therapy 
 
After sheath insertion, administer intravenous heparin (or alternative anticoagulation therapy, e.g., 
bivalirudin) in accordance with standard hospital practice. Maintain an ACT (activated clotting time) of > 
250 seconds throughout the procedure. Low molecular weight heparin and fondaparinux may not be 
used for procedural anticoagulation. 
 
6.3.4 Treatment Procedure 
 
Refer to IFU including storage and handling requirements, preparation for use, pre-use checks of safety 
and performance, and precautions to be taken after use. 
 
Femoral vein catheterization will be completed in accordance with the Instructions For Use (IFU).  
Subjects will be eligible for analysis upon femoral vein puncture in preparation for the TVRS System 
insertion.  
 
The Steerable Guide Catheter (Guide) is inserted into the femoral vein.  Fluoroscopic and 
echocardiographic (2D and/or 3D-TEE) guidance will be used during the procedure to visualize the 
device, vasculature and cardiac/valve anatomy.  See Appendix V: Monitoring Exposure to Ionizing 
Radiation for requirements for training and data gathering on ionizing radiation required per this 
protocol. For subjects with renal dysfunction, intravenous contrast should not be used during the 
procedure unless absolutely necessary.   
 
The Guide is positioned in the Inferior Vena Cava/Right Atrium (IVC/RA) and the TVRS Delivery 
System is inserted into the Guide and properly positioned over the tricuspid valve.  The TVRS Delivery 
Catheter is advanced until the TVRS Clip emerges from the tip of the Guide into the right atrium.  
Manipulations of the catheter tip (via the control knobs on the handles) will continue in the right atrium 
until the Clip is properly oriented perpendicular to the line of coaptation of the tricuspid valve leaflets.  
The Clip is opened and advanced across the tricuspid valve into the ventricle then pulled back to grasp 
the leaflets.  2- and/or 3-dimensional echocardiography and color flow Doppler are used to evaluate 
leaflet insertion, Clip position and TR severity.  If the Clip is not positioned properly or TR has not been 
adequately reduced, additional grasping may be attempted and the Clip may be inverted and retracted 
into the right atrium as required for additional grasping attempts.  When placement is successful, the 
Clip is closed and deployed from the Delivery Catheter.  The catheters are then removed from the 
subject. 

 
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If placement of one Clip does not result in reduction in TR to a level deemed acceptable by the 
operator, then a second Clip may be placed to further reduce TR. The Investigator should determine if 
there is adequate tricuspid valve orifice area to accommodate the second Clip without creating tricuspid 
stenosis. A maximum of three (3) Clips will be allowed to be implanted in subjects enrolled in this trial. 
However, a fourth Clip may be used in the special circumstance if a previous Clip has detached from 
one leaflet. 
 
Procedural echocardiograms (TTE and TEE) may be collected immediately post-procedure by the site.  
Procedural echocardiographic images do not need to be submitted to the ECL. 
 
6.4 Post-Procedure 
6.4.1 Post-procedure Imaging and Care 
 
Immediately following the TVRS procedure, heparin (or alternative anticoagulation therapy, e.g., 
bivalirudin) should be discontinued and the ACT should be monitored in accordance with hospital 
protocols.  Vascular sheaths should be removed according to usual hospital practice. 
Subjects will receive standard post-cardiac catheterization procedure care as judged appropriate by the 
Investigator.  Subjects should be advised to limit strenuous physical activity for the first month following 
the TVRS procedure or longer, as deemed appropriate by the Investigator. 
 
• 
Final TTE and TEE echocardiograms may be acquired and saved by the site: TR severity, 
tricuspid valve and leaflet condition, and any evidence of device embolization, Single Leaflet 
Device Attachment (SLDA), bleeding, perforation, etc. Treatments for these will be per 
physicians’ discretion.   
• 
Post-TVRS procedure anticoagulation is recommended per the Investigator’s discretion or as 
described in Section 6.4.2.2. 
 
Prior to discharge: 
• 
A discharge TTE echocardiogram will be performed, 
• 
Subject physical and vital signs (i.e., weight, blood pressure, heart rate, temperature) will be 
recorded.  Each subject implanted with a Clip(s) must be provided the Implant Identification 
Card, included in each TVRS System package.  The subject must be instructed to keep this 
Implant Identification Card on their person at all times.  The serial number of all implanted TVRS 
Clip(s) must be recorded on the Implant Identification Card. 
 
6.4.2 Post-Procedure Medications 
 
6.4.2.1 Antibiotic Therapy 
 
Administer additional intravenous doses of antibiotics at approximately 6 and 12 hours (or per institutional 
guidelines) after the completion of the procedure. 
The Investigator should instruct all subjects who receive the TVRS device of the need for endocarditis 
prophylaxis, as recommended in the ACC/AHA 2008 Guideline Update on Valvular Heart Disease: 

 
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Focused Update on Infective Endocarditis32.  Subjects should be instructed to notify the Investigator or 
the subject’s primary care physician in the event that a procedure recommended by this Guideline is 
planned, so that prophylactic antibiotics can be prescribed.  A prescription for endocarditis prophylaxis 
may be provided to the subject at discharge. 
 
6.4.2.2 Antiplatelet/Anticoagulation Regimen 
 
Following placement of the TVRS device, anticoagulation therapy is prescribed.  If a loading dose of 
clopidogrel was not given prior to the TVRS procedure, it may be administered after the procedure at 
investigator discretion.  Post-TVRS procedure anticoagulation is as follows: 
1. Reinitiate warfarin, dabigatran or factor Xa inhibitor (if discontinued for the TVRS procedure) at 
pre-procedure levels or as appropriate.  If chronic oral anticoagulation is used, aspirin and 
clopidogrel use are not recommended, but are allowed if otherwise indicated for other 
conditions. 
2. If chronic oral anticoagulation is not used, it is strongly recommended that either daily 
clopidogrel (75 mg) and/or aspirin (≥75 mg) is administered for 6 months or longer. If aspirin is 
to be used, a loading dose of 325 mg acetylsalicylic acid (ASA) may be administered either pre- 
or immediately post-TVRS procedure followed by ≥75 mg per day for 6 months or longer at the 
Investigator’s discretion. 
 
6.4.2.3 Management of Hypertension 
 
Subjects should have their blood pressure checked prior to discharge. Subjects should be prescribed 
medication as necessary following current standard of care to maintain normotensive blood pressure. 
 
6.4.3 Procedural and Discharge Data 
 
The following TVRS procedural information should be recorded on the appropriate eCRF(s) after implant 
or attempted implant of the TVRS Clip: 
 
• 
General procedure information 
• 
TVRS implant information 
• 
Laboratory and clinical tests 
• 
Antiplatelet/Anticoagulation medications 
• 
Concomitant cardiovascular medications 
• 
Fluoroscopy duration 
• 
Adverse events 
• 
Protocol deviations 
• 
Device deficiency 
 
 
 
32 Nishimura, et al.  ACC/AHA 2008 Guideline Update on Valvular Heart Disease: Focused Update on Infective 
Endocarditas: A Report of the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines: Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography 
and Interventions, and Society of Thoracic Surgeons.  Circulation 2008; 118(8):887-894. 

 
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At the Discharge visit (Discharge occurs when subject leaves the implanting hospital), the following 
required tests and procedures should be completed (> 16 hours post TVRS procedure and no later 
than day of discharge) as outlined below, and the information should be captured on the 
appropriate eCRFs: 
 
• 
12-lead ECG 
• 
Blood draw 
• 
Brief physical exam including vital signs (weight, heart rate, blood pressure and temperature) 
• 
Echocardiogram (TTE) - discharge TTE must be performed at least 16 hours post TVRS 
procedure and no later than 24 hours post-discharge 
• 
Modified Rankin Scale 
• 
Adverse events 
• 
Protocol deviations 
• 
Device deficiency 
 
6.5 
Follow-up for All Subjects 
 
Required clinical follow-up will be performed at the following intervals for all subjects with TVRS 
procedure attempt, regardless of whether a TVRS Clip was successfully implanted:  
 
• 
Discharge post-TVRS procedure 
• 
30 days (+14 days) follow-up office visit (this visit must be conducted even if subject is in 
hospital) 
• 
6 months (180 days ± 28 days) follow up office visit 
• 
1 year (365 days ± 28 days) follow up office visit 
• 
2 years (730 days ± 28 days) follow up office visit 
• 
3 years (1095 days ± 28 days) follow up office visit 
• 
Discontinuation 
 
Follow-up visits will be calculated from the date of the Procedure.  Follow-up assessments can be 
performed at any point in the window, and should be conducted, whenever possible, by the same 
individual who performed the baseline tests.  The subject should be followed at the investigational site 
where the subject was enrolled, and may be followed at another investigational site only with prior 
agreement from that site’s Investigator and from the Sponsor. 
 
During the physical examination at the 30-day follow-up clinic visit, the implanting or treating 
investigator shall examine the integrity of the TVRS Clip.  At the 30-day, 6-month, 1-year, 2-year and 3-
year follow-up visits, all subjects must be examined by the Investigator.  Subjects must continue to take 
baseline medications without change during follow-up, unless clinically (medically) necessary. If there 
are any cardiovascular medication changes (including dosage changes), these changes should be 
documented on the electronic case report form. In general, neurohormonal antagonists should not be 
changed. Subjects implanted with the TVRS Clip must also be evaluated for device integrity. Required 
tests and procedures outlined below must be completed.  Timing of specific tests will follow the Clinical 
Evaluation Schedule (Table 2) outlined above.   All visits and tests must be completed even if the 
subject is in hospital. 
 
