Evaluating the Benefit of Concurrent Tricuspid Valve Repair During Mitral Surgery
Phase: NA
Conditions: Mild Tricuspid Regurgitation, Moderate Tricuspid Regurgitation, Tricuspid Regurgitation
Sponsor: Icahn School of Medicine at Mount Sinai

  
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 1 of 63 
 
Date Effective: January 2020 
 
 
 
 
Cardiothoracic Surgical Trials Network 
Protocol 
EVALUATING THE BENEFIT OF CONCURRENT 
TRICUSPID VALVE REPAIR DURING MITRAL 
SURGERY 
 
 
 
 
Sponsored By the NHLBI and DZHK 
 
CT Surgery Network Research Group 
 
 
Data and Clinical Coordinating Center 
InCHOIR 
Icahn School of Medicine at Mount Sinai 
New York 
 
 
January 2020 
Revision 2.2 
 
 
CONFIDENTIAL 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 2 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
Cardiothoracic Surgical Trials Network 
Core Clinical Centers   
Baylor Research Institute (Michael Mack, MD) 
Cleveland Clinic Foundation (Marc Gillinov, MD)  
Duke University (Peter Smith, MD) 
Institut Universitaire de Cardiologie de Québec (Hôpital Laval) (Pierre Voisine, MD) 
Montefiore Medical Center - Albert Einstein College of Medicine (Robert Michler, MD) 
Montreal Heart Institute (Louis Perrault, MD) 
Hôpital du Sacré-Cœur de Montréal (Hugues Jeanmart, MD) 
University of Pennsylvania (Michael Acker, MD) 
University of Southern California (Michael Bowdish, MD) 
University of Virginia Health System (Gorav Ailawadi, MD) 
 
Consortium Centers 
Baylor College of Medicine (Todd Rosengart, MD) 
Dartmouth-Hitchcock Medical Center (Jock McCullough, MD) 
Emory University (Douglas Murphy, MD) 
London Health Center (Michael Chu, MD) 
Mayo Clinic (Juan Crestanello, MD) 
Medstar Heart and Vascular Institute (Christian Shultz, MD) 
Mission Hospital (Mark Groh, MD) 
Stanford University (Joseph Woo, MD) 
Toronto General Hospital (Mitesh Badiwala, MD) 
University of Alberta (John Mullen, MD) 
University of Maryland Medical Center (James Gammie, MD) 
University of Michigan (Steve Bolling, MD) 
University of Ottawa (Marc Ruel, MD) 
WakeMed Health and Hospitals (Bryon Boulton, MD) 
Yale University (Arnar Geirsson, MD) 
University of Wisconsin (Nilto Carias De Oliveira, MD) 
 
Universitäts-Herzzentrum Freiburg (Friedhelm Beyersdorf, MD) 
Deutsches Herzzentrum Berlin, (Volkmar Falk, MD) 
Deutsches Herzzentrum Munchen (Markus Krane, MD) 
Herzzentrum, Leipzig (Friedrich Mohr, MD) 
Herz-und Diabeteszentrum NRW Bad Oeynhausen (Kavous Hakim-Meibodi, MD) 
Universitatsklinikum Frankfurt (Anton Moritz, MD) 
Universitatsmedizin Gottingen (Bernd Danner, MD) 
Universitares-Herzzentrum Hamburg (Lennard Conradi, MD) 
Universitatsklinikum Jena (Torsten Doenst, MD) 
Herzzentrum Leipzig (Bettina Pfannmuller MD) 
 
 
Data Coordinating Center  
International Center for Health Outcomes and Innovation Research, Icahn School of Medicine at 
Mount Sinai (InCHOIR), (Annetine Gelijns, PhD; Alan J. Moskowitz, MD; Emilia Bagiella, PhD; 
Ellen Moquete, RN; Karen O’Sullivan, MPH; Anh Phung, BS; Anu Lala, MD; Donna Mancini, MD, 
Jessica Overbey, PhD, Stephanie Pan, MS) 
 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 3 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
Study Chair, Co-Chair, Vice-Chairs  
Marc Gillinov, MD, Cleveland Clinic Foundation; Mariell Jessup, MD, American Heart Association; 
Eric Rose, MD, Icahn School of Medicine at Mount Sinai; Michael Mack, MD, Baylor Research 
Institute 
 
Study Sponsors  
National Heart Lung and Blood Institute (Marissa Miller, DVM, MPH; Albert Lee, PhD; Wendy 
Taddei-Peters, PhD; Neal Jeffries, PhD; Nancy Geller, PhD)  
German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung) 
 
Protocol Development Committee 
James S. Gammie, MD (U Maryland) 
Steven Bolling, MD (U Michigan) 
Michael Parides, PhD (Montefiore-Einstein) 
Gorav Ailawadi, MD (UVA) 
Michael Argenziano, MD (Columbia) 
Emilia Bagiella, PhD (InCHOIR) 
Eugene Blackstone, MD (CCF) 
Denis Bouchard, MD (Montreal) 
Michael Bowdish, MD (USC) 
Helena L Chang, MS (InCHOIR) 
Julia Collins, CRC (U Maryland) 
Francois Dagenais, MD (Laval) 
Stephanie Deasey, PhD (U Maryland) 
Annetine Gelijns, PhD (InCHOIR) 
Nancy L Geller, PhD (NIH/NHLBI) 
Marc Gillinov, MD (CCF) 
Judy Hung, MD (MGH) 
Katherine Kirkwood, MS (InCHOIR) 
Irving L. Kron, MD (UVA) 
Anu Lala, MD (InCHOIR) 
Albert Lee, PhD (NHLBI) 
Michael Mack, MD (Baylor) 
Marissa Miller, DVM, MPH (NHLBI) 
Ellen Moquete, RN, BSN (InCHOIR) 
Alan Moskowitz, MD (InCHOIR) 
Patrick O'Gara, MD (Brigham and Women’s) 
Karen O'Sullivan, MPH (InCHOIR) 
Jessica Overbey, PhD (InCHOIR) 
Vivek Rao, MD (Toronto) 
Eric Rose, MD (Mount Sinai) 
Peter K. Smith, MD (Duke) 
Robert Smith, MD (Baylor) 
Wendy C. Taddei-Peters, PhD (NHLBI) 
Vinod Thourani, MD (Piedmont Heart 
Institute) 
Robert Villanueva, MPA (U Maryland) 
Bryan Whitson, MD (OSU) 
Volkmar Falk, MD (Berlin, Germany) 
Richard Weisel, MD (Toronto)

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 4 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
TABLE OF CHANGES ...................................................................................................... 5 
DEFINITIONS, ACRONYMS & ABBREVIATIONS ...................................................... 9 
ABSTRACT ...................................................................................................................... 11 
DATA COLLECTION SCHEDULE ............................................................................... 13 
OBJECTIVES ................................................................................................................... 14 
BACKGROUND AND SIGNIFICANCE ........................................................................ 14 
ENDPOINTS .................................................................................................................... 16 
STUDY DESIGN.............................................................................................................. 17 
MASKING ........................................................................................................................ 18 
STUDY POPULATION ................................................................................................... 18 
TREATMENT INTERVENTIONS.................................................................................. 20 
DEFINITIONS AND MEASUREMENT OF ENDPOINTS ........................................... 20 
CLINICAL CENTERS ..................................................................................................... 27 
INVESTIGATORS ........................................................................................................... 28 
SCREENING AND BASELINE ...................................................................................... 30 
RANDOMIZATION......................................................................................................... 33 
PROCEDURE ................................................................................................................... 33 
POST-RANDOMIZATION DATA COLLECTION ....................................................... 34 
DATA MANAGEMENT.................................................................................................. 38 
ANALYTICAL PLAN ..................................................................................................... 40 
ORGANIZATION OF THE STUDY ............................................................................... 46 
REFERENCES ................................................................................................................. 48 
Appendix I:  Moderate Tricuspid Regurgitation Trial Echocardiographic Image 
Acquisition Protocol ......................................................................................................... 51 
Appendix II:  Moderate Tricuspid Regurgitation Trial Echocardiographic Image 
Acquisition Protocol: 3D Image Echo Protocol................................................................ 59 
Appendix III: New York Heart Association Classification (NYHA) ............................... 60 
Appendix IV:  Six-Minute Walk Test Instructions ........................................................... 61 
Appendix V: Frailty Assessment – Gait Speed Test Instructions ..................................... 63 
 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 5 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
TABLE OF CHANGES 
Revision 
Section 
Change 
Reason 
Page 
2.0 
Headers and Footers 
Updated and reformatted 
Consistency with   
CTSN protocols 
All 
2.0 
Title page and other 
applicable pages 
Updated to new protocol version and date; 
added “and Clinical” to Data Coordinating 
Center to reflect the actual name and function  
Accuracy and 
consistency with other 
sections 
1,7, 
17,45 
2.0 
Protocol Development 
Committee 
Updated Personnel affiliation  
Staffing Update 
2 
2.0 
Table of Contents 
Added sections inadvertently left out in original 
protocol and new appendices 
Protocol Correction and 
Update 
4 
2.0 
Definitions, Acronyms, 
and Abbreviations 
Updated trial language 
Internal Protocol 
Consistency 
7-8 
2.0 
Abstract 
Added Frailty Assessment – Gait Speed Test  
Addition of Secondary 
Endpoint 
9 
2.0 
Abstract 
Minor revision to Target Population, Rx Arms, 
Inclusion/Exclusion Criteria language  
Protocol clarification for 
consistency 
10-11 
2.0 
Data Collection Schedule 
Revised baseline and visit windows; added Gait 
Speed assessment for frailty; revised 
assessment names (including UHC name to its 
current name, Vizient); added 6MWT to Day 
30 
Addition of secondary 
endpoint; Expansion of 
windows to allow for 
more complete data 
collection; and 
Clarification of 
assessment names; 
Corrected omission of 
Day 30 6MWT from 
Rev 1.0 
11 
2.0 
Objectives, Endpoints 
Clarification of “baseline” echo 
Clarification for 
consistency across 
centers 
12, 14 
2.0 
Endpoints 
Addition of Gait Speed Test as an Endpoint 
Addition of secondary 
endpoint 
14 
2.0 
Study Design 
Correction of when endpoints will be measured 
– added “18” months and deleted redundant 
wording  
Correction and update to 
protocol 
15 
2.0 
Study Population  
Minor revision to Inclusion/Exclusion Criteria 
language for consistency; added Footnote 1 for 
clarification 
Protocol Update  and 
Clarification 
16-17 
2.0 
Definitions and 
Measurements of 
Endpoints  
Clarified primary endpoint language; updated 
Appendix numbers; added Appendix where 
6MWT instructions are found; added Frailty 
endpoint; defined abbreviations upon first use 
Protocol Update and 
Clarification 
18-19 
2.0 
Definitions and 
Measurements of 
Endpoints –  Economic 
Measures 
Revised UHC’s name to its current name, 
Vizient; corrected an incomplete sentence in 
the last paragraph of this subsection; and 
revised cost and cost-effectiveness analysis to 
include US centers only. 
Protocol Update and 
Corrections 
20-21 
2.0 
Definitions and 
Measurements of 
Endpoints – Specific 
Adverse Event 
Definitions 
Clarified cardiac arrhythmias definition and 
neurologic dysfunction definition 
Clarification for 
consistency across 
centers 
21,24 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 6 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
Revision 
Section 
Change 
Reason 
Page 
2.0 
Investigators –  
Qualifications and 
Training 
Revised the procedure for providing surgical 
qualifications to the DCC (instead of faxing, 
sites will now upload forms to the Florence 
eRegulatory binder); added information on 
Echocardiologist and echo team training.  
Protocol Update 
26 
2.0 
Investigators – 
Echocardiography 
Qualification 
Revised this section to remove any reference to 
TEE and clarified TTE training; clarified TR 
grading 
Protocol Update and 
Clarification  
26-27 
2.0 
Investigators –  Conflict 
of Interest and Financial 
Disclosure Agreement 
Revised language for clarity 
Clarification 
27 
2.0 
Investigators – Site 
Approval  
Updated language in this section and clarified 
who must attend site initiation.  
Clarification and Update  
27-28 
2.0 
Screening and Baseline  
 