• 
12-lead ECG 
• 
Blood draw 

 
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• 
Brief physical exam including vital signs (weight, heart rate, blood pressure and 
temperature) 
• 
Echocardiogram – TTE at all follow-up visits and TEE at 30-day visit only 
• 
Modified Rankin Scale (Assessment of mRS should additionally be done at 90 days after 
onset of stroke)  
• 
6-Minute Walk Test (6MWT) (excluding discharge and 30-day follow-up visit)  – See 
APPENDIX VI for 6 Minute Walk Test Guidelines 
• 
Concomitant cardiovascular medications assessment 
• 
NYHA Functional Class assessment 
• 
QoL questionnaires to be completed by the subject; Note: To minimize bias and undue 
influence, the QoL questionnaires will be completed by the subject, unless the subject is 
unable to complete the questionnaire on their own (a note to file must be completed to 
document the inability of subject to complete the questionnaire) 
• 
Assess and record adverse events 
• 
Assess and record protocol deviations 
 
All subjects should continue to be monitored and treated per applicable standards of care consistent 
with the subject’s condition.  All subjects must be followed by the heart failure specialist investigator at 
all scheduled follow-up visits.  The site Principal Investigator should collaborate with the other site 
investigators as applicable in determining the treatment strategy for all subjects enrolled at their site. 
The electronic case report forms will document changes in treatment strategy (i.e. new use of CRT, 
PCI, tricuspid valve surgery, and/or mitral valve surgery) and who was involved with determining 
changes in treatment strategy.  Subjects implanted with the Clip must be evaluated for device integrity.  
  
Table 2 presents the Clinical Evaluation Schedule detailing assessments at baseline, discharge, 30 
days6 months, 1 year, 2 years and 3 years. These clinical assessments are standard assessments for 
most cardiac/structural heart interventional procedures and therefore should be administered per 
standard of care at each Institution. 
 
6.6 
Additional Follow-up Visits  
 
Additional subject visits may occur as clinically warranted. The following information must be collected 
as applicable:  
 
• 
Adverse events 
• 
Concomitant Cardiovascular Medications 
• 
Hospitalizations 
• 
Tricuspid valve surgery 
• 
Additional TVRS procedure(s) 
 
6.7 
Additional Interventions for TR Reduction 
 
It may be necessary for a subject to undergo additional interventions for TR reduction, such as an 
additional TVRS procedure or tricuspid valve surgery.  A TTE must be performed within 90 days prior to 
this additional intervention.  A 30-Day Post-TR Intervention Follow-up visit must be completed 30 days 
(+14 days) after the additional intervention.   
 
Requirements for this visit are as follows: 
 
• 
12-lead ECG 

 
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• 
Blood draw (Note: if serum creatinine is elevated by at least 0.5 mg/dl on any visit compared to 
the prior visit or to baseline, an additional serum creatinine must be obtained between 30 and 45 
days later to determine whether the increase is persistent) 
• 
Weight, temperature, blood pressure and heart rate 
• 
Transthoracic Echocardiogram (TTE) 
• 
Concomitant cardiovascular medications assessment  
• 
Assess and record adverse events  
• 
Assess and record protocol deviations  
 
Other scheduled follow-up visits from the date of the initial TVRS procedure must be conducted.   
 
6.8 
Heart-Related Office Visits 
 
A Heart-Related Office Visit eCRF should be completed if a subject is seen for a heart related reason at 
the investigational site or at any other facility. Information pertaining to adverse events, heart failure 
medication changes or hospitalizations, as appropriate, should also be collected. 
 
If an echocardiographic imaging study is performed at any visit, whether or not it is a study related visit, 
echocardiography images should be submitted to the ECL in a timely manner. 
 
6.9 
Tricuspid/Mitral Valve Surgery 
 
Tricuspid and/or mitral valve surgery should not be performed during the follow-up period, unless 
deemed necessary by the site investigator(s).  Tricuspid and/or mitral valve surgery will be considered 
a protocol deviation, unless the subject experiences a complication (e.g., endocarditis, clip detachment 
or leaflet injury) from the TVRS procedure. Subjects who undergo tricuspid and/or mitral valve surgery 
will continue to be followed per this Clinical Protocol. A TTE must be performed within 90 days prior to 
tricuspid and/or mitral valve surgery. 
 
A 30-Day Post-Tricuspid and/or Post-Mitral Valve Surgery Follow-up visit must be completed 30 days (-
3 /+14 days) after the tricuspid valve surgery. This visit should still be completed even if the subject is in 
the hospital. Requirements for this visit are described in Section 6.4 Follow-up for all Subjects. 
 
6.9.1 30-Day Post-Tricuspid and/or Post-Mitral Valve Surgery Follow-up 
 
Requirements for the 30-day Post-Tricuspid and/or Post-Mitral Valve Surgery Follow-up visit are 
described below. 
• 
12-lead ECG 
• 
Blood draw 
• 
Brief physical exam including vital signs (weight, heart rate, blood pressure and temperature) 
• 
Echocardiogram (TTE) 
• 
Modified Rankin Scale (Assessment of mRS should additionally be performed at 90 days after 
onset of stroke) 
• 
Concomitant cardiovascular medications assessment 
• 
NYHA Functional Class assessment 
• 
Assess and record adverse events 
• 
Assess and record protocol deviations 
 
Guidelines for the TTE/TEE are provided in Appendix VIII: Echocardiography Protocol. 

 
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6.10 
Explanted TVRS Clip 
 
The TVRS Clip may be explanted during tricuspid valve surgery or an autopsy. If possible, fluoroscopic 
images with side views of the device should be obtained prior to explant. Following explant of the TVRS 
Clip(s) during surgery, the subject will continue to be followed as defined in Section 6.4: Follow-up for 
All Subjects.  Explant information will be captured on the tricuspid Valve Surgery Form or Death Form. 
 
7.0 
ADVERSE EVENTS  
 
To comply with worldwide standards and guidelines on clinical trial adverse event reporting, Abbott has 
developed uniform and worldwide applicable standard definitions and reporting timelines to be used and 
adhered to by the investigators.  
 
7.1 
Definitions 
7.1.1 Adverse Event 
 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device. 
 
Note 1: This definition includes events related to the investigational medical device. 
 
Note 2: This definition includes events related to the procedures involved. 
 
Note 3: For users or other persons, this definition is restricted to events related to investigational medical 
devices. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product. 
 
7.1.2 Serious Adverse Event 
 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
 
1) Led to a death, 
2) Led to a serious deterioration in health that either: 
a) Resulted in a life-threatening illness or injury, or 
b) Resulted in a permanent impairment of a body structure or a body function, or 
c) Required in-patient hospitalization or prolongation of existing hospitalization, or 
d) Resulted in medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
3) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
4) An important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical judgment, 
may jeopardize the subject and/or may require intervention to prevent one of the outcomes 
listed in this definition. 

 
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Note 1: This includes device deficiencies that might have led to a serious adverse event if a) suitable 
action had not been taken or b) intervention had not been made or c) if circumstances had been less 
fortunate. These are handled under the SAE reporting system. 
 
Note 2: A planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered to be a serious adverse 
event. 
 
7.1.3 Device Deficiency/Device Malfunction 
 
Device deficiency (DD) is defined as an inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance, such as malfunction, misuse or use error and inadequate 
labeling. This includes the failure of the device to meet its performance specifications or otherwise 
perform as intended. Note: Performance specifications include all claims made in the labeling of the 
device. 
 
A device malfunction (DM) is the failure of a device to meet its performance specifications or otherwise 
perform as intended, when used in accordance with the instructions for use or CIP. 
 
7.2 
Device Relationship 
 
Determination of whether there is a reasonable possibility that an investigational 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). 
 
7.2.1 Unanticipated (Serious Adverse) Device Effect [U(S)ADE] 
 
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 
7.3 
Adverse Event/Device Deficiency/Product Experience Reporting 
7.3.1 Adverse Event Reporting 
 
All adverse events will be collected on each subject through the 3-year follow-up visit. 
 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be recorded 
on the AE eCRF page.  
 
Non-cardiac related abnormal laboratory values will not be considered AEs unless:  
1) the investigator determined that the value is clinically significant,  
2) the abnormal lab value required intervention, or  
3) the abnormal lab value required subject termination from the study. 
 

 
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The Investigator will monitor the occurrence of AEs for each subject during the course of the clinical 
trial/investigation and report as required by this Protocol in Section 7 per AE and SAE definitions. AEs 
need to be collected as of the time point of subject enrollment on the appropriate AE eCRF form. 
Additional information with regards to an adverse event should be updated within the appropriate case 
report form.  
 
A fax form will be made available to allow the investigator to report SAEs in the event the entry cannot 
be made in the EDC (SM FORM 589: SAE Notification). This does not replace the EDC reporting system. 
All information must still be entered in the EDC system as soon as feasible.  
 
The investigator should report all SAEs to the Sponsor as soon as possible but no later than outlined 
below.  
 
Study site 
Reporting timelines 
All Study Sites 
SAEs must be reported 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.  
 
Serious adverse events that occurred in the user or persons other than the study subject should not be 
entered in the EDC system however needs to be reported via the SAE Notification Form provided by 
Sponsor (SM FORM 589: SAE Notification).   
 
The Investigator will further report the SAE to the local IRB/EC according to the institution’s IRB/EC 
reporting requirements.    
 
7.3.2 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and IRB 
 
Abbott requires the Investigator to report any USADE to the sponsor within 3 calendar days of the 
investigator’s knowledge of the event, unless local requirements are more stringent, and to the IRB/EC 
per IRB/EC requirements.  
 
7.3.3 Device Deficiency/Device Malfunction Reporting 
 
All device deficiencies/malfunctions should be reported within the EDC System on the appropriate eCRF 
form.  A fax form will be made available to allow the investigator to report device deficiencies/malfunctions 
in the event that the entry cannot be made in the EDC (SM FORM 589: Device Deficiency (DD) Report 
Form). This does not replace the EDC reporting system. All information must still be entered in the EDC 
system as soon as feasible.  
 
In case a device deficiency/malfunction occurred before the patient ID is assigned, the device deficiency 
should be reported to the Sponsor via Abbott customer service via the fax form FRM2015541-ABT. 
 
The investigator should report all DDs/DMs to the Sponsor as soon as possible but no later than outlined 
below.  
 

 
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Study sites 
Reporting timelines 
All Study Sites 
DDs/DMs must be reported no later than 3 calendar days from the day the 
study personnel became aware of the event or as per the investigative site’s 
local requirements, if the requirement is more stringent than those outlined. 
 
The device, if not implanted or not remaining in the subject, should be returned to Abbott.   
 
Device deficiencies/malfunctions should be reported to the IRB/EC per the investigative site’s local 
requirements. 
 
7.3.4 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
 
The Sponsor will report the SAEs and DDs/PEs to the country regulatory authority, per local 
requirements.  For Germany only: German specific reporting requirements are outlined in the Germany 
Addendum #1. 
 
 
Clinical trial SAEs and device deficiencies reportable per MEDDEV 2.7/3 regulations will be submitted to 
European Competent Authorities by the Abbott Clinical Safety Group or designee. Contact details are 
provided in Appendix III.  
 
7.4 
Safety Monitoring by Data Safety Monitoring Board  
 
The DSMB will serve in an advisory role to Abbott to ensure safety by reviewing cumulative data from 
the clinical trial at prescribed intervals for the purpose of safeguarding the interests of trial participants.  
 
The DSMB may consider a recommendation for modifications or termination of the trial based on any 
perceived safety concerns regardless of statistical significance. The recommendations of the DSMB are 
not binding, and all final decisions related to trial modifications rest with Abbott. 
 
8 
ADJUDICATION OF EVENTS 
 
8.1 
The Clinical Events Committee (CEC) 
 
The Clinical Events Committee is comprised of qualified physicians who are not investigators in the trial. 
The CEC will review and adjudicate pre-specified events reported by trial investigators or identified by 
the Safety & Surveillance personnel/designate for the trial as documented in CEC Manual of Operations 
(MOPs). 
 
9. 
STATISTICAL ANALYSIS 
 
9.1 
Statistical Overview  
 
This study aims to evaluate the safety and effectiveness of the TVRS for the treatment of patients with 
symptomatic moderate or greater TR who are high-risk for tricuspid valve surgery and the benefit-risk 
analysis supports utilization of percutaneous transcatheter intervention by the site heart team. The 

 
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primary effectiveness endpoint is at least one grade of Tricuspid Regurgitation (TR) reduction at 30 days 
(success rate). The primary safety endpoint is major adverse events (MAE) at 6 months. 
 
9.2 
Analysis Populations  
 
Subjects who have a signed and dated Informed Consent form are considered enrolled in the study. The 
primary analysis population is defined as enrolled subjects who have an attempted TVRS procedure 
upon, femoral vein puncture (i.e., analysis subjects).  
 
In addition, analysis will be performed on the “Per-Treatment Evaluable” population, which is defined as 
enrolled subjects who have at least one TVRS Clip deployed and implanted. Subjects who have TVRS 
procedure attempted but no TVRS Clip implanted will be excluded from the “Per-Treatment Evaluable” 
population.  
 
Adverse events collected on screen failure patients or in those who are enrolled but have not attempted 
TVRS procedure, upon femoral vein puncture, will be reported separately.   
 
9.3  
Sample Size Calculations and Assumptions  
9.3.1  Primary Effectiveness Endpoint: 
 
The primary effectiveness endpoint of the study is echocardiographic TR reduction at least 1 grade at 30 
days post-procedure, and it will be tested against a pre-specified performance goal.  
 
The statistical hypotheses for the primary efficacy endpoint are as follows: 
 
H0: P ≤ 35% 
H1: P > 35%, 
 
where P is proportion of subjects with at least one grade of TR reduction at 30 days.  
 
The sample size calculation for the primary endpoint success rate at 30 days is based on the following 
assumptions: 
• 
Expected primary endpoint success rate at 30 days = 60% 
• 
Performance Goal = 35% 
• 
One-sided type I error rate = 2.5% 
• 
Exact binomial test 
 
Based on the above assumptions, a total of 75 subjects will provide at least 95% power to conclude that 
the primary effectiveness endpoint meets its performance goal. Assuming approximately 10% attrition 
rate at 30 days due to missing TR assessment as a result of death, withdrawal, loss to follow-up or 
unreadable echo images, a total of 85 subjects will undergo the TVRS procedure. 
 
Power calculations were performed using Power Analysis and Sample Size (PASS) 11 Software. Further 
details on statistical analysis, including event rate assumptions and justification of the performance goals 
are described in the Statistical Analysis Plan (SAP).      
 
9.3.2 Primary Safety Endpoint: 
 

 
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The primary safety endpoint of MAE rate at 6 months will be tested against a pre-specified performance 
goal.  
 
 
The statistical hypotheses for the primary safety endpoint are as follows: 
 
H0: P ≥ 39% 
H1: P < 39%, 
 
where P is the MAE rate at 6 months.  
 
The power calculation for the primary safety endpoint of MAE at 6 months is based on the following 
assumptions 
• 
Expected the true MAE rate at 6 months   = 23% 
• 
Performance Goal = 39% 
• 
One-sided type I error rate = 2.5% 
• 
Exact binomial test 
 
Based on the above assumptions, a total of 75 subjects will provide approximately 82% power to 
conclude that the MAE rate at 6 months meets its performance goal. Assuming a 10% attrition rate (due 
to withdrawal, lost to follow-up, or non-cardiovascular death without an MAE) at 6 months, a total of 85 
subjects will undergo the TVRS procedure. 
 
Power calculations were performed using PASS 11.  Further details on statistical analysis, including 
event rate assumptions and justification of the performance goals are described in the SAP.     
 
9.4 
Statistical Analyses  
 
Detailed analyses of endpoints will be performed when all the patients complete their follow-up visit at 
each time point. Baseline demographic, clinical, echocardiographic, procedure and device data, and 
treatment results will be summarized using descriptive summary statistics.  
 
9.4.1 Primary Effectiveness Endpoint Analysis  
 
The primary endpoint of TR reduction at least 1 grade at 30 days post-procedure will be analyzed based 
on the primary analysis population defined in Section 9.2.  Exact binomial test will be used to test the 
success rate against a PG of 35%.  
 
9.4.2 Primary Safety Endpoint Analysis 
 
The primary safety endpoint of MAE rate at 6 months will be tested against a pre-specified performance 
goal of 39% based on the primary analysis population. The Kaplan-Meier analysis will be used to compute 
the MAE rate at 6 months; the standard error and confidence limits will be computed using Greenwood’s 
method. Subjects who have not experienced any MAE event, and die due to non-cardiovascular cause 
within 6 months, will be censored at the date of death. Subjects who have not experience any MAE event, 
and withdrew prior to 6 months, will be censored at the date of withdrawn.  
 

 
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9.4.3 Secondary & Exploratory Endpoint Analyses  
 
Analyses of secondary and exploratory endpoints will be descriptive in nature. Refer to Statistical 
Analysis Plan for statistical method. 
 
9.4.4 Handling of Multiplicity Issues  
 
Both the primary effectiveness endpoint and the primary safety endpoint must be met for study success. 
Therefore, the overall Type I error rate of the study is conservatively controlled at 2.5% and there is no 
need to adjust the level of significance for multiplicity.   
9.4.5 Labeling Claim  
 
Any pre-specified endpoint of the study may be considered for labeling.  
 
9.4.6 Procedures for Accounting for Missing, Unused or Spurious Data 
 
All analyses will be based on available data with missing data excluded. Any unused or spurious data 
will be noted as appropriate in the final report. Sensitivity analysis for the primary safety and effectiveness 
endpoints will be performed to assess the impact of missing data on the results and is described in the 
SAP.  
 
9.5  
Deviations from the Original Statistical Plan 
 
Any major changes to the statistical plan will be documented in an amendment to the statistical analysis 
plan. Less significant changes to the planned analyses will be documented in the final report. 
 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
The investigator/institution will permit direct access to source data/documents in order for clinical 
investigation-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 
investigation. The investigator will obtain, as part of the informed consent, permission for clinical 
investigation monitors or regulatory authorities to review, in confidence, any records identifying the 
subjects in this clinical investigation. This information may be shared with regulatory agencies; however, 
Sponsor undertakes not to otherwise release the subject's personal and private information. 
 
11. 
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 investigation of 
the Clinical Investigation device. Sites will be selected based upon review of a recent site assessment, if 
applicable, and the qualifications of the Principal Investigator or multidisciplinary team at the site. 
 
 

 
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11.2  Protocol Amendments  
 
Approved Protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment. The Principal Investigator is responsible for notifying the IRB/EC or 
equivalent committee of the Protocol amendment (administrative changes) or obtaining IRB’s/EC’s 
approval of the Protocol amendment (changes in subject care or safety), according to the instructions 
provided by the Sponsor with the Protocol amendment.  Other regulatory bodies will be notified of 
protocol amendments, as required per country regulation. 
 
Acknowledgement/approval by the IRB/EC of the Protocol amendment must be documented in writing 
prior to implementation of the Protocol amendment. Copies of this documentation must also be 
provided to the Sponsor. 
 