 
Updated “Echocardiogram” subsection - 
accreditation and reference to new appendix; 
added new subsection - Gait Speed Test; 
corrected the form name under “Randomization 
Eligibility”  
Protocol Update  
29-30 
2.0 
Screening and Baseline, 
Post-Randomization Data 
Collection  
Expanded data collection windows to allow for 
more complete data collection 
Protocol Update  
29-35 
2.0 
Randomization 
Deleted text on ID code, which is assigned at 
an earlier stage via the EDC 
Protocol Update 
31 
2.0 
Procedure 
Corrected language; added Appendix II; 
revised to include additional TV Annuloplasty 
Rings 
Clarification and Update 
31-32 
2.0 
Post-Randomization Data 
Collection – Study Visits 
Added 18-month visit, which was inadvertently 
omitted from protocol revision 1.0  
Correction 
32 
2.0 
Post-Randomization Data 
Collection – Study Visits 
and Echocardiogram 
Clarified statement on primary endpoint 
assessment requirements 
Clarification 
32,34 
2.0 
Post-Randomization Data 
Collection 
Updated or added Appendix numbers  
Protocol Update 
34-35 
2.0 
Post-Randomization Data 
Collection  
Added Gait Speed Test subsection 
Addition of secondary 
endpoint (frailty) 
34 
2.0 
Post-Randomization Data 
Collection – Event 
Driven Data Collection 
Added sentence to refer to the Manual of 
Procedures for partial withdrawal of consent 
and limited data collection in Study 
Completion/Early Termination subsection  
Clarification   
36 
2.0 
Analytical Plan—
Methods of Analysis 
Clarified definition of treatment failure 
Clarification 
38 
2.0 
Analytical Plan – Data 
Monitoring and Analysis 
Revised futility sentence in Interim Analysis 
subsection 
Correction 
41 
2.0 
Analytical Plan – Data 
Monitoring and Analysis 
Added Gait Speed data analysis to Analytical 
Plan (to 6MWT analysis paragraph) and 
updated analysis. 
Addition of secondary 
endpoint  
42 
2.0 
Appendix II 
Added 3D Acquisition Protocol 
Added for consistency 
across centers 
57 
2.0 
Appendix II-IV 
Renumbered appendices 
Update 
57-59 
2.0 
Appendix V 
Added appendix on Gait Speed Test 
Instructions 
Addition of secondary 
endpoint 
61 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 7 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
Revision 
Section 
Change 
Reason 
Page 
2.1 
Headers and Footers 
Updated and reformatted 
Consistency with   
CTSN formatting 
All 
2.1 
Title page 
Updated to new protocol version and date 
Protocol update 
1 
2.1  
Throughout protocol 
Administrative changes to correct spacing, 
numbering, and other inconsistencies; to add 
study sponsor; and to update abbreviations 
Internal protocol 
consistency and 
accuracy 
All 
2.1 
Consortium Centers 
Updated listing of participating sites 
Protocol update 
2-3 
2.1 
Study Sponsors 
Revised to reflect sponsorship by the 
Deutsches Zentrum für Herz-Kreislauf-
Forschung 
Protocol Update 
3 
2.1 
Definitions, Acronyms 
and Abbreviations  
Added abbreviations and acronyms for German 
collaborators and sponsor 
Protocol update 
8 
2.1 
Randomization 
Updated specifics on timing of randomization 
At the request of study 
investigators to allow 
for planning of surgical 
approach prior to 
randomization 
16, 32 
2.1 
Pleural Effusion 
Updated definition of pleural effusion to 
include medical management 
At the request of study 
investigators to allow 
for analysis of fluid 
management in this 
patient population 
23 
2.1 
Clinical Centers, 
Organization of the Study 
Updated number of sites from 30 to 50  
To account for the 
German clinical sites 
joining the protocol 
team 
26, 45 
2.1 
Tricuspid Valve Surgery 
Removed St. Jude Flexible Annuloplasty Band 
For internal consistency 
within protocol 
33 
2.2 
Headers and Footers 
Updated and reformatted 
Consistency with   
CTSN formatting 
All 
2.2 
Title page 
Updated to new protocol version and date  
Protocol update 
1 
2.2 
Throughout protocol 
Administrative changes to correct spacing and 
other inconsistencies 
Internal protocol 
consistency and 
accuracy 
All 
2.2 
Cardiothoracic Surgical 
Trials Network pages 
Updated sites participating, personnel, and 
affiliations 
Site and staffing update 
2-3 
2.2 
Abstract 
Clarified TR severity strata used for 
randomization 
Clarification 
11 
2.2 
Data Collection Schedule 
Added ‘X’ to denote that hospitalization form 
is completed at pre-discharge 
For internal consistency 
within protocol 
13 
2.2 
Definitions and 
Measurement of 
Endpoints 
Clarified that readmissions and re-operations 
are collected through 24 months post-
randomization 
Clarification for 
consistency 
22 
2.2 
Post-randomization Data 
Collection 
Clarified that follow-up surgical procedures, re-
hospitalizations, and outpatient interventions 
are collected through 24 months post-
randomization 
Clarification for 
consistency 
35, 37 
2.2 
Analytical Plan 
Added ‘potential’ before interim analysis 
 
Clarification for 
consistency 
40 
2.2 
Analytical Plan 
Corrected the plan for handling missing data  
Correction  
41-42 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 8 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
Revision 
Section 
Change 
Reason 
Page 
2.2 
Analytical Plan 
Added at statement that sample size re-
estimation will not be done if no interim 
analysis is conducted or accrual is complete at 
the time of the first interim analysis 
Clarification 
43 
2.2 
Analytical Plan 
Added that mortality will also be assessed at 24 
months 
Correction and Update 
43 
2.2 
Analytical Plan 
Revised the analytical approach for reoperation 
for TR to account for death as a competing risk 
Correction and Update 
43-44 
2.2 
Analytical Plan 
Revised the analytical approach for MACCE to 
time to event 
Update 
44 
2.2 
Analytical Plan 
Removed specification of alpha level for 
secondary analyses 
Update 
44 
2.2 
Analytical Plan 
Clarified that Adverse Events will be assessed 
through 24 months post-randomization 
Clarification for 
consistency 
45 
2.2 
Analytical Plan 
Removed sentence on “Readmissions” and 
revised the analytical approach for “Hospital 
readmission” to Poisson regression from chi- 
squared test 
Correction and Update 
45 
2.2 
Organization of the Study 
Fixed incomplete sentence 
Correction 
47 
2.2 
References 
Added a reference for Fine and Gray (1999) 
Update 
48 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 9 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
DEFINITIONS, ACRONYMS & ABBREVIATIONS 
 
ACE  
Angiotensin converting enzyme antagonist 
AE 
 
Adverse event 
AICD  
Automatic implantable cardioverter defibrillator 
ARB  
Angiotensin receptor blocker 
ASD  
Atrial septal defect 
AV 
Atrioventricular 
CABG 
Coronary artery bypass grafting 
CEA  
Cost-effectiveness analysis 
CHF  
Congestive heart failure 
CIHR  
Canadian Institutes of Health Research 
CTA  
Clinical Trial Agreement 
CW 
 
Continuous wave 
DCC  
Data and Clinical Coordinating Center 
DGTHG 
German Society for Thoracic and Cardiovascular Surgery (Deutschen 
Gesellschaft für Thorax-, Herz- und Gefäßchirurgie) 
DSMB  
Data and Safety Monitoring Board 
DZHB  
German Heart Center Berlin (Deutsches Herzzentrum Berlin) 
DZHK 
German Centre for Cardiovascular Research (Deutsches Zentrum für 
Herz- Kreislauf-Forschung) 
EAC  
Event Adjudication Committee 
EC 
 
Ethics Committee 
EDC  
Electronic data capture system 
EDV  
End diastolic volume 
EROa  
Effective Regurgitant Orifice area  
EQ-5D  
EuroQoL 
ESV 
 
End systolic volume 
ESVI   
End systolic volume index 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICER  
Incremental cost effectiveness ratio 
InCHOIR 
International Center for Health Outcomes & Innovation Research 
IRB 
 
Institutional Review Board 
KCCQ  
Kansas City Cardiomyopathy Questionnaire 
LA 
 
Left atrium 
LAA  
Left atrial appendage 
LBBB  
Left bundle branch block 
LOS 
 
Length of stay 
LV 
 
Left ventricle 
LVEDP 
Left ventricular end diastolic pressure 
LVEF  
Left ventricular ejection fraction 
LVESVI  
Left ventricular end systolic volume index 
MACCE 
Major adverse cardiac and cerebrovascular event 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 10 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
MI 
 
Myocardial infarction 
MR 
 
Mitral regurgitation 
mRS  
modified Rankin scale 
MV 
 
Mitral valve 
MVR   
Mitral valve repair 
MVRR  
Mitral valve repair/replacement 
MVS  
Mitral valve surgery 
NHLBI 
National Heart, Lung, and Blood Institute 
NIHSS  
National Institutes of Health Stroke Scale 
NINDS 
National Institute of Neurological Disorders and Stroke  
NYHA  
New York Heart Association 
PA 
 
Pulmonary artery 
PCWP  
Pulmonary capillary wedge pressure 
PFO 
 
Patent foramen ovale 
PISA  
Proximal isovelocity surface area 
POD  
Post-operative day 
PR 
 
Pulmonic regurgitation 
PV 
 
Pulmonic valve 
PVI 
 
Pulmonary vein isolation 
PW 
 
Pulsed wave 
QALY  
Quality adjusted life years 
QOL  
Quality of Life 
REB 
 
Research Ethics Board 
RV 
 
Right Ventricle 
RVFAC 
Right ventricular fractional area change 
RVol  
Regurgitant volume 
SAE 
 
Serious adverse event 
SAX  
Short axis 
SF-12  
Short Form 12 
STEMI 
ST segment elevation myocardial infarction 
6MWT 
Six Minute Walk Test 
TAPSE 
Tricuspid annular plane systolic excursion 
TEE 
 
Trans-esophageal echocardiography 
TIA 
 
Transient ischemic attack 
TR 
 
Tricuspid regurgitation 
TTE 
 
Transthoracic echocardiography 
TV 
 
Tricuspid valve 
TVI 
 
Tissue velocity imaging 
VTI 
 
Velocity time integral 
 
 
 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 11 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
ABSTRACT 
 
Objectives 
The primary objective of this trial is to evaluate the efficacy and safety of performing 
tricuspid valve (TV) repair in patients with either moderate tricuspid regurgitation (TR) or 
less than moderate TR with tricuspid annular dilation undergoing mitral valve surgery 
(MVS). 
Study Design 
Prospective, multi-center, randomized, controlled trial 
Target 
Population 
Patients undergoing MVS (repair or replacement) for degenerative mitral regurgitation 
(MR) who have either  
(a) moderate TR OR  
(b) tricuspid annular dimension ≥ 40 mm (index: ≥21mm/M2 BSA) and none/trace or mild 
TR, determined by echocardiography. 
Rx arms 
(a) TV annuloplasty using a rigid, nonplanar, undersized (nominal 26, 28, or 30 mm) 
annuloplasty ring at the time of MVS  
(b) MVS alone 
Randomization will be stratified based on TR severity (i.e. moderate or less than moderate 
TR) and by clinical center. 
Sample Size 
400 patients provides 90% power to detect a decrease in “failure” from 25% without  
tricuspid valve repair to 12% in patients with repair. 
Duration 
60 months following randomization 
1 Endpoints 
 
Composite of death, reoperation for TR, or progression of TR from baseline by 
two grades or the presence of severe TR at 24 months 
Degree of TV regurgitation will be categorized according to American Society of 
Echocardiography guidelines as none/trace/mild/moderate/severe 
2 Endpoints 
Clinical and Functional Outcomes 
 Composite of major adverse cardiac and cerebrovascular events (MACCE), 
including stroke, death, and serious heart failure events 
 NYHA classification and diuretic requirements 
 Six-minute walk test (6MWT) 
 Gait Speed Test for Frailty 
Echocardiography 
 Degree of TR at index hospital discharge 
 Degree of TR at 12 and 24 months 
 Right ventricular size at 12 and 24 months 
 Right ventricular function [normal, mildly impaired, moderately impaired, 
severely impaired, peak tricuspid annular velocity, tricuspid annular plane systolic 
excursion (TAPSE), right ventricular fractional area change (RVFAC)] at 12 and 
24 months 
 Pulmonary artery pressure at 12 and 24 months 
 Right ventricular volume at 12 and 24 months 
Quality of Life 
 SF-12 
 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 EuroQoL (EQ-5D) 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 12 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
Survival 
 Perioperative mortality (greater in-hospital or 30 day mortality) 
 Mortality  
Serious Adverse Events 
 Frequency of serious adverse events (SAEs) 
 Atrioventricular (AV)-Block requiring pacemaker implantation  
 New-onset atrial fibrillation 
Hospitalizations 
 Index hospitalization length of stay (LOS) and intensive care unit (ICU) days 
 All-cause readmissions, and readmissions for heart failure and TR reoperations 
Economic Outcomes 
 Cost 
 Cost-effectiveness 
Selected 
Inclusion 
Criteria 
1. Age  > 18 years 
2. Undergoing MVS for degenerative MR 
3. (a) moderate TR as determined by echocardiography, or (b) none/trace or mild TR and 
tricuspid annular dimension ≥ 40 mm 
Selected 
Exclusion 
Criteria 
1. Functional MR 
2. Evidence of sub-optimal fluid management (e.g., lack of diuretics, weight in excess of 
dry weight) in the opinion of the cardiology investigator 
3. Structural/organic TV disease 
4. Severe TR, as determined by echocardiography 
5. Implanted pacemaker or defibrillator, where the leads cross the TV from the right 
atrium into the right ventricle 
6. Concomitant cardiac surgery other than atrial fibrillation correction surgery 
[pulmonary vein isolation (PVI), Maze, left atrial appendage (LAA) closure, closure of 
patent foramen ovale (PFO) or atrial septal defect (ASD), or coronary artery bypass 
grafting (CABG) 
7. Cardiogenic shock at the time of randomization 
8. ST segment elevation myocardial infarction (STEMI) requiring intervention within 7 
days prior to randomization 
9. Evidence of cirrhosis or hepatic synthetic failure 
10. Severe, irreversible pulmonary hypertension in the judgment of the investigator 
11. Pregnancy at the time of randomization 
12. Unable or unwilling to provide informed consent 
13. Unable or unwilling to comply with study follow up in the opinion of the investigator 
 