11.3 
Training 
 
11.3.1 Site Training  
 
All Investigators/trial personnel are required to attend Sponsor training sessions, which may be 
conducted at an Investigator meeting, a site initiation visit or other appropriate training sessions. Over-
the-phone or self-training may take place as required. Training of Investigators/trial personnel will include, 
but is not limited to, the Protocol requirements, investigational device usage, echocardiographic imaging, 
electronic case report form completion and trial personnel responsibilities. All Investigators/trial personnel 
that are trained must sign a training log (or an equivalent) upon completion of the training. Prior to signing 
the training log, Investigator/trial personnel must not perform any trial-related activities that are not 
considered standard of care at the site.  
 
11.3.2 Training Required for the Use of the Device 
 
 
TVRS implanting investigators will be trained in accordance with the approved TVRS System Instruction 
for Use (IFU) and established TVRS Therapy Training. Training will include, but will not be limited to, the 
use of a heart model and demonstration unit to ensure that investigators understand the mechanics and 
characteristics of the TVRS System, including echocardiographic imaging techniques necessary for 
proper imaging of the tricuspid apparatus. Sponsor staff will conduct this training and a training log will 
be used to document the training. Only physicians who receive all required device training and complete 
a training log can perform the TVRS procedure under this Clinical Investigational Plan. The Sponsor will 
be available to provide technical support to answer questions regarding the function and operation of the 
TVRS System. 
 
11.3.3 Training of Sponsor’s Monitors 
 
 
Sponsor and/or designated monitors will be trained to the Protocol, case report forms and investigational 
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.  
 

 
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The Sponsor should be contacted for additional information on the person(s) responsible for monitoring 
activities at the following address:  
 
Abbott Vascular, Inc. 
3200 Lakeside Drive 
Santa Clara, CA 95054, USA 
 
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/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 the Protocol for any reason without prior written approval from 
Sponsor except in cases of medical emergencies, when the deviation is necessary to protect the rights, 
safety and well-being of the subject or eliminate an apparent immediate hazard to the subject. In that 
event, the Investigator will notify Sponsor immediately by phone or in writing. All deviations must be 
reported to the Sponsor. In subject-specific deviations from the Protocol, a Protocol deviation case report 
form will be completed. The occurrence of Protocol deviations will be monitored by the Sponsor for 
evaluation of investigator compliance to the Protocol and regulatory requirements and dealt with 
according to written procedures. Investigators will inform their IRB/EC or equivalent committee of all 
Protocol deviations in accordance with their specific IRB/EC or equivalent committee reporting policies 
and procedures.  
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or company 
representative will attempt to secure compliance by one or more of the following (and not limited to):  
• 
Visiting the investigator and/or delegate 
• 
Telephoning the investigator and/or delegate 
• 
Corresponding with the investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the Protocol or any other conditions of the study 
may result in further escalation in accordance with the Sponsor’s written procedures including securing 
compliance or, at its sole discretion; Sponsor may terminate the investigator's participation in the study.  
 

 
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11.6 
Quality Assurance Audit 
 
 
A Sponsor representative or designee may request access to all clinical investigation 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 investigation, 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 investigation (e.g., Form FDA 483, Inspectional Observations, Warning Letters, Inspection 
Reports, etc.). Sponsor may provide any needed assistance in responding to regulatory audits. 
 
11.7 
Sponsor Support to Clinical Trial/Investigation Site for Regulatory Body Inspection 
 
In the event that an Investigator is contacted by a Regulatory Agency in relation to this clinical 
investigation, the Investigator will notify the Sponsor immediately and 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 investigation.  The Sponsor 
may provide any needed assistance in responding to regulatory inspections. 
 
11.8 
Committees  
11.8.1 Study Steering Committee  
 
The Steering Committee is assigned by the Sponsor and comprises the Primary Investigator, as specified 
on the cover page of this Protocol, the Study Chairman (if applicable) and four/five dedicated members 
from the investigational sites. The Chairman of the core laboratories and other sponsor’s personnel may 
also participate in the Committee meetings if appropriate. Meeting minutes from this committee will be 
filed with the sponsor. 
 
The Steering Committee is responsible for overseeing the scientific and operational aspects of the study. 
This committee will meet regularly to monitor patient enrollment, general data collection and non-
compliance with the investigation plan at individual centers, to review and act upon recommendations of 
the Data and Safety Monitoring Board (DSMB), to review operational issues that may arise and warrant 
a Protocol amendment or other corrective action and to determine policy regarding any publications 
arising from data generated from the performance of the study. 
 
11.8.2 Data Safety Monitoring Board (DSMB) 
 
The Data Safety Monitoring Board (DSMB) is an independent multidisciplinary group that is restricted to 
individuals free of apparent significant conflicts of interest. The source of these conflicts may be financial, 
scientific, or regulatory in nature. The DSMB is typically composed of at least two physicians with relevant 
interventional experience (e.g., vascular surgeon, interventional radiologist, interventional cardiologist) 
and a biostatistician and is responsible for making recommendations regarding endpoint analyses and 
any potentially significant patient safety-related observations. The composition of the DSMB, frequency 
of the DSMB sessions and the statistical monitoring guidelines are described in detail in the DSMB 
charter. DSMB meeting minutes and recommendations are forwarded to Abbott Vascular.   
 

 
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11.8.3 Clinical Events Committee (CEC) 
 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of qualified 
physicians who are not participants in the trial. The CEC will review and adjudicate events as defined in 
the CEC charter and according to definitions provided in this Protocol.  (See Section 8.1). 
 
11.8.4 Eligibility Committee  
The Eligibility Committee consisting of a Cardiac Surgeon, an Interventionalist and an Echocardiographer 
reviews data provided by the investigational site and echo data from the echo core laboratory, and 
conducts clinical assessment.  The Eligibility Committee finally decides whether a patient can be enrolled 
in the clinical trial or not (Appendix IX). 
 
12. 
DATA HANDLING AND RECORD KEEPING 
 
 
Data Management will include documentation of the systems and procedures used in data collection for 
the duration of the trial.  
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 Vascular. 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 trial, 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 investigational site and a backup copy archived with Abbott Vascular.  
For the clinical trial/investigation duration, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical trial/investigation progress records, 
laboratory reports, electronic case report forms, signed ICFs, device accountability records, 
correspondence with the IRB/EC and clinical trial/investigation monitor/Sponsor, adverse event reports, 
and information regarding subject discontinuation or completion of the clinical trial/investigation. 
 
12.1 
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 investigation: 
• 
Medical history/physical condition of the subject before involvement in the trial sufficient to verify 
Protocol entry criteria 
• 
Dated and signed notes on the day of entry into the trial referencing the Sponsor, Protocol number 
or name, subject ID number and a statement that informed consent was obtained 
• 
Dated and signed notes from each subject visit (for specific results of procedures and exams) 
• 
Adverse events reported and their resolution including supporting documents such as discharge 
summaries, catheterization laboratory reports, ECGs, and lab results including documentation of 
site awareness of SAEs and of investigator device relationship assessment of SAEs. 

 
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• 
Study required laboratory reports and 12-lead ECGs, reviewed and annotated for clinical 
significance of out of range results.  
• 
Notes regarding Protocol-required and prescription medications taken during the trial (including 
start and stop dates) 
• 
Subject’s condition upon completion of or withdrawal from the trial 
• 
Any other data required to substantiate data entered into the CRF 
 
12.2 
Electronic Case Report Form Completion 
 
Primary data collection based on source-documented hospital and/or clinic chart reviews will be 
performed clearly and accurately by site personnel trained on the Protocol and eCRF completion. eCRF 
data will be collected for all patients that are enrolled into the trial. 
 
12.3 
Record Retention 
 
 
The Sponsor will archive and retain all documents pertaining to the trial as per the applicable regulatory 
record retention requirements. The Investigator must obtain permission from Sponsor in writing before 
destroying or transferring control of any clinical trial/investigation records. 
 
12.4 
Investigational Devices 
12.4.1 Investigational Device Accountability 
 
Abbott ships investigational devices only to the site Principal Investigator or his/her designee at each site.   
 
The Investigator will maintain adequate records of the receipt and disposition of the investigational device, 
including part number and serial number, date used, patient ID number and treating physician.  
Inventory Accountability Log supplied by the Sponsor will be used. The Inventory Accountability Log must 
document the disposition of all investigational devices including those that have been returned to Sponsor. 
 
All investigational devices that are associated with a device failure or device deficiency must be returned 
immediately to the Sponsor. 
 
13. 
ETHICAL CONSIDERATION 
13.1 
Institutional Review Board/Medical Ethics Committee Review  
 
Institutional Review Board (IRB)/ Ethics Committee (EC) approval for the Protocol and ICF/other written 
information provided to the patient will be obtained by the Principal Investigator at each investigational 
site prior to participation in this clinical trial/investigation. The approval letter must be received prior to 
the start of this clinical trial/investigation and a copy must be provided to the Sponsor. No changes will 
be made to the Protocol or ICF or other written information provided to the patient without appropriate 
approvals, including IRB/EC, the Sponsor, and/or the regulatory agencies.  
 
Until the clinical trial/investigation is completed, the Investigator will advise his/her IRB/EC of the progress 
of this clinical trial/investigation, per IRB/EC requirements. Written approval must be obtained from the 
IRB/EC yearly to continue the clinical trial/investigation, or according to each institution’s IRB/EC 

 
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requirements (US studies only). Further, any amendments to the Protocol as well as associated ICF 
changes will be submitted to the IRB/EC and written approval obtained prior to implementation, according 
to each institution’s IRB/EC requirements. 
 
No investigative procedures other than those defined in this Protocol will be undertaken on the enrolled 
subjects without the written agreement of the IRB/EC and the Sponsor. 
 
14. 
PUBLICATION POLICY 
 
 
The data and results from the trial 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 trial. The Investigators will not use 
the Clinical trial/investigation-related data without the written consent of the Sponsor for any other 
purpose than for Clinical trial/investigation completion or for generation of publication material, as 
referenced in the Clinical trial/investigation Site Agreement. The publication and/or presentation of results 
from a single clinical trial/investigation site are not allowed until publication and/or presentation of the 
multi-center results. The Sponsor acknowledges that the trial’s Principal Investigator intends to publish a 
multi-center publication regarding the clinical trial/investigation 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 
trial/investigation Site Agreement. 
 
The Sponsor will register the Clinical Investigation on www.clinicaltrials.gov, in accordance with the 
International Committee of Medical Journal Editors guidelines, or any other applicable guidelines. 
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 Trial. 
A full report of the pre-specified outcomes, including any negative outcomes, will be made public through 
the ClinicalTrials.gov website according to the requirements of Section 801 of the FDA Amendments Act.  
 
15. 
RISK ANALYSIS 
 
15.1 
Anticipated Clinical Benefits 
 
The causes of tricuspid regurgitation (TR) can be classified as degenerative (or primary) when due to 
abnormal tricuspid valve (TV) pathology, functional (or secondary), or induced by pacemaker or 
defibrillator leads1. Functional tricuspid regurgitation (FTR) is the most common and an increasingly 
recognized source of morbidity in patients with left-sided valvular heart disease, particularly those with 
chronic mitral valve regurgitation (MR)2. FTR occurs mainly from tricuspid annular dilation and right 
ventricular enlargement, which can result from heart failure due to myocardial or valvular causes, right 
ventricular volume and pressure overload, or dilation of cardiac chambers. 
Current guidelines indicate medical therapy (i.e. diuretics) to address venous congestion and/or 
treatment of the underlying disease to reduce TR. Surgical treatment of FTR is recommended at the time 
of left sided valve repair3. FTR may diminish or disappear as right ventricular function improves following 
treatment for the underlying cause. If Functional tricuspid regurgitation (FTR) is left untreated at the time 
of surgical mitral valve repair, significant residual FTR can negatively impact perioperative outcomes, 
functional class, and survival. TR does not reliably resolve after successful mitral valve surgery. 
Severe TR is an independent predictor of long-term mortality given that 1-year survival rate in patients 
with severe TR is 65% compared with 90% of patients without TR4. If treated surgically, it is often in late 

 
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stage of the disease with poor outcomes. Operative mortality in high risk patients has been reported to 
be 22%5.  
Tricuspid Valve Repair System (TVRS) would be used to treat symptomatic moderate or severe TR 
subjects who are not responding to medical therapy.  Left untreated these patients will continue to 
progress with higher morbidity and mortality rates associated with this disease. 
 
Thus, the potential benefits of the TVRS include, but may not be limited to, the following:  
• 
Reduction in heart failure hospitalization rates 
• 
Improved symptomatic status and functional capacity 
• 
Improved NYHA classification 
• 
Improved quality of life 
• 
Improved RV function  
• 
Reduced mortality 
 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects  
 
Risks associated with the TVRS and procedure, together with their likely incidence, is described in the 
IFU and Appendix IV. There may be risks related to the device that are unknown at present.  Likewise, 
the exact frequency of the risk may be unknown.   
 
15.3 
Residual Risks Associated with the Investigational Device, as Identified in the Risk 
Analysis Report 
 
The residual risks to the patient was identified from the literature review or the complaint data review. 
 
15.4 
Risks Associated with Participation in Clinical Investigation 
 
The risks related to the procedure have been included in Appendix IV. 
 
15.5 
Possible Interactions with Protocol-Required Concomitant Medications 
 
The most prevalent risks associated with the anticoagulant and antiplatelet medications have been 
included in Appendix IV. 
  
15.6 
Steps that will be Taken to Control or Mitigate the Risks 
 
In-depth recommendations, special precautions and instructions regarding patient selection, device 
handling, device placement and system removal are included in the IFU. 
 
Risks associated with the use of the TVRS during this clinical study are minimized through device design, 
investigator selection and training, pre-specified patient eligibility requirements, study monitoring to 
ensure adherence to the protocol and the use of a DSMB.  
 
These risk management aspects are detailed below: 
 
Device Design: The design of the TVRS includes many features aimed at minimizing potential risks. 
The major safety features of the device are described below:  

 
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• 
The Clip Delivery System is designed to deploy the implant in a way that requires multiple steps 
to ensure safe delivery of the device. 
• 
It is a percutaneously implanted mechanical Clip. The TVRS Clip grasps and coapts the tricuspid 
valve leaflets resulting in fixed approximation of the tricuspid leaflets throughout the cardiac cycle.  
• 
The TVRS is placed without the need for arresting the heart or cardiopulmonary bypass. The 
implantable Clip is manufactured with metal alloys and polyester fabric (Clip cover) that are 
commonly used in cardiovascular implants. 
• 
The TVRS arms can be adjusted to any position from fully opened, fully inverted and fully closed. 
These positions are designed to allow the Clip to grasp and approximate the leaflets of the 
tricuspid valve using controls on the Delivery Catheter Handle. The Clip can be locked, unlocked 
and repeatedly opened and closed. The Grippers can be raised or lowered repeatedly. 
• 
The TVRS is covered with polyester fabric to promote tissue in-growth which anchors the device 
to the leaflets. 
• 
The TVRS is constructed from well-characterized, biocompatible materials that have undergone 
extensive testing. 
 
Investigator Selection and Training: It is also stated in the IFU that the devices can only be used by 
physicians who have received appropriate training on how to use the device. This statement is 
interpreted to mean that the physician users are expected to be aware of the known and foreseeable 
safety risks associated with the use of the devices including the surgical and/or non-surgical treatment 
of these conditions. 
 
• 
Only physicians who are skilled in the manipulation of catheter based technology in the 
vasculature and heart, and have a good understanding of the risks associated with these 
manipulations, will be selected as investigators for this trial. In addition, site investigators will 
undergo training on the techniques required to optimally place the device on the tricuspid 
leaflets. The physician users are expected to be aware of the known and foreseeable safety 
risks associated with the use of the devices including the surgical and/or non-surgical treatment 
of these conditions.  
• 
Emergency surgical back-up should be available as per the institution’s standard procedures. The 
Sponsor will be available to provide technical support to answer questions regarding the function 
and operation of the TVRS.  
• 
Each case would be proctored by an Abbott field personnel. 
• 
Pre-specified patient eligibility requirements - as stated in Section 5 of the protocol. 
 
Ensuring Strict Adherence to the Clinical Protocol  
 
The trial will be carefully monitored by the Sponsor monitor (or designee) to ensure adherence to the 
Clinical Investigational Plan. Adverse events and device deficiencies will be reported to Abbott /designee 
and will be monitored internally for safety surveillance purposes. A DSMB will be used for the study. 
Stopping rules will be discussed with the DSMB and applied for subject safety through enrollment 
 
15.7 
Risk to Benefit Rationale  
 
Current treatments for clinically significant TR are generally limited to medical management and/or 
tricuspid valve repair or replacement. Medical management may reduce symptoms and improve quality 
of life in some patients, but fails to address the underlying pathophysiology of TR (e.g., malcoaptation of 
tricuspid valve leaflets).  Tricuspid valve replacement (TVR) is associated with high mortality and 
morbidity. Frequently, TVR is performed in critically ill patients with high frequency of re-intervention. 
Patients with clinically significant TR who are difficult for tricuspid valve surgery have limited therapeutic 

 
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options and present with a high rate of heart failure hospitalizations, poor quality of life, and impaired 
functional capacity. The potential benefit derived from improvements in quality of life for non-operable 
patients greatly outweighs the potential of any risks associated with the introduction of a new therapeutic 
approach. An analysis of risk-benefit of a particular therapy must take into account treatment results 
across the intended population spectrum. Unable to undergo surgery, high risk patients place a large 
burden on their families and the medical care system as they demand a high level of ongoing care, 
including frequent hospitalizations. The potential risks of a novel therapy are therefore mitigated by the 
unique needs of an ailing, highly symptomatic TR population with poor quality of life and limited treatment 
options. According to published literature, at least 95 patients (off-label or compassionate use; as of 
March 2017) have received the MitraClip device at the tricuspid valve with low adverse event rates, 
reduction in TR severity, and improvement in symptoms. 
 
Thus, TVRS indicates a potentially safe procedure, addresses the unmet clinical needs of a difficult-to-
treat patient population and the potential benefit of TR reduction from TVRS outweighs any potential risk 
associated with the novel procedure. 
 