 
 

 
InCHOIR  
 
 Date Written: November 2015 
Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 13 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
DATA COLLECTION SCHEDULE 
 
 
 
Assessment 
Screening/ 
Baseline 
(60 days 
pre-op) 
Intra-
Operative 
Pre-
discharge 
30 Days 
(-7 days, 
+35 days) 
6 Mos 
(± 30 
days) 
12 Mos 
(± 30 
days) 
18 Mos 
(± 30 
days) 
 
24 Mos 
(± 60 
days) 
36, 48 
& 60 
Mos    
(± 60 
days) 
Event 
Driven 
 
 
 
General 
  
  
 
  
  
  
 
  
 
  
Eligibility Criteria 
X 
  
 
 
  
  
 
  
 
  
Informed Consent 
X 
  
 
  
  
  
 
  
 
  
Release of Medical Information 
X 
 
 
 
 
 
 
 
 
 
Screening Log and Registration  
X 
  
 
  
  
  
 
  
 
  
Medical History 
X 
  
 
  
  
  
 
  
 
  
Medications 
X 
  
 
X 
X 
X 
 
X 
 
X 
Physical Exam 
X 
  
 
X 
X 
X 
 
X 
 
  
Gait Speed Test 
X 
 
 
 
 
X 
 
X 
 
 
Laboratory Assessment 
X 
  
 
 
  
  
 
  
 
 X 
Screening Outcome 
X 
  
 
 
  
  
 
  
 
  
Hospitalization 
X 
  
X 
  
  
  
 
  
 
X 
Vital Status Check 
 
 
 
 
 
 
 
 
X 
 
Cardiac 
  
  
 
 
  
  
 
  
 
  
Surgical Procedure  
  
X 
 
  
  
  
 
  
 
 X  
TEE 
  
X 
  
  
  
 
  
 
  
NYHA Heart Failure Classification  
X 
  
 
X 
X 
X 
 
X 
 
  
2D Echo (TTE) 
X 
  
X 
  
X 
X 
 
X 
 
  
Six Minute Walk Test (6MWT) 
X 
 
 
X 
X 
X 
 
X 
 
 
3D Echo (TTE) 
X 
 
 
 
 
X 
 
X 
 
 
Quality of Life (QOL) 
  
  
 
  
  
  
 
  
 
  
KCCQ 
X 
  
 
  
X 
X 
X 
X 
 
  
SF-12 
X 
 
 
 
X 
X 
X 
X 
 
 
EQ-5D 
X 
  
 
  
X 
X 
X 
X 
 
  
Event Driven Data 
  
  
 
  
  
  
 
  
 
  
Adverse Events  
  
  
 
  
  
  
 
  
 
X 
Missed Visit 
  
  
 
  
  
  
 
  
 
X 
Protocol Deviation 
 
 
 
 
 
 
 
 
 
X 
Mortality  
  
  
 
  
  
  
 
  
 
X 
Study Completion/Early Termination 
  
  
 
  
  
  
 
  
 
X 
End of Study/Investigator Statement 
  
  
 
  
  
  
 
  
 
X 
Cost 
  
  
 
  
  
  
 
  
 
  
UB-92 Forms & Hospital Bills 
  
  
 
  
  
  
 
  
 
X 
Vizient Data 
 
 
 
 
 
 
 
 
 
X 
 

 
InCHOIR  
 
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Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
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Date Effective: January 2020 
 
CONFIDENTIAL 
 
OBJECTIVES 
The overall objective of this study is to evaluate the safety and efficacy of tricuspid valve 
(TV) repair in the setting of mitral valve surgery (MVS) for degenerative mitral valve 
(MV) disease.  Specifically, this study compares the surgical approach of combining TV 
annuloplasty with clinically indicated MVS to performing MVS alone. 
 
 The primary aim of this trial is to evaluate the impact of these two surgical 
approaches on the composite endpoint of death and reoperation for tricuspid 
regurgitation (TR), or progression of TR, either by two grades from baseline (i.e. 
prior to randomization),  or by the presence of severe TR at 2 year follow-up.   
 
 Secondary aims of this trial include assessment of the impact of these two surgical 
approaches on right heart performance and function, mortality, adverse events 
(AEs), quality of life (QOL), functional status, presence and severity of TR, and 
health resource use.  
BACKGROUND AND SIGNIFICANCE 
Etiology & Prognosis 
The presence of moderate or severe TR is commonly encountered, affecting over 1.6 
million people in the United States alone (Taramasso, Vanermen et al. 2012). Intrinsic 
pathology of the TV is rare resulting in most TR being functional, which is defined as 
regurgitation in the presence of anatomically normal leaflets and chords. TR produces 
fewer observable symptoms compared with other valvular pathology, and its assessment 
by physical exam can be challenging.  As a result, the presence and severity of TR is 
often appreciated solely on echocardiography.  
The precise mechanism by which functional TR develops is thought to be due to tricuspid 
annular dilation, as well as right ventricular (RV) enlargement and dysfunction associated 
with left heart disease and/or significant pulmonary hypertension (Dreyfus, Randolph et 
al. 2015). Left heart disease in this context mainly refers to MV pathology in the presence 
of systolic and/or diastolic dysfunction. Up to one third of patients with mitral stenosis 
have moderate or greater TR. However reports of the prevalence of TR and/or annular 
dilation in patients undergoing surgery for mitral regurgitation (MR) vary, ranging from 
8-65% (Sagie, Freitas et al.1997; Dreyfus, Corbi et al. 2005; McCarthy 2007; Chan, 
Burwash  et al. 2009; Chikwe, Itagaki et al. 2015; TM Koelling, Aaronson et al. 2002).  
In 1967, Braunwald and colleagues demonstrated that correction of left-sided disease 
allowed for resolution of TR (Morrow, Oldham et al. 1967). In more recent years 
however this philosophy has been challenged by some, on account of observations that 
TR may in fact resolve only in a minority of cases. Overall data on the postoperative 
course and clinical sequelae of TR are conflicting, largely due to heterogeneous surgical 
management and MV pathologies. Dreyfus et al, for example, have reported that up to 
48% of patients have an increase of up to 2 grades of TR (Raja and Dreyfus 2009), 
whereas other investigators have demonstrated only small increases in mean TR over a 5-
year postoperative period.  

 
InCHOIR  
 
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Date Revised: January 2020 
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CONFIDENTIAL 
 
Although the clinical context in which TR occurs may influence prognosis, there are 
numerous reports that demonstrate the presence of TR being associated with increased 
mortality. Nath and colleagues showed that moderate or more severe TR conferred 
inferior survival even after adjusting for age, left ventricular and RV function in a cohort 
of over 5000 male Veteran patients (Nath, Foster and Heidenreich 2004).  These findings 
were supported by a study by Lee et al, who reported a 74% 5-year survival for patients 
with moderate or severe TR who were medically managed (Lee, Song et al. 2010; 
Nishimura, Otto et al. 2014).  Importantly, TR may influence the quality of survival as 
well. Decreased exercise tolerance has been reported in patients with TR after MV 
replacement, and patients who go on to develop more severe TR are more likely to 
develop New York Heart Association class III-IV symptoms (Groves, Lewis et al. 1991; 
Ruel, Rubens et al. 2004).   
Rationale for the Trial 
Medical therapy for TR is limited only to diuretics and potential treatment of elevated 
pulmonary pressures. Echocardiographic assessment of severity can be dynamic in that 
degree of TR is highly dependent on preload, afterload and RV function. Though 
functional TR is a result of annular dilation, routine measurement on echocardiography is 
not common in clinical practice.  
In patients with severe TR already undergoing surgery for left valvular pathology, 
surgical correction is recommended by the AHA/ACC and ESC guidelines (Nishimura, 
Otto et al. 2014).  Significant equipoise exists, however, as to the optimal approach for 
patients with only moderate TR or mild TR with annular dilation. Some centers argue that 
performing a TV annuloplasty at the time of MVS influences the incidence of right heart 
failure and improves long term survival, yet others believe the risk of an additional 
surgical procedure outweighs the potential benefit (Yilmaz, Suri et al. 2011). According 
to the STS database, among 46,500 isolated primary MV operations performed between 
2011 and 2014, TV repair was performed in 4% of patients with none or mild TR, 35% of 
patients with moderate TR, and 79% of patients with severe TR. These practice patterns 
serve to reflect an uncertainty of benefit of concomitant TV repair for moderate TR as 
well as variability in practice.  
 
Establishing whether or not definitive benefit is conferred by performing TV repair at the 
time of MVS for degenerative MV disease should provide the level of evidence needed to 
provide rigorous recommendations for the management of this significant patient 
population.  As such, the Network has designed a trial to evaluate the efficacy and safety 
of concomitant TR annuloplasty at the time of MVS.  
 
Justification of Primary Endpoint Selection 
Ideally, the effectiveness of TR repair should be measured by the degree to which it 
reduces relevant clinical events.  However, the combination of the relatively low 
expected two-year event rate in the target population of degenerative MR with moderate 
or less TR, and logistical constraints on the sample size for the trial, precludes using an 
endpoint defined in terms of clinical events alone.  Instead, we propose a composite 
endpoint of death from any cause, progression of TR (measured echocardiographically) 

 
InCHOIR  
 
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Date Revised: January 2020 
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CONFIDENTIAL 
 
or TV reoperation.  There is evidence that the presence of severe TR is independently 
correlated with decreased late survival (Nath, Foster et al. 2004) and that the presence of 
significant TR after MV operations is correlated with RV dysfunction and decreased RV 
reverse remodeling (Goldstone, Howard et al. 2014; Van de Veire, Braun et al. 2011; 
Benedetto, Melina et al. 2012; Bertrand, Koppers et al. 2014; Vargas Abello, Klein et al. 
2013).  Among patients with systolic heart failure, the presence of significant TR is 
associated with an increased risk of hospital admission for congestive heart failure, and 
TR in combination with RV dysfunction is associated with renal dysfunction and excess 
mortality (Agricola, Marini et al. 2015). 
 
We also considered cardiac MRI for the primary evaluation modality but thought the test 
onerous and likely to constrain enrollment and increase missing data.  While MRI is the 
gold standard for determination of RV structure and function, compliance with initial 
(preoperative) MRI in a pilot study has been obtained in only 67 % (N=40) of patients 
due to contraindications or patient refusal, with follow-up compliance and acquisition 
rates significantly lower.  RV volume as measured by 3D echocardiography is a potential 
alternative to MRI.  However, this promising but emerging modality still presents 
technical limitations.  In addition, established longitudinal data on 3D echo assessment of 
RV remodeling after TR annuloplasty do not exist as of yet. We, therefore, felt that RV 
volume by 3D echo was not appropriate as the primary endpoint, but did include it as a 
secondary endpoint. 
 
ENDPOINTS  
 
Primary  
Composite of death, reoperation for TR, or progression of TR from baseline (i.e., prior to 
randomization) by two grades or the presence of severe TR at 2 years. 
 
Degree of TV regurgitation will be categorized according to American Society of 
Echocardiography guidelines as none/mild/moderate/severe. Trace regurgitation is also 
used in the event that regurgitation is barely detected.  
 