 
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APPENDIX I: ABBREVIATIONS AND ACRONYMS 
 
6MWT or 6MWD – Six Minute Walk Test (Distance) 
AE – Adverse Event 
APS – Acute Procedural Success 
CRO – Contract Research Organization 
CRT or CRT-D – Cardiac Resynchronization Therapy Device 
CV - Cardiovascular 
CVA – Cerebrovascular Accident 
DBP – Diastolic Blood Pressure 
DD or DM – Device Deficiency or Device Malfunction 
DSMB – Data Safety Monitoring Board 
EC – Ethics Committee 
ECL – Echocardiographic Core Laboratory 
eCRF – Electronic Case Report Form 
EFS – Early Feasibility Study 
EROA – Effective Regurgitant Orifice Area 
ESC – European Society of Cardiology 
FDA – Food and Drug Administration 
IB – Investigator Brochure 
ICD - Implantable cardioverter-defibrillators 
ICF – Informed Consent Form 
IFU - Instruction for Use 
IRB – Institutional Review Board 
IVC – Inferior Vena Cava 
KCCQ – Kansas City Cardiomyopathy Questionnaire 
LVEF – Left Ventricular Ejection Fraction 
MAE – Major Adverse Event 
MI – Myocardial Infarction 
MR – Mitral Regurgitation 
NYHA – New York Heart Association 
PAP – Pulmonary Artery Pressure 
PISA – Proximal Isovelocity Surface Area 
QoL – Quality of Life 
RA – Right Atrium 
RV – Right Ventricle 
RVEDD - Right Ventricular End Diastolic Dimension 
RVEDV – Right Ventricle End Diastolic Volume 
RVEF - Right Ventricular Ejection Fraction 
RVESD - Right Ventricular End Systolic Dimension 
RVESV - Right Ventricular End Systolic Volume 
RVSP - Right Ventricular Systolic Pressure 
SBP – Systolic Blood Pressure 
SF-36 – Short Form 36 
SLDA – Single Leaflet Device Attachment 
STS – Society of Thoracic Surgery 
TAPSE - Tricuspid Annular Plane Systolic Excursion 
TEE – Trans-esophageal Echocardiogram 
TR – Tricuspid Regurgitation 

 
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TTE – Transthoracic Echocardiogram 
TVRS – Tricuspid Valve Repair System 
VC – Vena Contracta 
 
 
 
 

 
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APPENDIX II: DEFINITIONS 
 
ANTICIPATED ADVERSE EVENT 
Derived from ISO14155, MEDDEV 2.7.3: an effect which by its nature, incidence, severity or outcome 
has been previously identified as “POTENTIAL COMPLICATIONS AND ADVERSE EVENTS”, as 
documented in the IFU or CIP (Appendix IV). 
 
ATRIAL FIBRILLATION (AF) 
Per Heart Rhythm Society Guidelines 
 
• 
Paroxysmal: Recurrent (≥ 2) atrial fibrillation episodes that terminate spontaneously within 7 days. 
• 
Persistent:  Atrial fibrillation that is sustained beyond 7 days, or lasting less than 7 days but 
necessitating pharmacologic or electrical cardioversion. 
• 
Longstanding Persistent AF: Continuous atrial fibrillation of greater than 1 year duration. 
• 
Permanent:  Atrial fibrillation in which cardioversion has failed or not been attempted.  
 
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 TVRS Clip from the tricuspid leaflets as assessed by the study site. 
 
Diagnosis and management of any occurrence or suspected occurrence of device embolization will be 
per the site investigator’s best medical judgment.  Some recommendations for clinical diagnosis and 
management of device embolization include but are not necessarily limited to those outlined below: 
• 
Diagnosis:  
o Observation of patient’s clinical symptoms,  
o Assessment of Clip status via TTE examination of valve, and/or  
o Fluoroscopy and/or x-ray imaging. 
• 
Management will depend on the specific patient’s clinical situation and will be determined by the 
site investigator’s best medical judgment including assessment of overall risks and benefits of 
further intervention.  Some methods of management to consider are:  
o Continued regular clinical monitoring of the patient and the embolized device; 
o Transcatheter manipulation method(s) to stabilize device position;  

 
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o Removal through percutaneous approach and/or  
o Removal through surgical approach. 
 
 
DEVICE THROMBOSIS 
Formation of an independently moving thrombus on any part of the TVRS Clip evidenced by 
echocardiography or fluoroscopy.  If the TVRS Clip is explanted or an autopsy is performed, this 
diagnosis should be confirmed. 
 
ENDOCARDITIS 
A diagnosis of endocarditis based on the following Duke criteria, from The ACC/AHA Guidelines for the 
Management of Patients with Valvular Heart Disease, JACC, Vol 32, No.5,November 1, 1998:pg1541, 
Table 21) 
 
Endocarditis is based on the confirmation of either Pathological Criteria or Clinical Criteria.   
 
Diagnosis for Clinical Criteria of Endocarditis must at least meet 1 of the following combinations: 
• 
2 major criteria or 
• 
1 major plus 3 minor criteria or 
• 
5 minor criteria 
 
Pathological Criteria 
 
Microorganisms: culture or histology in a vegetation, in a vegetation that has embolized, or 
in an intracardiac abscess, OR  
 
Pathological lesions: vegetation or intracardiac abscess present, confirmed by histology 
showing active endocarditis 
 
OR 
 
Clinical Criteria 
 
Major Criteria 
Persistently positive blood cultures: 
Typical organisms for endocarditis: Streptococcus viridans, S bovis, “HACEK” group, 
community acquired Staphylococcus aureus or enterococci, in the absence of a 
primary focus  
Persistent bacteremia:  
≥ 2 positive cultures separated by ≥12 hours or ≥ 3 positive cultures ≥ 1 h apart or 
70% blood culture samples positive if ≥ 4 are drawn 
Evidence of endocardial involvement 
Positive echocardiogram 
Oscillating vegetation 
Abscesses 
Valve perforation 
New partial dehiscence of prosthetic valve 
New valvular regurgitation 
 
 

 
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Minor Criteria 
Predisposing heart condition: 
Mitral Valve Prolapse, bicuspid aortic valve, rheumatic or congenital heart disease, 
intravenous drug use  
Fever 
Vascular phenomena:  
Major arterial emboli, septic pulmonary emboli, mycotic aneurysm, intracranial 
hemorrhage, Janeway lesions 
Immunologic phenomena 
Glomerulonephritis, Osler's nodes, Roth spots, and rheumatoid factor 
Positive blood culture: not meeting major criteria  
Echocardiogram: positive but not meeting major criteria 
 
ETIOLOGY OF TRICUSPID REGURGITATION 
Will be determined as Degenerative, Functional, or Lead-Induced.  
 
• 
Degenerative Tricuspid Regurgitation 
Tricuspid regurgitation primarily due to abnormality of the tricuspid apparatus 
 
• 
Functional Tricuspid Regurgitation 
Global or regional right ventricular wall motion abnormalities causing leaflet restriction or 
tethering with or without dilatation of the tricuspid annulus, but with no significant 
abnormalities of the tricuspid leaflets 
• 
Lead-Induced Tricuspid Regurgitation 
ICD or pacemaker trans-tricuspid lead directly interfering with leaflet coaptation. 
 
GASTROINTESTINAL COMPLICATIONS 
Complications as a result of the TVRS procedure affecting the gastrointestinal tract requiring surgery.  
May include fecal impaction, bowel obstruction, etc. 
 
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 
 

 
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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. 
 
LIVER FAILURE 
New onset liver failure is defined as elevated alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) greater than 15 times the ULN. 
 
MAJOR ADVERSE EVENT (MAE) 
MAE is a CEC-adjudicated composite of cardiovascular mortality, stroke, myocardial infarction, new onset 
renal failure, endocarditis requiring surgery, and non-elective cardiovascular surgery for TVRS device related 
adverse events occurring after the index procedure 
 
MAJOR BLEEDING  
Major bleeding is defined as bleeding ≥ Type 3 based on a modified Bleeding Academic Research 
Consortium (BARC)33 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  
 
 
 
33 Mehrana R, Rao SV, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report 
from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-2747. 

 
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o 
Perioperative intracranial bleeding within 48 h 
o 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
o 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
o 
Chest tube output ≥2L within a 24-h period 
• 
Type 5: Fatal bleeding  
o 
Type 5a  
 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
o 
Type 5b  
 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation  
*Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL hemoglobin) 
†Cell saver products are not counted 
 
MAJOR VASCULAR COMPLICATION 
Any major complication, relating to, or affecting, the circulatory system as a result of the TVRS procedure, 
including new onset of any of the following:   
• 
Hematoma at access site >6 cm.; 
• 
Retroperitoneal hematoma; 
• 
Arterio-venous fistula; 
• 
Symptomatic peripheral ischemia/ nerve injury with clinical signs or symptoms lasting >24 hours;  
• 
Vascular surgical repair at catheter access sites;  
• 
Pulmonary embolism; 
• 
Ipsilateral deep vein thrombus; or 
• 
Access site-related infection requiring intravenous antibiotics and/or extended hospitalization. 
 
 
MODIFIED RANKIN SCALE SCORE DESCRIPTIONS 
0. 
No symptoms at all 
1. 
No significant disability despite symptoms; able to carry out all usual duties and activities 
2. 
Slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance 
3. 
Moderate disability; requiring some help, but able to walk without assistance 
4. 
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance 
5. 
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
6. 
Dead 
 
MYOCARDIAL INFARCTION 
Myocardial infarction (MI) classification and criteria for diagnosis is defined as follows:  
 
Peri-procedural MI (≤ 72 hours after TVRS procedure) 
Mandatory: CK-MB (preferred) ≥10x ULN within 72 hrs. post-TVRS procedure in patient with 
normal baseline CK-MB  
 
OR 
 
Mandatory: CK-MB ≥5x ULN within 72 hrs. post-TVRS procedure in patient with normal baseline 
CK-MB plus new pathological Q-waves in ≥2 contiguous leads, or new LBBB  
 
Post-surgery 
Mandatory: CK-MB ≥10x ULN (preferred) within 24 hrs. of cardiothoracic surgery plus 1 of the 
following: 

 
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• 
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 TVRS procedure)  
Any one of the following criteria: 
 
• 
Detection of rise and/or fall of cardiac biomarkers (CK-MB) with at least one value above 
the upper limits of normal (ULN), together with evidence of myocardial ischemia with at 
least one of the following:  
 
o ECG changes indicative of new ischemia [new ST-T changes or new left bundle 
branch block (LBBB)] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion 
abnormality 
 
• 
Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST elevation, 
or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or at 
autopsy, but death occurring before blood samples could be obtained, or at a time before 
the appearance of cardiac biomarkers in the blood. 
 