Secondary  
Clinical and Functional Outcomes 
 Composite of major adverse cardiac and cerebrovascular events (MACCE), 
including stroke, death, and serious heart failure events  
 NYHA classification 
 6MWT 
 Gait Speed Test for Frailty 
 
Echocardiography 
 Degree of TR at index hospital discharge 
 Degree of TR  at 12 and 24 months 

 
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Date Revised: January 2020 
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Date Effective: January 2020 
 
CONFIDENTIAL 
 
 RV size at 12 and 24 months  
 RV function  (normal, mildly impaired, moderately impaired, severely impaired, 
peak tricuspid annular velocity, TAPSE, RVFAC) at 12  and 24 months 
 Pulmonary artery pressure at 12 and 24 months 
 RV volume at 12 and 24 months 
 
Quality of Life  
 SF-12  
 KCCQ 
 EQ-5D 
 
Survival 
 Perioperative mortality (greater in-hospital or 30-day mortality) 
 Mortality 
 
Serious Adverse Events 
 Frequency of SAEs 
 AV-Block requiring pacemaker implantation  
 New-onset atrial fibrillation 
 
Hospitalizations 
 Index hospitalization LOS and ICU days 
 All-cause readmissions and readmissions for heart failure and TR re-operation 
 
Economic Outcomes 
 Cost 
 Cost-effectiveness 
 
STUDY DESIGN 
This is a multi-center randomized clinical trial.  The trial will be conducted in highly 
experienced clinical centers participating in the NIH/CIHR supported Cardiothoracic 
Surgical Trials Network (CTSN) and the Deutsches Zentrum für Herz- Kreislauf-
Forschung (DZHK) supported German Society for Thoracic and Cardiovascular Surgery 
(DGTHG). The estimated enrollment period is 24 months (n = 400), and all patients will 
be followed for 60 months post-randomization.  Endpoints will be measured at 30 days, 
6, 12, 18, and 24 months.  Survival will continue to be measured after the 24-month visit 
via vital sign checks at 36, 48 and 60 months. 
 
RANDOMIZATION  
Patients will be randomly assigned (1:1) to MVS + TV annuloplasty or MVS alone.  
Patient randomization will be stratified by TR severity and by clinical center.  The 
randomization procedure will be performed intra-operatively, following the placement 
of the TEE probe and after visualization and confirmation of cardiac anatomy 
eligibility, in order to minimize the likelihood of enrolling patients in the study with 

 
InCHOIR  
 
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Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
Page 18 of 63 
 
Date Effective: January 2020 
 
CONFIDENTIAL 
 
unexpected surgical contra-indications to TV repair.  Randomization will be performed 
centrally through a Web-based data collection system that automates the delivery of the 
randomization assignments.  The treatment assignment will be viewed by the site 
coordinator electronically, in a secure fashion, and electronic verification of the treatment 
assignment will be required before proceeding with the treatment intervention.  From that 
point on, primary efficacy will be analyzed by intention-to-treat; that is, the patients will 
be grouped by their assignment at randomization whether or not they actually received 
the treatment to which they were assigned.  
 
MASKING 
Neither patients nor investigators will be blinded to treatment assignment due to the 
nature of the treatment intervention.  Investigators will, however, be blinded to all data 
from other clinical sites, except serious unexpected AEs that are possibly or probably 
related to the investigational procedure for IRB/REB/EC reporting purposes.  All 
echocardiograms will be analyzed by echocardiography core laboratory (Echo Core Lab) 
personnel who will be blinded to clinical outcomes.  Adverse events (AEs) will be 
adjudicated by an Event Adjudication Committee (EAC) and trial oversight will be 
provided by an independent Data and Safety Monitoring Board (DSMB).   
 
STUDY POPULATION 
The patient population for this trial consists of adult patients undergoing MVS via full or 
minimal-access sternotomy or right thoracotomy for degenerative MV disease using 
legally marketed devices. Specific inclusion and exclusion criteria are listed below. All 
patients who meet the eligibility criteria may be included in the study regardless of 
gender, race, or ethnicity. 
 
Inclusion Criteria 
1. Undergoing MVS for degenerative MR1 with  
 
(a) Moderate TR as determined by transthoracic 2D echocardiography, or  
(b) Tricuspid annular dimension ≥ 40 mm (index: ≥21mm/M2 BSA) and none/trace or 
mild TR, determined by echocardiography. 
 
2. Age ≥ 18 years  
 
3. Able to sign Informed Consent and Release of Medical Information forms 
 
Exclusion Criteria 
1. Functional MR 
                                                 
1 “Degenerative mitral valve disease refers to a spectrum of conditions in which morphologic changes in the connective 
tissues of the mitral valve cause structural lesions . . ., such as chordal elongation, chordal rupture, leaflet tissue 
expansion, and annular dilation typically resulting in mitral regurgitation due to leaflet prolapse.” This definition 
excludes rheumatic heart disease.  (Anyanwu AC, Adams DH.  (2007)  Etiological classification of degenerative mitral 
valve disease: Barlow’s disease and fibroelasticity deficiency. Semin Thorac Cardiovasc Surg; 19(2): 90-6). 

 
InCHOIR  
 
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Date Revised: January 2020 
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Date Effective: January 2020 
 
CONFIDENTIAL 
 
 
2. Evidence of sub-optimal fluid management (e.g., lack of diuretics, weight in 
excess of dry weight) in the opinion of the cardiology investigator  
 
3. Structural / organic TV disease 
 
4. Severe TR as determined by preoperative transthoracic echocardiography (TTE) 
 
5. Implanted pacemaker or defibrillator, where the leads cross the TV from the right 
atrium into the right ventricle 
 
6. Concomitant cardiac surgery: other than atrial fibrillation correction surgery (PVI, 
Maze, LAA closure), closure of PFO or ASD, or CABG   
 
7. Cardiogenic shock at the time of randomization 
 
8. STEMI requiring intervention within 7 days prior to randomization 
 
9.  Evidence of cirrhosis or hepatic synthetic failure 
 
10.  Severe, irreversible pulmonary hypertension in the judgment of the investigator 
 
11.  Pregnancy at the time of randomization 
  
12.  Therapy with an investigational intervention at the time of screening, or plan to 
enroll patient in additional investigational intervention study during participation 
in this trial 
 
13. Any concurrent disease with life expectancy < 2 years 
 
14. Unable or unwilling to provide informed consent 
 
15. Unable or unwilling to comply with study follow up in the opinion of the 
investigator 
 
 
Recruitment Strategies 
Based on a survey of the clinical sites, it is estimated that approximately 150-200 patients 
could be enrolled annually through active screening and recruitment by the participating 
CTSN and DGTHG centers.  These strategies may include: mailings to referring 
physicians of the study hospitals, symposia and health care events targeted towards this 
population, as well as telephone calls to neighboring health care facilities.  The Data and 

 
InCHOIR  
 
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Date Revised: January 2020 
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Date Effective: January 2020 
 
CONFIDENTIAL 
 
Clinical Coordinating Center (DCC) will regularly assess actual enrollment in relation to 
pre-specified goals, and additional interventions to increase enrollment will be 
implemented as needed.  The Screening Log will identify numbers of patients screened 
and reasons for non-enrollment in the trial.   
 
Inclusion of Women and Minorities 
The inclusion of women and minorities in clinical trials is critical for scientific, ethical, 
and social reasons, and for the generalizability of trial results.  The CTSN is strongly 
committed to ensuring a balanced recruitment of patients regardless of sex or ethnicity.  
The North American clinical sites will recruit at least 30% women and 25% minorities.  
The following measures will be employed to ensure adequate representation of these 
groups: (1) documentation of the number of women and minorities screened and enrolled 
via screening/exclusion logs; (2) monitoring of such logs from each clinical center on a 
monthly basis; and (3) if necessary, the development and implementation of outreach 
programs designed to recruit adequate numbers of women or minorities.  
 
TREATMENT INTERVENTIONS 
Patients will be randomly assigned to the following treatment groups: 
 
Mitral Valve Surgery + Tricuspid Valve Annuloplasty 
     
Mitral Valve Surgery Alone   
 
DEFINITIONS AND MEASUREMENT OF ENDPOINTS  
Primary Endpoint 
The primary outcome of this trial is treatment failure defined as the composite of (1) 
death from any cause, (2) reoperation for TR, (3) presence of severe TR at two years post 
randomization or, for patients enrolled with less than moderate TR and annular dilatation, 
progression by two grades (i.e., from none/trace TR to moderate TR) at two years post 
randomization.  
 
Secondary Endpoints 
Clinical and Functional Outcomes 
MACCE (Major Adverse Cardiac and Cerebrovascular Events)  
MACCE is defined as a non-weighted composite score comprised of the 
following components: 
o Death 
o Stroke 
o Serious heart failure events  
 
NYHA Classification and Diuretic Use   
Functional status will be assessed by the NYHA Classification scale. Complete 
NYHA classification guidelines can be found in Appendix III.  The diuretic 
requirements of patients will be assessed. 
 

 
InCHOIR  
 
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Date Revised: January 2020 
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CONFIDENTIAL 
 
Six Minute Walk Test (6MWT) 
The total distance walked in six minutes will be assessed.  Complete 6MWT 
guidelines can be found in Appendix IV. 
 
Gait Speed Test for Frailty  
Frailty will be assessed using the Gait Speed Test administered at baseline and 
reassessed at 12 and 24 months post-randomization.  Complete Gait Speed Test 
guidelines can be found in Appendix V. 
 
Physiologic  
Echocardiographic Parameters (Appendix I and Appendix II) 
 Degree of TR at Index Hospital Discharge  
 Degree of TR at 12 and 24 months  
 RV Size at 12 and 24 months 
 RV Function (normal, mildly impaired, moderately impaired, severely 
impaired, peak tricuspid annular velocity, TAPSE, RVFAC) at 12 and 24 
months 
 Pulmonary Artery Pressure at 12 and 24 months  
 RV volume at 12 and 24 months as measured by transthoracic 3D 
echocardiography 
 
Quality of Life  
The change in QOL from baseline will be measured, using the disease-specific 
KCCQ score, the SF-12 general health status index, and EQ-5D measures of 
health state preference from the individual and societal perspective.  The KCCQ 
is a widely used tool in heart failure populations. The SF-12 is a general health 
status measure.  This instrument examines 8 quality of life dimensions (physical 
activity, social activity, role/physical, body pain, general mental health, 
role/emotional, vitality and general health perception).  The EQ-5D is a 
standardized instrument for measuring health-related quality of life. This 
questionnaire provides a simple descriptive profile that consists of 5 dimensions.  
The 5 domains are anxiety/depression, pain/discomfort, usual activities, self-care, 
and mobility.  The instrument also has a self-assessment of health status.   
 
For this trial, the SF-12, EQ-5D, and KCCQ are available in English, Spanish, 
French and German.  Inability to read and complete these instruments in the 
available languages does not preclude a patient from enrollment in the trial (a 
family member may assist in completing the QOL questionnaires).   
   
Survival 
Perioperative and all-cause mortality over 60 months will be assessed.  
 

 
InCHOIR  
 
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CONFIDENTIAL 
 
Hospitalizations  
Length of Index Hospitalization 
Overall length of stay (LOS) for the index hospitalization will be measured (and 
broken down by days spent in the ICU versus days spent on telemetry and regular 
floors).  LOS will be measured as time from index surgery to discharge.  In 
addition, we will capture discharge location. 
 
Readmission and Reoperations 
Readmission rates will be calculated for the first 30 days following intervention 
and through 24 months post-randomization.  Hospitalizations will be classified for 
all causes, including cardiovascular and heart failure readmissions and 
readmissions for TR operation.  Classification of a readmission as heart failure 
related requires at least 2 out of the following signs and symptoms of acute 
decompensated heart failure: 
 
 Dyspnea felt related to heart failure  
 Treatment with intravenous diuretic, vasodilator or inotropic therapy 
 X-ray evidence of pulmonary edema or pulmonary vascular congestion 
 Rales on physical exam 
 PCWP or LVEDP > 18 mmHg 
 
All readmissions will be classified by the investigator and adjudicated by the 
EAC. 
 
All re-operations and re-operation for TR in particular will be recorded through 
24 months post-randomization.  Freedom from re-operation will be analyzed. 
 
Economic Measures 
Inpatient costs will be measured through the collection of hospital billing and 
resource utilization information. In addition to index hospitalization costs, costs 
associated with subsequent readmissions will also be included in the study. 
Patients will also be asked at each follow-up visit if they have been hospitalized at 
another hospital and if yes for how long.  
 
For those institutions who participate in Vizient (formerly the University 
Healthsystems Consortium [UHC]), hospital costs and resource utilization data 
will be collected. Vizient works with academic medical centers around the 
country to collect and warehouse clinical, safety, operational and financial data.  
These data are used to compare performance among peer hospitals and identify 
best practice patterns.  Participating centers will provide unique trial information 
and the dates of participation in the trial to Vizient who will provide a de-
identified data set of the financial data for the trial to the investigators for 
analysis.     
 