• 
Pathological findings of an acute myocardial infarction. 
 
NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA CLASS) 
 
Class I 
Patients with cardiac disease but without resulting limitations of physical 
activity. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical activity.  
Patients are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical activity.  
Patients are comfortable at rest.  Less than ordinary physical activity causes 
fatigue, palpitation dyspnea, or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
 
 
NON-ELECTIVE (i.e., URGENT or EMERGENT) CARDIOVASCULAR SURGERY FOR 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 

 
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lead to non-elective cardiovascular surgery include, myocardial perforation, Single Leaflet Device 
Attachment (confirmed by Echo Core Lab), embolization of the TVRS Clip or TVRS System components, 
iatrogenic atrial septal defect, or the need for tricuspid valve replacement instead of repair due at least 
in part to the TVRS procedure or the presence of the TVRS Clip. 
 
OPTIMAL MEDICAL THERAPY OR OPTIMAL THERAPY  
For Tricuspid Regurgitation:  Currently per ESC 2012 guidelines, the only medical therapy described is, 
“Diuretics reduce congestion. Specific therapy of the underlying disease is warranted.”  These TR 
patients typically would have some level of left heart failure by the time TR is detected.  Hence, optimal 
therapy for TR at the present time will follow that defined for patients with left heart failure issues, example 
mitral regurgitation. 
 
For Mitral Regurgitation: Subjects with current or prior symptoms of heart failure and reduced LVEF 
should be on stable optimally uptitrated medical therapy recommended according to current guidelines 
(J Am Coll Cardiol. 2013 Jun 5. doi:pii: S0735-1097(13)02114-1.) as standard of care for heart failure 
therapy in the United States. This minimally includes an ACE-inhibitor (ACE-I) at stable doses for 30 days 
prior to subject enrollment in the trial, if tolerated, and a beta blocker (carvedilol, sustained release 
metoprolol succinate, or bisoprolol) for 90 days prior to subject enrollment in the trial, if tolerated, with a 
stable up-titrated dose for 30 days prior to subject enrollment in the trial. This also includes an Angiotensin 
II Receptor Blocker (ARB) at stable doses for 30 days prior to subject enrollment in the trial, if tolerated, 
when ACE-I is not tolerated. Stable is defined as no more than a 100% increase or a 50% decrease in 
dose. 
 
If the subject is intolerant to ACE-I, ARB, or beta blockers, documented evidence must be available. In 
those intolerant to both ACE-I and ARB, combination therapy with hydralazine and oral nitrate should be 
considered. Therapeutic equivalence for ACE-I substitutions is allowed within the trial enrollment stability 
timelines. Aldosterone receptor antagonists [or mineralocorticoid receptor antagonists] are 
recommended in patients with NYHA class II-IV heart failure and who have LVEF of 35% or less, unless 
contraindicated, to reduce morbidity and mortality. Patients with NYHA class II should have a history of 
prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels to be considered for 
aldosterone receptor antagonists. If aldosterone inhibitor therapy is to be administered, it must be initiated 
and optimized at least 30 days prior to trial enrollment. Stability criteria are the same as for other 
neurohormonal antagonists. Eplerenone requires dosage stability for 30 days prior to subject enrollment 
in the trial similar to the other agents. Diuretics may be used as necessary to keep the subject euvolemic. 
All heart failure therapeutics and dosages should be documented in the electronic case report forms.  
 
It is recognized that approximately two-thirds of patients with HF have underlying CAD (ischemic 
cardiomyopathy). Therefore, it is imperative that appropriate treatment for CAD be used, according to 
the ACC/AHA Guidelines for Heart Failure. Specific recommendations listed in those guidelines are listed 
as follows: 
• 
Use of nitrates and beta blockers for the treatment of angina, 
• 
Coronary revascularization according to recommended guidelines in patients who have both HF 
and angina, 
• 
Patients with coronary artery disease and HF should be treated in accordance with recommended 
guidelines for chronic stable angina, 
• 
Use of antiplatelet agents for prevention of MI and death in patients with HF who have underlying 
coronary artery disease 
 
In addition, revascularization (i.e., percutaneous coronary intervention, etc.) should occur prior to 
subject enrollment in the trial as applicable. 

 
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RENAL FAILURE 
For this trial, new onset renal failure is defined as new need for dialysis or a creatinine increasing to 3.5 
mg/dL or greater 
Note: Increase of creatinine less 1.0 mg/dL over baseline is NOT considered renal failure 
 
SINGLE LEAFLET DEVICE ATTACHMENT (SLDA) 
Defined as unilateral TVRS detachment from one leaflet as assessed by the study site and confirmed by the 
ECL.  Reasons for TVRS Detachment include leaflet tearing, TVRS unlocking, TVRS fracture or inadequate 
TVRS placement.  Not included are any fractures or other failures of the TVRS that do not result in TVRS 
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, 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 
 

 
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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. 
 
 
SYMPTOMATIC TRICUSPID REGURGITATION 
Symptomatic refers to limitation of physical activity (i.e. NYHA Classification II, III or IV) 
 
TRICUSPID VALVE STENOSIS 
Defined as a tricuspid valve orifice of ≤ 1.0 cm2 and/or mean gradient ≥5 mmHg as measured by the 
Echocardiography Core Laboratory. Other parameters (PHT ≥ 190 msec or CW TV VTI >60 cm) may 
also suggest significant tricuspid stenosis. 
 
TRICUSPID REGURGITATION SEVERITY 
TR grading will be based on a 5-point scale: mild, moderate, severe, very severe and torrential.  Mild, 
moderate, and severe will be graded based on the 2017 ASE Guidelines (Zoghbi 2017).  Massive and 
torrential have been developed by the Echo Scientific Committee to provide further granularity in the 
range beyond severe.   See Appendix VIII for further grading information.  
 
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 

 
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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 III: 
CONTACT INFORMATION 
 
A list of investigational site coordinators can be obtained upon request from the Clinical Project Manager 
(Nadia Bouhdi at nadia.bouhdi@av.abbott.com or +32-2-71-41577) for the study.  
 
 
Clinical trial SAEs and device deficiencies reportable per MEDDEV 2.7/3 regulations will be submitted to 
European Competent authorities by the Abbott Clinical Safety Group or designee.  
 
 
Ravindra Kumar 
Manager - Clinical Safety 
Culliganlaan 2B 
1831 - Diegem 
Belgium 
E-mail: safety.eusafety@av.abbott.com 
Requests for further clarifications on submitted reports can be sent to safety.eusafety@av.abbott.com  
 

 
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APPENDIX IV: 
RATES OF FORESEEABLE ADVERSE EVENTS 
 
Potential risks associated with the TVRS procedure are similar to those for standard cardiac catheterization techniques, administration 
of anesthesia, use of fluoroscopy, TEE and TTE. Although anticipated risks for TVRS are described below, due to the nature of this 
study, there may also be other risks, which are not known at this time. Likewise, the exact frequency of the risk may be unknown. 
The frequencies of the foreseeable events indicated in the table below are based on clinical trials using the MitraClip device for mitral 
regurgitation indication (55 patients treated in EVEREST I, 178 patients treated in EVEREST II RCT, 60 patients treated in 
EVEREST II roll in, 75 patients treated in EVEREST II High risk registry, 324 patients treated in REALISM high risk study, 272 
patients treated in REALISM non-high risk, 567 patients in Access-EU). Currently no data is available for the Tricuspid indication. 
The rationale for basing frequencies on mitral valve procedures is that MitraClip is a similar device used for valvular repair and has 
been evaluated in both US and OUS studies.  
 
Anticipated adverse event 
Frequency observed in MitraClip in the mitral valve clinical studies 
Very common: 
≥10% 
Common: 
≥ 1.0% to < 10% 
Uncommon: 
≥ 0.1% to < 
1.0% 
Rare: 
≥ 0.01% to < 
0.1% 
Very Rare: 
< 0.01% 
Allergic reactions or hypersensitivity to latex, contrast agent, 
anaesthesia, device materials (nickel alloy), and drug reactions to 
anticoagulation, or antiplatelet drugs 
 
 
 
 
X 
Vascular access complications which may require transfusion or 
vessel repair,  including: 
X 
 
 
 
 
• 
Wound dehiscence 
 
X 
• 
Catheter site reactions 
 
X 
• 
Bleeding (including ecchymosis, oozing, hematoma, 
haemorrhage, retroperitoneal haemorrhage) 
X 
• 
Arteriovenous fistula, pseudoaneurysm, aneurysm, 
dissection, perforation/rupture, vascular occlusion 
X 
• 
Emboli (air, thrombotic material, device, device 
component) 
 
X 
• 
Peripheral nerve injury 
 
X 
Lymphatic complications 
 
 
 
 
X 
Pericardial complications which may require additional intervention, 
including: 
 
X 
 
 
 
• 
Pericardial effusion 
 
X 
• 
Cardiac tamponade 
X 
• 
Pericarditis 
 
X 
Cardiac complications which may require additional intervention or 
emergency cardiac surgery, including cardiac perforation 
 
 
 
 
X 
Tricuspid valve complications, which may complicate or prevent 
later surgical repair, including: 
 
X 
 
 
 
• 
Chordal entanglement/rupture 
 
X 
• 
Single Leaflet Device Attachment (SLDA) 
X 
• 
TVRS Clip device thrombosis 
 
• 
Dislodgement of previously implanted devices 
 
• 
Tricuspid perforation/rupture 
 
• 
Tricuspid valve stenosis 
 
X 
 

 
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• 
Worsening or persistent tricuspid regurgitation 
 
X 
• 
Endocarditis 
X 
Cardiac arrhythmias (including conduction disorders, atrial 
arrhythmia, ventricular arrhythmia) 
X 
 
 
 
 
Cardiac ischemic conditions (including myocardial infarction, 
myocardial ischemia, and unstable/stable angina) 
 
X 
 
 
 
Venous thromboembolism  
 
X 
 
 
 
Stroke/Cerebrovascular accident (CVA) and Transient Ischemic 
Attack (TIA) 
 
X 
 
 
 
System organ failure: 
X 
 
 
 
 
• 
Cardio-respiratory arrest 
 
X 
• 
Worsening heart failure 
 
X 
• 
Pulmonary congestion 
X 
• 
Respiratory dysfunction/ failure/ atelectasis 
X 
 
• 
Renal insufficiency or failure 
X 
• 
Shock (including cardiogenic and anaphylactic) 
 
X 
Blood cell disorders (including coagulopathy, hemolysis, and 
Heparin Induced Thrombocytopenia (HIT)) 
 
X 
 
 
 
Hypotension/hypertension 
 
X 
 
 
 
Infections, including: 
 
X 
 
 
 
• 
Urinary Tract Infection (UTI) 
X 
• 
Pneumonia 
X 
• 
Septicaemia 
X 
Nausea and vomiting 
 
X 
 
 
 
Chest pain 
 
 
 
 
X 
Dyspnoea 
 
 
 
 
 
Oedema 
 
X 
 
 
 
Fever or hyperthermia 
 
 
 
X 
 
Pain 
 
X 
 
 
 
Death 
X 
 
 
 
 
Fluoroscopy, Transoesophageal echocardiogram (TEE) and 
Transthoracic echocardiogram (TTE) -related complications:  
 
X 
 
 
 
• 
Skin injury or tissue changes due to exposure to ionizing 
radiation 
 
X 
• 
Oesophageal irritation 
 
• 
Oesophageal perforation 
 
• 
Gastrointestinal bleeding 
X 
 
References-  
1. 
Rogers JH, Bolling SF. The Tricuspid Valve: Current perspective and evolving management of tricuspid regurgitation. Circulation 
(May) 2009; 119 (20): 2718-2725 
2. 
Zhu TY, Min XP, Zhang HB, Meng X. Preoperative risk factors for residual tricuspid regurgitation after isolated left-sided valve 
surgery, Cardiology 2014; 129(4): 242–249 
3. 
 Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O'Gara PT, Ruiz CE, Skubas NJ, Sorajja P., Sundt 
TM 3rd, Thomas JD. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease. Circulation (Jun) 
2014; 129 (23): 2440-2492 

 
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4. 
Matsunaga A, Duran CMG. Progression of tricuspid regurgitation after repaired functional ischemic mitral regurgitation. Circulation 
2005; 112 [suppl I]: I-453–I-457 
5. 
Filsoufi F, Anyanwu AC, Salzberg SP, Frankel T, Cohn LH, Adams DH. Long-term outcomes of tricuspid valve replacement in the 
current era. Ann Thorac Surg (Sep) 2005; 80 (3): 845–850 
 
 
 

 
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APPENDIX V:  
MONITORING EXPOSURE TO IONIZING RADIATION 
 
(1) Implanting Investigator Training 
 
Prior to treating patients with the TVRS Clip, all implanting investigators shall complete the 
TVRS therapy training curriculum, including training to this section of the study Clinical 
Investigational Plan. 
 
(2) Pre, Peri and Post-TVRS Procedure 
 
The implanting investigator shall be responsible for patient radiation levels and shall ensure 
that radiation dose accumulation is continuously monitored during the procedure (NCRP 
2010). Documentation of dose levels shall be in accordance with the individual requirements 
of the respective institution’s quality management program. In addition, the following shall 
apply:  
 
a. Dose Measurements required for TVRS procedure 
 
Where the fluoroscopy system has the functionality for the output of data, the following dose 
measurements shall be recorded in the subject records and reported in the eCRFs. 
 
• 
Total fluoro time: to be reported in minutes 
• 
Total number of fluoro frames: to be reported as whole numbers, no associated units 
• 
Air kerma-area product (PKA) (dose area product): to be reported in Gy cm2 
• 
Air kerma at the reference point (Ka,r): to be reported in Gy 
• 
Peak skin dose (Dskin, max): to be reported in Gy 
 
Investigational centers that are unable to provide the information due to the limitations 
oftheir fluoroscopy systems are exempt from the reporting requirements. 
 
b. Substantial Radiation Dose Level (SRDL) 
 
The SRDL is a trigger level to initiate follow-up of a radiation dose that may produce a 
clinically relevant injury in an average patient. Procedures, such as the MitraClip 
procedure, that are performed using biplane fluoroscopy systems are a special situation 
because the dose received from each plane should be considered independently when 
the fields do not overlap. When they do overlap, the doses are additive and if it is uncertain 
whether the fields overlap, it should be assumed that they do.  
 
The following are suggested values for first and subsequent notifications and the SRDL 
based upon a 100cm2 field at the subject’s skin. The implanting investigator should adjust 
the notifications and the SRDL proportionally to the actual procedural field size. 
 
When the SRDL has been exceeded, the implanting investigator shall document the dose 
exceeded and the justification for the radiation dose level used (NCRP 2010). 
 

 
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(1) Acute Evaluation 
 
Subjects should be advised of the possibility of a skin injury due to a tissue reaction, and 
should be told to examine the beam entrance site at 2-4 weeks after the procedure and 
report any observations to the site Principal Investigator or designee During the physical 
examination at the 30-day follow-up clinic visit, the site Principal Investigator or designee 
shall examine the integrity of the subject’s skin at or near the beam entrance site. If there 
is evidence of skin injury, the site Principal Investigator or designee shall report it as an 
adverse event in accordance with the adverse event reporting requirements. 
 
(2) Long-term Evaluation 
 
The site Principal Investigator or designee is responsible for the ongoing collection and 
monitoring of radiation doses. An examination of the subject’s skin at or near the beam 
entrance site shall be performed by the site Principal Investigator or designee. If skin 
injury resulting from radiation exposure during the MitraClip procedure is ongoing 
beyond the 30-day follow-up, the site Principal Investigator or designee should arrange 
for follow-up care. Observations of skin injury shall be reported as an adverse event in 
accordance with the adverse event reporting requirements. 
 
 
 

 
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APPENDIX VI: 
6 MINUTE WALK TEST GUIDELINES – AMERICAN THORACIC 
SOCIETY 
 
Six minute walk test will be performed as outlined in the published guidelines by the American 
Thoracic Society. 
 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.. ATS 
statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 
1;166(1):111-7. 
 

 
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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 (see Appendix III for contact information). 
 

 
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APPENDIX VIII:  
ECHOCARDIOGRAPHY ACQUISITION GUIDELINE 
 
TR grading will be performed based on a modified version of the 2017 ASE guidelines for TR grading34.  
The “mild”, “moderate”, and “severe” grading in the guideline will continue to be used for this trial.  Based 
on experience by the Echo Scientific Committee, the addition of a “Massive” and “Torrential” grading will 
provide more granularity in the severe range.  This reflects the type of TR severity observed in other 
studies regarding TR.  Patients in the highly torrential range of TR will likely be excluded from the study 
due to potential limitations in clipability (i.e. large coaptation gaps, flatten valves, etc), as determined by 
the site heart team and ECL.   
 
A qualitative, semi-quantitative, and quantitative integrative approach for assessment of TR grading will 
be performed by the ECL using the below Tricuspid Regurgitation Grading Scale for TRILUMINATE.   
 
 
 
34 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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Tricuspid Regurgitation Grading Scale for TRILUMINATE 
 
 

 
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APPENDIX IX: 
 ELIGIBILITY COMMITTEE RULES 
 
The Eligibility Committee reviews data provided by the investigational site and echo data from the echo 
core laboratory and conducts clinical assessment.  Then the Eligibility Committee finally decides whether 
a patient is appropriate for the TVRS Procedure or not.   
 
1. Purpose 
The Eligibility Committee (hereinafter "Committee") conducts clinical assessment and finally decides 
whether a patient is appropriate for the TVRS Procedure or not. 
 
2. Organization of the Committee 
The Committee consists of a cardiac surgeon, an echocardiographer and a interventionalist in 
external medical institutions (i.e., physicians who are not employee of the sponsor) (see the "List of 
the Eligibility Committee members"). 
 
3. Procedures  
3.1 Provision of patient information 
The sponsor provides the patient information provided by the investigational site, the data of the 
echo core laboratory to the Committee members. 
3.2 Patient assessment 
The Committee member conducts clinical reviews based on the patient information. The 
Committee members may ask questions or request additional information necessary for clinical 
reviews to the investigational sites through the sponsor. 
3.3 Reply of results 
1) The Committee member returns the reply with comments on assessment promptly after 
receiving the information. 
2) A patient may be enrolled in the trial if all of the Committee members approve the eligibility 
of the patient.  (Committee member may not decide for their own patients.  An alternate 
committee member may decide.)  
3.4 Notification of assessment results 
The sponsor notifies the investigator at the trial site and clinical research coordinator of final 
assessment results of the Committee. 
 
Further details are described in the Eligibility Committee Manual of Operations.