 
InCHOIR  
 
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CONFIDENTIAL 
 
For institutions who do not participate in Vizient, hospital billing data from the 
UB-92 form will be collected in a de-identified manner from the institutional 
billing departments.  As hospitalization practices differ substantially and detailed 
accounting data are unavailable for the participating Canadian and German 
centers, the cost and cost-effectiveness analysis will be restricted to US centers 
only.   
 
Safety  
Adverse Events 
Please refer to the CTSN Clinical and Adverse Event Reporting and Adjudication 
Procedures guidance document for general reporting procedures and guidance on the 
determination of intervention-expected AEs. 
 
Specific Adverse Event Definitions 
 
AV Conduction Block leading to Permanent Pacemaker Placement 
See “Cardiac Arrhythmias” below 
 
New-onset Post-Operative Atrial Fibrillation 
See “Cardiac Arrhythmias” below 
 
Bleeding 
A bleeding event is defined by any one of the following: 
o Transfusion of > 5 units RBC within the first 24 hours following surgery 
o Death due to hemorrhage 
o Re-operation for hemorrhage or tamponade 
 
NOTE: Hemorrhagic stroke is considered a neurological event and not as a separate 
bleeding event. 
 
Cardiac Arrhythmias 
Any documented arrhythmia that results in clinical compromise (e.g., hemodynamic 
compromise, oliguria, pre-syncope or syncope) that requires hospitalization or 
requires a physician visit or occurs during a hospital stay.   
 
Cardiac arrhythmias are classified as follows:  
o Cardiac arrest  
o    Sustained ventricular arrhythmia requiring defibrillation or 
cardioversion. 
o    Sustained supraventricular arrhythmia requiring drug treatment or 
cardioversion (classified as either pre-existing or post-operative onset) 
o Cardiac conduction abnormalities or sustained bradycardia requiring 
permanent pacemaker placement (includes all PPMs whether 
associated with a serious AE or not)  
 

 
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CONFIDENTIAL 
 
Pericardial Fluid Collection 
Accumulation of fluid or clot in the pericardial space that requires surgical 
intervention or percutaneous catheter drainage.  This event will be subdivided into 
those with clinical signs of tamponade (e.g., increased central venous pressure and 
decreased cardiac output) and those without signs of tamponade. 
 
Pleural Effusion 
Accumulation of fluid or clot in the pleural space documented by chest radiogram or 
chest CT that requires evacuation with surgical intervention, chest tube or pigtail 
placement or medical management such as diuresis.   
 
Pneumothorax 
Presence of gas in the pleural space, documented by chest radiogram or chest CT, 
which requires evacuation or prolongs the duration of chest tube drainage. 
 
Hepatic Dysfunction 
Liver injury and impaired liver function defined as: 
o ALT  3xURL and total bilirubin*  2xURL (>35% direct), or  
o ALT  3xURL and INR** > 1.5.  
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick.  If fractionation is 
unavailable and ALT  3xURL and total bilirubin  2xURL, then the event is 
still to be reported as an SAE. 
** INR testing not required per protocol and the threshold value does not apply 
to subjects receiving anticoagulants.  If INR measurement is obtained, the value 
is to be recorded on the SAE form. 
Major Infection 
 
A new clinical infection accompanied by pain, fever, drainage and/or leukocytosis 
that is treated by anti-microbial agents (non-prophylactic).  A positive culture from 
the infected site or organ should be present unless strong clinical evidence indicates 
the need for treatment despite negative cultures.  The general categories of infection 
are listed below:  
 
Localized Infection  
 
 
 
Infection localized to any organ system or region (e.g., mediastinitis) without 
evidence of systemic involvement (see “sepsis” below), ascertained by standard 
clinical methods and either associated with evidence of bacterial, viral, fungal or 
protozoal infection, and/or requiring empirical treatment.  
 
Endocarditis 
Signs, symptoms and laboratory findings consistent with endocarditis, including 
but not limited to fever ≥ 38.0o C, positive blood cultures, new regurgitant 
murmurs or heart failure, evidence of embolic events (e.g., focal neurologic 

 
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impairment, glomerulonephritis, renal and splenic infarcts, and septic pulmonary 
infarcts), and peripheral cutaneous or mucocutaneous lesions (e.g., petechiae, 
conjunctival or splinter hemorrhages, Janeway lesions, Osler's nodes, and Roth 
spots).  Echocardiographic evidence of new, intra-cardiac vegetation with or 
without other signs and symptoms should be considered adequate evidence to 
support the diagnosis of endocarditis.  TEE should be the modality of choice for 
diagnosis of prosthetic valve endocarditis.  
 
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood 
cultures and/or hypotension. 
 
Myocardial Infarction 
Myocardial infarction (MI) should be classified when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischemia.  Under these 
conditions, any one of the following criteria meets the diagnosis for myocardial 
infarction[1]:   
 
Myocardial Infarction (Non-Procedure Related) 
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with 
at least one value above the 99th percentile of the upper reference limit (URL) 
together with evidence of myocardial ischemia with at least one of the 
following: 
o Symptoms of ischemia; 
o ECG changes indicative of new ischemia (new ST-T changes or new 
left bundle branch block [LBBB]); 
o Development of pathological Q waves in the ECG; 
o Imaging evidence of new loss of viable myocardium or new regional 
wall motion abnormality. 
 
Peri-CABG Myocardial Infarction                                                                      
For CABG in patients with normal baseline troponin values, elevations of 
cardiac biomarkers above the 99th percentile URL are indicative of peri-
procedural myocardial necrosis.  By convention, increases in biomarkers > 5 x 
99th percentile URL plus either new pathological Q waves or new LBBB, or 
angiographically documented new graft of native coronary artery occlusion, or 
imaging evidence of new loss of viable myocardium have been designated as 
defining CABG-related MI. 
 
Peri-Percutaneous Intervention (PCI) Myocardial Infarction 
For PCI in patients with normal baseline troponin values, elevations of cardiac 
biomarkers above the 99th percentile URL are indicative of peri-procedural 
                                                 
[1] Joint ESC/ACCF/AHA/WHF Task for the Redefinition of Myocardial Infarction, Circulation. 2007; 
116:0-0. 

 
InCHOIR  
 
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Document Number: TR Trial Protocol Rev 2.2 
 
Date Revised: January 2020 
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Date Effective: January 2020 
 
CONFIDENTIAL 
 
myocardial necrosis.  By convention, increases in biomarkers > 3 x 99th 
percentile URL have been designated as defining PCI-related MI.  A subtype 
related to a documented stent thrombosis is recognized. 
 
Note:  Sudden unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by presumed new 
ST elevation or new LBBB, and/or evidence of fresh thrombus by coronary 
angiography and/or autopsy, with death occurring before blood samples obtained, 
or at a time before the expected appearance of cardiac biomarkers in blood will be 
classified as a mortality due to MI. 
 
Neurologic Dysfunction 
Any new, temporary or permanent, focal or global neurological deficit ascertained by a 
standard neurological examination (administered by a neurologist or other qualified 
physician and documented with appropriate diagnostic tests and consultation note).  The 
examining physician will distinguish between a transient ischemic attack (TIA), which is 
fully reversible within 24 hours (and without evidence of infarction), and a stroke, which 
lasts longer than 24 hours (or less than 24 hours if there is evidence of infarction on 
neuroimaging).  The NIH Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) must 
be administered within 24 hours following the event if the event is not captured at a 
protocol-defined assessment time point, to document the presence and severity of 
neurological deficits.  
Each neurological event must be subcategorized as:  
o TIA defined as an acute event that resolves completely within 24 hours with 
no imaging evidence of infarction.  
o Hemorrhagic stroke 
o Ischemic stroke  
o Toxic Metabolic Encephalopathy, defined as a disorder of the brain function 
that arises from abnormal systemic metabolism, infection, or exogenous 
substances, altering awareness and/or consciousness, in which there is a non-
focal neurological examination and a negative brain image. 
o Seizure, defined as an abnormal paroxysmal cerebral neuronal discharge that 
results in alteration of sensation, motor function, behavior, or consciousness 
o Other 
 
Renal Failure  
 
 
 
 
New requirement for hemodialysis related to renal dysfunction.  This definition excludes 
aquapheresis for volume removal alone. 
 
Respiratory Failure 
Impairment of respiratory function requiring re-intubation, tracheostomy or the inability 
to discontinue ventilator support within 48 hours post-surgical intervention. This 
excludes intubation for re-operation or temporary intubation for diagnostic or therapeutic 
procedures. 
 

 
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CONFIDENTIAL 
 
Heart Failure  
Signs of inadequate organ perfusion or congestion, or a syndrome of compromised 
exertional tolerance manifested by dyspnea or fatigue that requires:  
o intravenous therapy (diuretics, inotropic support, or vasodilators) and prolongs 
hospital stay in the judgment of the investigator, or  
o introduction of intravenous therapy (diuretics, inotropic support, or vasodilators) 
at any point following discharge from the index hospitalization, or  
o readmission for heart failure 
 
Arterial Non-CNS Thromboembolism 
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ system 
due to thromboembolism confirmed by one or more of the following:  
o Standard clinical and laboratory testing 
o Operative findings 
 
 
 
o Autopsy findings 
 
This definition excludes neurological events. 
 
Venous Thromboembolic Event 
Evidence of venous thromboembolic event (e.g., deep vein thrombosis, pulmonary 
embolism) by standard clinical and laboratory testing.   
 
Wound Dehiscence 
Disruption of the apposed surfaces of a surgical incision, excluding infectious 
etiology, and requiring surgical repair. 
 
 
Other 
All other SAEs (events that cause clinically relevant changes in the patient’s health, or 
any event that is life-threatening, results in a fatality, results in permanent disability, 
requires hospitalization, or prolongs an existing hospital stay).  
 
CLINICAL CENTERS 
The study will be conducted in up to 50 clinical centers participating in the NIH/CIHR 
supported CTSN and the DZHK supported DGTHG.  Each clinical center will be 
required to obtain IRB/REB/EC approval for the protocol and consent revisions in a 
timely fashion, to recruit patients, to collect data and enter it accurately into the electronic 
data capture (EDC) system, to faithfully follow the protocol and adhere to the standards 
of Good Clinical Practice (GCP) and HIPAA regulations (US sites), the Personal 
Information Protection and Electronic Documents Act (PIPEDA) regulations (Canadian 
sites) or the European Union’s Privacy Directive (German sites).  In addition, centers will 
be required to provide the DCC with the information necessary for interim, annual, and 
final reports, to provide source documents, data and regulatory documents for study 
monitors, provide prompt responses to DCC inquiries, and to participate in analyses and 
reporting of study results. 
 

 
InCHOIR  
 
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CONFIDENTIAL 
 
INVESTIGATORS 
All surgeons, cardiologists, coordinators and other investigators involved in the trial must 
complete the Investigator Contact Form with their hospital affiliation, address, contact 
numbers (phone, fax, cell, pager), and email address.  All investigators must send their 
CV, Clinical Study Agreement/Conflict of Interest Statement, Good Clinical Practice 
Certificates, and HIPAA or other Privacy Protection certification as required by the local 
institution to the DCC. 
 
Qualifications and Training  
Clinical investigators will be cardiothoracic surgeons with expertise in surgical 
management of the mitral and tricuspid valves.  To qualify as a surgeon participating in 
this trial, the surgical investigator must have performed at least 10 MV and 5 TV 
procedures annually (averaged over a 2-year period).  Surgical qualifications for all 
participating surgical investigators will be collected on the Surgical Certification Form 
and uploaded to the Florence eRegulatory binder prior to accreditation.  The clinical site 
Principal Investigator (PI) will be responsible for overseeing the ongoing performance of 
the other participating surgical investigators at that site over the course of the study.   
 
All clinical site investigators and coordinators will be trained by the DCC in the specifics 
of the protocol during site initiation in advance of patient enrollment.  The designated 
echo cardiologist and echocardiography teams will be trained in echo acquisition 
protocols separate from the site initiation.  In addition, the investigators and coordinators 
will undergo a separate training session to gain familiarity with the EDC. 
 
Echocardiography Qualification 
Each clinical site echocardiography lab involved in image acquisition for this trial will be 
certified by the Echocardiography Core Lab to perform the protocol defined TTE.   
Importantly, the TTE assessments will be used to determine eligibility in terms of patients 
having moderate TR or a tricuspid annular dimension ≥ 40 mm (index: ≥21mm/M2 BSA) 
and none/trace or mild TR. 
 
The site certification for the TTE is as follows: 
 
Prior to being open to enrollment, the site will send a sample 2D and 3D TTE which 
follows the echo acquisition protocol.  The site must receive Echo Core Lab approval for 
the TTE in advance of performing any study related images.  
 
Once open to enrollment, the site will acquire and adjudicate the degree of TR on the 
research TTE 2D images for consented patients.  Prior to the scheduled surgical 
procedure, the site will upload the de-identified images along with the adjudication of the 
degree of TR to the EDC for review and over-reading by the Echo Core Lab to confirm 
eligibility.  Once the Echo Core Lab has confirmed that the site has successfully 
adjudicated the degree of TR for eligibility inclusion in the trial for 3 patients, the site 
will be certified to continue eligibility determination independently.  

 
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CONFIDENTIAL 
 
The clinical sites will upload all echoes to the EDC website as they are acquired.  The 
Echo Core Lab will read these echoes as they are uploaded.  The Core Lab will carefully 
monitor compliance of site acquisition and interpretation of the TTE images used for 
eligibility determination.   If the Core Lab determines that the eligibility TTE did not 
meet the protocol defined criteria, the Core Lab will provide immediate feedback to the 
site echocardiography site investigator and create a corrective action plan which will 
include re-training of site echocardiography investigators.   
 
Delegation of Authority and PI Oversight 
Principal Investigators are responsible for all study activities at their sites.  They may 
delegate study tasks to qualified staff members while continuing to oversee all study 
activities.  The Delegation of Authority Log will list each staff member’s title and 
responsibilities for the study.  The PI is responsible for careful review of each staff 
member’s qualifications which includes training for the tasks to which each staff member 
is delegated.  Each task should be assigned to more than one staff member to ensure 
proper coverage.  Only staff members delegated for each task on the Delegation of 
Authority Log may conduct study-specific assessments.  The Delegation Log will also 
contain the signature of each staff member.  The PI will initial any additions to the 
Delegation of Authority Log that occur during the course of the study.  The PI should 
document oversight of study activities throughout the life of the trial by indicating review 
of key elements such as eligibility, abnormal laboratory values and AEs via signature and 
date on appropriate source documentation. 
 
Conflict of Interest and Financial Disclosure Agreement  
This statement verifies that an investigator has no conflict of interest with any institution 
that may influence his/her participation in this study.  All investigators must complete 
this statement.  Investigators will also submit a financial disclosure agreement. 
 
Site Approval 
The following documents must be collected prior to site approval to open to enrollment: 
o Fully executed Clinical Trial Agreement (CTA) with the CTSN DCC: InCHOIR, 
Department of Population Health Science & Policy, Icahn School of Medicine at 
Mount Sinai or Deutsches Herzzentrum Berlin (DZHB) for German research sites.   
o Curricula vitae 
o IRB/REB/EC roster 
o IRB/REB/EC approval, version and date for protocol and consent 
o HIPAA/PIPEDA/Privacy Directive compliance approval 
o Surgical Investigator Certification 
o Echo Core Lab Certification for TTE 2D and 3D image acquisition 
o National Institutes of Health Stroke Scale (NIHSS) Training Certification 
o Modified Rankin Scale (mRS) Certification 
o Delegation of Authority Log 
o Clinical Center Laboratory Certification(s) 
o Laboratory normal ranges 
Other regulatory and training documentation may be required prior to site initiation. 

 
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CONFIDENTIAL 
 
Prior to enrolling the first patient, representatives from the DCC will conduct a site 
initiation for all investigators, echocardiologists, study coordinators and any other health 
care professionals who may be involved in the conduct of the study.   
 
Patient Confidentiality 
All patients’ records will be kept confidential according to privacy regulations. Study 
Investigators, site IRBs/REBs/ECs, the DCC, EAC, medical monitors and NHLBI 
personnel may review source documentation as necessary but all unique patient and 
hospital identifiers will be removed from source documents which are sent to the DCC. 
The aggregate data from this study may be published as per publication policy 
documented in the CTA; however, no data with patient identifiers will be published. 
 
SCREENING AND BASELINE 
Screening Registration Form  
Prior to informed consent 
Prior to approaching a patient to begin the informed consent process, the study personnel 
will review data on prospective patients to determine eligibility for inclusion in the trial. 
All pre-screened patients (patients who are not consented) who are not enrolled are 
recorded on the top portion of the screening registration form. The data collected is 
compliant with privacy regulations and does not include patient identifiers but does 
include screening quarter, screening year, age, gender, and reason not eligible or not 
enrolled.  
 
Consent 
Prior to screening data collection and protocol-defined procedures 
Prior to screening, a thorough explanation of the risks and benefits of the study will be 
outlined by the investigator or designee to the potential study subject.  Study personnel 
will begin the informed consent process as soon as possible during the preoperative 
evaluation phase for each patient.  Timing for the informed consent process must be 
consistent with the center's IRB/REB/EC and privacy policies and, in accordance with the 
CTSN guidelines, the consent process must begin at least the day before the surgical 
procedure.  This is to ensure that all subjects will be given adequate time to review the 
informed consent document and consider participation in the trial.  All questions will be 
answered to the satisfaction of the subject prior to signing the informed consent 
document.  Site source records will include documentation of the informed consent 
process for each subject.  No study specific procedures will be performed prior to signing 
of the informed consent document. 
   
Release of Medical Information Form 
Prior to screening data collection and protocol defined procedures 
The patient must sign the Release of Medical Information form or equivalent that 
authorizes release of medical records, including hospital costing data, to the study 
sponsors, investigators and monitors. 
 

 
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CONFIDENTIAL 
 
Demographics Form  
At initiation of screening 
A screened patient is defined as a consented subject who was referred to, or identified at 
a clinical site for consideration of entry into the study, and for whom some preliminary 
(i.e., medical record) data have been collected and/or reviewed. For all patients screened, 
date of birth, ethnic origin, and sex will be captured on the registration form.   The EDC 
will generate a unique 5-digit identification code that will identify the patient throughout 
the course of the study. 
 
Echocardiogram  
Within 60 days prior to randomization 
A complete TTE will be performed according to the specifications defined in the 
Echocardiographic Image Acquisition Protocol (Appendix I and Appendix II) within 60 
days prior to randomization.  The pre-randomization 2D echo will be read by the 
clinical site echocardiography investigator to assess the degree of TR which will 
determine echocardiographic eligibility for participation in the trial. (See 
Echocardiography Qualification above) After this initial assessment, the study echo will 
be sent to the Echocardiography Core Lab for centralized reading.  The site 
echocardiography lab must be accredited by the Echo Core Lab in advance of performing 
any study echocardiograms. In addition, the sites will perform a 3D TTE to assess RV 
volume. 
 
Medical History  
Within 60 days prior to randomization 
This form captures the information pertaining to the medical history, including but not 
limited to previous myocardial infarction, myocardial revascularization, arrhythmias, 
AICD, permanent RV or biventricular pacemaker, stroke and other comorbidities such as 
diabetes and peripheral vascular disease.   
 
Six Minute Walk Test 
Within 60 days of randomization  
This form captures the distance in feet walked on a level hallway in six minutes (See 
Appendix IV).  A research clinician trained on the protocol and designated by the PI will 
oversee the 6MWT.  This assessment is repeated at various protocol-defined periods 
during the trial.   
 
Gait Speed Test for Frailty 
Within 60 days prior to randomization 
A patient’s frailty status will be assessed through the use of the Gait Speed assessment 
(see Appendix V). The assessment averages the time it takes a patient to walk 5 meters 
during three separate attempts.    
 

 
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CONFIDENTIAL 
 
New York Heart Association Classification (NYHA) 
Within 60 days prior to randomization 
The presence of heart failure will be assessed, and when present, classified according to 
the NYHA scale.  NYHA classification will be determined by investigative center 
personnel delegated to perform this assessment and documented on either the New York 
Heart Association Classification form or in the body of the medical record.  The NYHA 
classification scheme is detailed in Appendix III.  
 
Medications  
Within 60 days prior to randomization 
This form captures current medications at one pre-operative time point. 
 
Physical Examination  
Within 60 days prior to randomization 
This form captures the comprehensive physical examination including vital signs 
cardiopulmonary examination, abdominal examination, and anthropometrics (height, 
weight).  
 
Quality of Life 
Within 60 days prior to randomization 
The KCCQ, SF-12, and EQ-5D questionnaires will be completed by the patient to assess 
QOL.  Data regarding completeness of QOL data collection and reasons for missing 
responses to questionnaires will be collected on the QOL Checklist. 
 
Laboratory Assessment  
Within 60 days prior to randomization 
 
Hematology, including white blood cell (103/µL), Hemoglobin (g/dL), Hematocrit 
(%), Platelet count (103/µL) 
 
Coagulation profile, including prothrombin time (PT/sec), partial thromboplastin 
time (PTT/sec),  International Normalized Ratio (INR) 
 
Blood chemistries, including sodium (mM/L), potassium (mM/L), blood urea 
nitrogen (BUN, mg/dL), creatinine (mg/dL) 
 
Liver function tests, including total bilirubin (mg/dL), alanine aminotransferase 
(ALT, U/L), aspartate aminotransferase (AST, U/L), albumin (g/dL). 
At time of randomization 
 
Urine or serum beta HCG (IU/L) is required for women who have the potential to 
become pregnant  
 
Randomization Eligibility 
Prior to randomization 
The inclusion and exclusion criteria will be documented by the clinical site study 
coordinator and verified with the site Principal Investigator in the Randomization 
Eligibility Form. The degree of TR will also be recorded for stratification purposes.  All 
screened patients (patients who are consented) who are not randomized in the trial will 
have the reasons for non-randomization documented in the Randomization Eligibility 

 
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CONFIDENTIAL 
 
Form. The data collected is compliant with privacy regulations and includes reason for 
not being randomized.  
 
A representative from the DCC will be available to discuss any questions regarding 
patient eligibility.   
 
RANDOMIZATION 
The randomization procedure will be performed intra-operatively, following the 
placement of the TEE probe and after visualization and confirmation of cardiac 
anatomy eligibility.  Randomization to the study assignment will be generated by the 
EDC once the checklist of inclusion and exclusion criteria has been completed and 
verified. For the purpose of the primary analysis, patients are considered enrolled in the 
study once they are randomized.   
 
PROCEDURE 
Surgical Procedure 
Patients will be randomized to either (a) TV repair using a legally marketed annuloplasty 
ring in addition to the MVS, or (b) MVS alone. 
 
After induction of anesthesia, all patients will undergo a TEE.  The TEE will be 
performed under loading conditions as close as possible to the patient’s baseline.  Intra-
operative TEEs will be performed according to standardized acquisition protocol 
developed by the Echo Core Lab (Appendix I and Appendix II).  A laminated copy of 
this acquisition protocol will be provided to the site and affixed to the operating room 
echo machine.   
 
All procedures will be performed using cardiopulmonary bypass support and cardioplegic 
arrest. The management of cardiopulmonary bypass and myocardial protection will be at 
the discretion of the surgeon, using standard techniques.  MV repair or replacement will 
be performed using standard techniques.   
 
Tricuspid valve surgery  
Patients randomly assigned to receive TV repair in addition to MVS will undergo 
concomitant TV repair.   
 
It is recognized that surgical techniques for TV surgery may need to be adjusted at the 
discretion of the surgeon based on intra-operative findings that may not be previously 
recognized in the preoperative evaluation. The common elements for tricuspid 
annuloplasty planned as part of this study are listed below: 
 
 All procedures will be performed with cardiopulmonary bypass and with bicaval 
cannulation 
 Both trans-septal and bi-atriatomies are acceptable as the approach to the TV 
 Performance of TV repair on the arrested or the beating heart will be at the 
discretion of the surgeon 

 
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CONFIDENTIAL 
 
 TV repair will be performed with a rigid, incomplete, nonplanar, undersized 
annuloplasty ring 
 Nominal annuloplasty ring sizes 26, 28, or 30 mm will be used.  It is anticipated 
that normal tricuspid annular dimensions will be restored in most cases with a size 
26 or 28 mm annuloplasty ring 
 Commercially available rigid incomplete nonplanar tricuspid annuloplasty rings 
include: 
 
o Edwards MC3 tricuspid annuloplasty ring (model 4900) 
o Medtronic Contour 3D tricuspid annuloplasty ring (model 690R) 
o Medtronic Tri-Ad tricuspid annuloplasty ring (model 900SFC) 
o ATS TriAd Tricuspid Annuloplasty Ring 
o Carpentier-Edwards Classic tricuspid annuloplasty ring (model 4500)2 
o Carpentier-Edwards Physio Tricuspid ring (model 6200)  
 
 Interrupted non-pledgeted mattress sutures will be placed from 9:00 o’clock to 
6:00 o’clock (the mid-point of the septal leaflet) around the tricuspid annulus.  In 
general, 10 to 12 sutures will be required to assure reliable seating of the tricuspid 
annuloplasty ring.   
 
Peri-operative Management  
Peri-operative hemodynamic support may be necessary. A variety of strategies may be 
utilized to optimize postoperative ventricular function. These strategies may include 
pacing, infusions of vasopressors or positive inotropic agents including both beta receptor 
agonists and/or phosphodiesterase inhibitors such as milrinone. Occasionally, patients 
may require mechanical support, either intra-aortic balloon pumping or ventricular assist 
devices. 
 
Other Treatment 
All patients enrolled in this trial are to receive standard medical management for their 
regurgitant mitral / tricuspid valvular disease and other co-morbid conditions in 
accordance with current medical practice guidelines.  This includes when clinically 
indicated and tolerated, but is not limited to, beta-blockade, angiotensin converting 
enzyme inhibitors (ACE) or angiotensin receptor blockers (ARB), antiplatelet agents, 
statin therapy (or alternative lipid lowering agent), aldosterone antagonists, 
antiarrhythmic therapy, implantable defibrillators and cardiac resynchronization therapy.  
 
POST-RANDOMIZATION DATA COLLECTION 
 Study Visits 
o 
Post-Randomization Day 30 (-7 days, + 35 days) 
o 
6 (± 30 days), 12 (± 30 days), 18 (+ 30 days) and 24 months (± 60 days) post-
randomization  
                                                 
2Needs to be manually bent into nonplanar shape similar to other commercially available annuloplasty rings  
 

 
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CONFIDENTIAL 
 
o 
36, 48 and 60 months vital status check (± 60 days) 
 
For patients who are unable to return to the clinical site for the 6- and 12-month 
assessments because of extreme geographic distance, the clinical coordinator will obtain 
the required data from a remote clinical site outside of the CTSN sites.  The remote 
clinical site must be identified in advance of discharge from the index hospitalization.  
All efforts must be made to acquire all follow-up at the CTSN clinical site.  All 24-month 
(Primary Endpoint) assessments must be performed in accordance with the protocol 
defined data collection whether the visit is conducted at a CTSN clinical site or remotely.    
The 36, 48 and 60 month vital status checks may be conducted via telephone or via a 
search of medical records. 
 
Surgical Procedures  
Initial surgical intervention and event driven 
The initial surgical procedure (MV surgery ± TV repair) will be reported on the initial 
surgical Procedure form and all subsequent operations must be reported on the follow up 
surgical procedure form within 48 hours of the knowledge of the event. If the operation is 
to address a complication, the coordinator must also complete an AE report.  
 
Initial Surgical Procedure 
Routine information will be collected on the standard surgical procedure, the MV 
procedure, TV procedure and any concomitant procedures. 
 
Follow-up Surgical Procedure 
Information about any surgical procedure(s) performed following the initial 
surgical procedure and during the follow-up period through 24 months post-
randomization will be collected on this form.   
  
Hospitalizations 
Index hospitalization   
For all patients, the index (baseline) hospitalization must be reported on the 
Hospitalization form. This form collects limited information about LOS, days in ICU, 
and disposition at time of discharge (home, skilled nursing facility, rehabilitation facility, 
death). 
 
Medications 
At 30 days (-7 days, +35 days), 6 (± 30 days), 12(± 30 days), and 24 months (± 60 days) 
post randomization and event driven  
All cardiovascular medications will be recorded at each study visit, and also as indicated 
at the time of associated AEs.   
 
Physical Examination  
At 30 days (-7 days, +35 days), 6 (± 30 days), 12 (± 30 days), and 24 months (± 60 days) 
post randomization  

 
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CONFIDENTIAL 
 
In this limited physical examination, vital signs, weight and cardiopulmonary 
examination will be captured.  
 
New York Heart Association Classification  
At 30 days (-7 days, + 35 days), 6(± 30 days), 12(± 30 days), and 24 months (± 60 days) 
post randomization  
The presence of heart failure will be assessed, and when present, classified according to 
the NYHA scale.  We will assess diuretic requirements of patients as well.  
 
Six Minute Walk Test 
At 30 days (-7 days, +35 days), 6 (± 30 days), 12 (± 30 days), and 24 months (± 60 days) 
post randomization  
This form captures the distance in feet walked on a level hallway in six minutes (See 
Appendix IV).  A research clinician trained on the protocol and designated by the PI will 
oversee the 6MWT. 
 
Gait Speed Test for Frailty 
At 12 (± 30 days) and 24 months (±60 days) 
A patient’s frailty status will be assessed through the use of the Gait Speed assessment at 
12 and 24 months post-randomization.  Refer to Appendix V for instructions.     
 
Echocardiogram  
At Pre-discharge, 6(±30 days), 12(± 30 days), and 24 months (± 60 days) post 
randomization  
A complete TTE will be performed at the CTSN clinical site, according to the 
specifications defined in the Echocardiographic Image Acquisition Protocol (Appendix I) 
at each of the designated time points.  All patients must be euvolemic, (i.e., optimal 
fluid management in the judgment of the cardiology investigator) at all follow up 
echos.  For patients who are unable to return to the clinical site for the 6- and 12-month 
assessments because of extreme geographic distance, an echo may be obtained at a 
remote center (see Echocardiogram Image Acquisition section).  The remote echo center 
must be identified in advance of discharge from the index hospitalization.  All efforts 
must be made to acquire all follow-up echocardiograms at the clinical site.  All 24-month 
(Primary Endpoint) assessments must be performed in accordance with the protocol 
defined data collection whether the visit is conducted at a CTSN clinical site or remotely.   
All study echos will be sent to the Echo Core Lab for centralized reading by a blinded 
investigator.   In addition, a 3D TTE (Appendix II) will be performed to measure RV 
volume at 12 and 24 months. 
 
Quality of Life 
At 6(±30 days), 12(±30 days), 18 (±30 days) and 24 months (± 60 days) post 
randomization  
The KCCQ, SF-12, and EQ-5D Questionnaires will be completed by the patient to assess 
QOL.  Data regarding completeness of QOL data collection and reasons for missing 
responses to questionnaires will be collected on the QOL Case Report Form. 

 
InCHOIR  
 
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CONFIDENTIAL 
 
Vital Status Check 
At 36, 48 and 60 months (± 60 days) post randomization 
The patient’s vital status will be collected via telephone or a review of medical records. 
 
Cost 
Direct costing data for all randomized patients (from US sites) will be obtained by the 
DCC at the conclusion of the trial.  
 
Event Driven Data Collection  
 
Follow-Up Surgical Procedures  
Event Driven 
All operations following the initial study defined surgical intervention must be reported 
on the surgical procedure form within 48 hours of the knowledge of the event. If the 
operation is to address a complication, the coordinator must also complete an AE report. 
All intra-operative transfusion requirements must be documented. All follow-up surgical 
procedures will be recorded through month 24.  
 
Adverse Events 
Event Driven 
Detailed information regarding AEs will be recorded at the time an AE occurs. 
Investigators will be asked to make a judgment as to the seriousness and relationship of 
the event to the surgical intervention. All AEs will be recorded through month 24.  
 
Re-Hospitalizations 
Event driven 
All ED visits (of any duration) and re-hospitalizations (>24 hours for any reason) must be 
reported on the Re-Hospitalization Form. This form collects limited information about 
hospital procedures, LOS, days in ICU, and discharge if applicable, as well as patient 
condition and disposition for each hospitalization.  All re-hospitalizations will be 
recorded through month 24.  
 
Outpatient Intervention 
Event driven within 48 hours of knowledge of event 
All outpatient procedures following the index hospitalization must be reported on the 
surgical procedure form within 48 hours of the knowledge of the event. If the 
intervention is to address a complication, the coordinator must also complete an AE 
report.  All outpatient interventions will be recorded through month 24.  
 
Missed Visit Assessment 
Event Driven 
If a patient is unable to return for follow-up before the closure of a study visit window, a 
missed visit assessment that captures the reason for missing the visit must be recorded on 
the protocol deviation form.  
 

 
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CONFIDENTIAL 
 
Mortality 
Event Driven within 24 hours of knowledge of event 
The investigator will record the date of death, immediate cause of death, primary 
underlying cause of death, notation of autopsy being performed, and clinical narrative of 
the event.   
 
Study Completion/Early Termination 
Event Driven 
This form records the date and reason for study completion or early termination.  The 
anticipated reasons for a patient to be withdrawn from this study, is either the patient’s 
request or at the physician’s discretion, details of which will also be documented on this 
form.  Please refer to the Manual of Procedures for partial withdrawal of consent and 
limited data collection. 
 
Investigator’s Statement  
End of study 
The Principal Investigator will review all of the electronic case report forms (eCRFs) and 
patient summaries.  Their electronic signatures attest to the accuracy and completeness of 
the data collected.  
 
 
DATA MANAGEMENT 
All study data will be entered in the web-based EDC (specified in detail in the Operations 
Manual). Study personnel requiring access will have their own Login/Password. Access 
to clinical study information will be based on individuals' roles and responsibilities. The 
application provides hierarchical user permission for data entry, viewing, and reporting 
options. For optimum security, the system operates Secure Socket Layer (SSL) 128-bit 
encryption protocol over Virtual Private Networks (VPN). This application is designed to 
be in full compliance with International Conference on Harmonization and Good Clinical 
Practices (ICH-GCP), the FDA’s Code of Federal Regulations (CFR) Number 21 Part 11 
Electronic Record and Electronic Signatures, the FDA's "Guidance: Computerized 
Systems Used in Clinical Trials, and the Privacy Rule of the Health Insurance Portability 
and Accountability Act of 1996 (HIPAA).  
 
Quality Assurance 
The data quality assurance tool has been designed as an automatic feature of the EDC.  
When a form is submitted the system conducts instantaneous validation and cross-form 
validation checks.  A query is generated and sent to the site coordinator electronically so 
that data may be verified and corrected. All changes made to a form are stored in an audit 
log.  
 
Additional external cross-form checks for data consistency and validation will be made 
by the DCC’s data management team. Data will be monitored remotely at the DCC on an 
ongoing basis to check for inconsistencies in information across forms and for data 
outliers (typically values that fall in the highest or lowest 10% of the accumulated data 

 
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and/or values that are outside the range of what is typically considered to be 
physiologically possible). Monitors will enter these queries through the EDC for site 
coordinators to either correct or verify. 
 
Monitoring 
The DCC monitoring team employs a risk-based approach to centralized and on-site 
monitoring.  This approach focuses efforts on the most crucial data and process elements 
to allow for more efficient monitoring practices while maintaining the quality of the 
overall study conduct.  Through the combination of centralized and on-site monitoring, 
instantaneous electronic validation via the EDC, and visual cross-validation by the 
InCHOIR monitors to detect complex errors, it is anticipated that the best possible quality 
and most complete data will be collected.   
 
The centralized, or remote, monitoring of clinical trial data via the EDC is performed 
with a focus on safety, study endpoints, data completion and data outliers.  DCC monitors 
will remotely monitor source documentation, study logs including the Informed Consent 
Log, the Protocol Violation/Deviation Log and the Serious Adverse Event/Safety Report 
Log periodically to ensure that the sites are adhering to the study protocol and 
procedures. In collaboration with the DCC data management team, the monitors will 
create and utilize reports outlining data completeness and timeliness, missing and outlier 
values as well as cross form consistency validations to generate queries and optimize 
reconciliation of data.  This process significantly increases the efficiency of monitoring 
both remotely and while on site. 
 
The DCC may conduct on-site monitoring visits after enrollment begins approximately 
once each year for every clinical site depending on site enrollment and other data quality 
metrics for the duration of the study.  Copies of all source documents must be kept in the 
patient source binders at each site for review by the monitors. 
 
The monitors will review the source documents to determine whether the data reported in 
the EDC are complete and accurate.  They will also verify that all AEs exist on the source 
documents, are consistent with the protocol, and are documented in the appropriate 
format.  Source documents include medical charts, initial hospital admission reports, 
operative procedure records, discharge and re-admission reports, consult notes, radiology 
reports, lab reports, clinic records, and other study-related notes. The study monitors 
reserve the right to copy de-identified records in support of all AEs and outcomes.  
 
The monitors will also confirm that the regulatory binder is complete and that all 
associated documents are up to date.  The regulatory binder should include all revisions 
of the protocol and informed consent, IRB/REB/EC roster, IRB/REB/EC approvals for 
all of the above documents, IRB/REB/EC correspondence, investigator’s agreements, 
delegation of authority log, CVs of all study personnel, Human Subjects Protection 
training certificates, institutional HIPAA or other privacy training certificates, monitor 
site visit log, telephone contact log, and correspondence with the DCC. 
 

 
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Given the combination of approximately yearly on-site monitoring and ongoing 
monitoring using the EDC that includes instantaneous electronic validation and visual 
cross-validation to detect complex errors, it is anticipated that the best possible quality 
and most complete data will be collected.  
 
 
ANALYTICAL PLAN    
General Design Issues 
This study is a prospective, multi-center, randomized clinical trial. Enrolled patients will 
have degenerative MV disease with a clinical indication for MVS. This trial will compare 
the surgical approach of combining TV annuloplasty with clinically indicated MVS to 
performing the MVS alone. 
 
Sample size  
Sample size is based on previously published data, and on ensuring the ability to detect, 
with high probability, a clinically meaningful presumed benefit for patients undergoing 
TV repair (Goldstone, Howard et al. 2014; Nath, Foster and Heidenreich 2004; Koelling, 
Aaronson et al. 2002). 
 
For computing sample size, we assume that at two years post randomization, 25% of 
patients treated with only MVS will experience the primary composite endpoint. We 
believe a meaningful effect worth detecting is at least a 50% relative reduction to 12%, 
for patients undergoing TV annuloplasty in addition to MVS. A total of 400 patients, 
randomized with equal probability to each arm, provides approximately 90% power to 
detect such a difference. For simplicity, power is based on a 0.05 level two-tailed chi-
squared test. The sample size takes account of a potential single interim analysis to be 
performed in addition to the final analysis, and a minimal (less than 3%) rate of 
crossover. 
 
Randomization Design and Procedure 
Patients will be randomized using a 1:1 allocation to TV annuloplasty plus MVS or to 
MVS alone. The randomization will be stratified by clinical center (i.e., a separate 
randomization scheme will be employed in each center) and by whether severity of TR is 
moderate or not. A random permuted block design will be employed, with blocks of size 
2, 4, or 6 randomly chosen. Randomization will be implemented as described in 
Randomization Section. 
 
Data Monitoring and Analysis 
 
Methods of Analysis 
The primary outcome of this trial is treatment failure defined as the composite of (1) 
death from any cause, (2) reoperation for TR, (3) presence of severe TR at two years post 
randomization or, for patients enrolled with less than moderate TR and annular dilatation, 
progression by two grades (i.e., from none/trace TR to moderate TR) at two years.  The 
null hypothesis is that there is no difference in the probability of treatment failures at two 
years post randomization between patients randomized to undergo TV repair during MVS 

 
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compared to patients randomized to undergo MVS alone. The primary null hypothesis 
will be tested in an intent-to-treat analysis using a 0.05 level two-tailed normal 
approximation (Wald) test.  
 
A log binomial regression model will be used to estimate and test differences in treatment 
failure between randomization groups.  Similar to the logistic regression model, the log-
binomial model is a generalized linear model. The models differ only in the link function 
used for the "success" probability p; logit (log odds) for logistic regression and log (log 
p) for log-binomial. The different links parameterize the model differently, with 
parameters of the log-binomial model yielding log relative risks rather than the log odds 
ratios of the logistic model. 
 
The basic form of the log binomial models is:  
 
log 𝑃[𝑌𝑖= 1|𝑋1𝑖, 𝑋2𝑖] = 𝛽0 + 𝛽1𝑋1𝑖+ 𝛽2𝑋2𝑖 , 
 
where Yi  is a binary indicator  of treatment failure for the ith patient,  X1i  is a binary 
indicator of randomization assignment for the ith  patient and  X2i  is an indicator of 
moderate or less TR at baseline, a factor by which randomization will be stratified.  
While randomization will also be stratified by randomizing center, the analysis will not 
adjust for center due to their relatively large number compared to the proposed sample 
size.  The exponentiated estimate of 1 (𝑒𝛽̂1) in this model is the risk ratio for the 
composite endpoint for patients randomized to TV repair compared to patients 
randomized to no TV repair.  The risk ratio and its associated 95% confidence interval 
will be used to quantify the relative risk of the composite endpoint.  Differences between 
randomization groups in the risk of the composite endpoint will be determined by testing 
the null hypothesis H0:1= 0 versus a two-sided alternative (H1:1≠ 0) using a 0.05 level 
intention-to-treat normal approximation test (i.e., the Wald test). 
 
Imputation of missing data 
We expect relatively few patients to be missing the primary endpoint due to withdrawal 
or refusal. Patients with missing data  will have their 24 month status imputed via 
multiple imputation assuming that the data are missing at random, i.e., the missing nature 
of the variable is independent of the value of the variable given the observed data.  The 
specific imputation model to be used will be determined prior to examination of any 
outcome data and will be included in an accompanying statistical analysis plan. 
 
The main feature of the imputation approach is the creation of a set of clinically 
reasonable imputations for treatment failure for each patient with missing data.  This will 
be accomplished using a set of repeated imputations created by predictive models based 
on the majority of participants with complete data.  The imputation models will reflect 
uncertainty in the modeling process and inherent variability in patient outcomes, as 
reflected in the complete data.    
 

 
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After the imputations are completed, all of the data (complete and imputed) will be 
combined and the analysis performed for each imputed-and-completed dataset.  Rubin’s 
method of multiple (i.e., repeated) imputation will be used to estimate treatment effect.  
We propose to use 30 datasets.  For simplicity our primary analysis will not be stratified 
by clinical center, although the randomization will stratify by clinical center.  This should 
result in only a small loss of efficiency. 
 
Interim Analysis 
We plan to perform a single interim analysis with respect to the primary endpoint to give 
the option of stopping early should results strongly favor one arm or the other. The 
proposed timing of this analysis is at 0.5 on the information scale, i.e., after one-half of 
patients (200) reach the primary endpoint. The utility of performing this analysis will 
depend on the rate of accrual of patients into the trial. As the decision to terminate early 
would likely occur after most, if not all, patients were randomized, the principal benefit 
of early termination would be prompt dissemination of results, and no further 
randomization to an inferior treatment. A group sequential procedure will be used to 
allow for flexibility in the number and timing of interim analyses should the DSMB 
choose to modify the proposed plan, or should accrual mitigate the usefulness of an 
interim look. We will use the Lan-DeMets approach, implementing an O'Brien-Fleming-
type spending function that allots most of the type I error to the final look. The resulting 
critical values to be used for each analysis are 2.963 at the first interim analysis, 1.969 at 
the final analysis.  
 
In addition to the ethical concern of continuing a trial that shows a clear benefit in favor 
of one treatment, there is also a corresponding ethical concern of continuing a trial that 
has little chance of ever showing a benefit of one treatment compared to the other. We 
propose that the trial’s conditional power, under the original alternative hypothesis, be 
computed at the interim look and that the DSMB use this to determine whether 
randomization, if not completed, be halted for futility.   We propose that consideration be 
given to halting the trial for futility if, given the data up to the point of the interim 
analysis, the probability of detecting a relative 52% reduction (from 25% to 12%) in the 
incidence of treatment failure for patients receiving TV annuloplasty in addition to MVS 
and patients randomized to MVS alone is less than 10%.   
 
We do not propose any a priori stopping criteria based on AEs. The treatments in this 
trial are not experimental, and have well known AE profiles. Moreover, we believe that 
incident rates of AEs and mortality must be interpreted along with information about the 
consistency of related measures, consistency across centers, data completeness, and any 
external factors including scientific developments that might impact patient safety. In 
addition to considering the data generated by this trial, the DSMB will consider all 
relevant background knowledge about the treatment of MR. The DSMB would be 
capable, and uniquely suited, to determine decisions for convening outside the schedule 
of meetings, and to determine decisions to suspend or terminate the trial. These decisions 
should be at the discretion of the DSMB alone, based on all relevant information reported 
by the DCC and the Medical Monitors. We therefore recommend that the DSMB should 

 
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be responsible for defining its deliberative processes, including event triggers that would 
call for an unscheduled review. 
 
Sample Size Re-estimation 
We propose considering increasing sample size should the observed primary endpoint 
event rate among patients randomized to no repair of the TV be appreciably less than the 
assumed rate of 25%.  The planned sample size of 400 patients has been determined to 
ensure that power is at least 90% to detect a 52% relative reduction of “failure” for 
patients randomized to tricuspid repair compared to no repair. Should the “failure” rate 
among controls be 20%, 400 patients provides approximately 83% power to detect a 52% 
relative reduction;  for a 15% “failure” rate among controls there is approximately 70% 
power to detect a 52% relative reduction. Therefore, we suggest that the primary endpoint 
event rate be examined in control patients, using the same analysis set to be used for the 
interim analysis, and that the sample size be increased by up to 100 additional patients in 
order to maintain 80% power under the original alternative hypothesis for control rates as 
low as 15%.  If no interim analysis is conducted or accrual is complete at the time of the 
first interim analysis, the sample size re-estimation will not be considered. 
 
Assessment of Balance of the Randomization 
The success of the randomization procedure in balancing important covariates between 
randomization groups will be assessed at the interim analysis and at the final analysis. 
Continuous measures will be compared using t-tests, while chi-squared tests will be used 
to compare categorical variables.  As 400 patients will be randomized, no substantial 
imbalances are expected.  However, should any covariate differ significantly between 
treatment groups at the 0.01 level, and be substantively large, we will adjust for those 
covariates in a secondary analysis of the primary endpoint.   
 
Additional analysis of the primary endpoint 
A subgroup analysis of the primary endpoint will be performed with subgroups defined 
by whether or not patients received a CABG procedure during the initial surgery. This 
analysis will be performed in the same manner as that described for the primary analysis. 
 
Analyses of Secondary Endpoints 
Individual components of the primary endpoint 
Mortality:  Differences in the rate of mortality between randomization groups over the 
first 24 months and the planned 60 months of follow-up will be assessed using Cox 
proportional hazards regression. 
 
Reoperation for TR:  The difference in the rate of requiring subsequent TV annuloplasty 
after the initial MVS will be compared between randomization groups.  Reoperation for 
TR may not occur because death from any cause precedes the event; thus, it is possible 
that censoring patients at all-cause mortality will lead to biased estimates when analyzing 
time to first event. Therefore, competing risks analysis using the methods of Fine and 
Gray (1999) will be used to estimate group differences.  
 

 
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Degree of TR:  Between group differences in the presence of severe TR at two years post 
randomization or, for patients enrolled with less than moderate TR, the progression by 
two grades will be compared using a two-tailed 0.05 level chi-squared test of the equality 
of two proportions. 
 
MACCE:  The proportion of patients experiencing major adverse cerebrovascular and 
cardiac events, defined as the composite event of death, stroke, and the serious heart 
failure events, is of particular interest. Given that this trial’s primary endpoint is likely to 
be determined by echocardiographic assessments, it will be important to supplement the 
finding of a treatment effect (or lack of one) for the primary endpoint with a 
corresponding effect on a more clinical endpoint such as MACCE (and its component 
elements). As the trial is not powered to detect a difference in MACCE, a statistically 
significant treatment difference in MACCE is not expected; however, an observed 
difference in MACCE, consistent in direction with that observed for the primary endpoint 
will serve to validate the trial’s findings. No matter the result, the interpretation of the 
trial’s results will necessarily consider the difference in MACCE observed between 
treatment groups. The rate of major cerebrovascular or cardiac events will be compared 
between randomization groups over 24 months post-randomization using a Cox 
proportional hazards regression model. We expect MACCE two-year event rates to be 
approximately 15% for patients randomized to MVS alone. With a total of 400 patients 
randomized with equal allocation to MVS alone or to TR repair plus MVS, there is 90% 
power to detect an absolute decrease in MACCE to approximately 9-10% for patients 
randomized to TR plus MVS compared to MV surgery alone. 
 
A number of additional secondary analyses are planned to supplement the primary 
analysis and aid interpretation of the trial’s results.   
 
Six Minute Walk and Gait Speed Tests:  Differences between groups in gait speed and the 
distances travelled during the 6MWT will be compared using the Wilcoxon Rank-Sum 
test. We will also assess the extent to which changes over time (in gait speed and distance 
walked) are related to other outcomes.  
 
Additional echo parameters:  RV function (normal, mildly impaired, moderately 
impaired, severely impaired, peak tricuspid annular velocity, TAPSE, RVFAC) at 12 and 
24 months and pulmonary artery pressure at 12 and 24 months will be compared between 
groups. RV volume as assessed by 3D TTE at 12 and 24 months will be compared 
between groups. Continuous variables will be compared for between group differences 
using the Wilcoxon Rank Sum test, and the level of function by chi-squared test.  
 
Quality of life:  QOL will be measured using the KCCQ, SF-12, and EQ-5D. We will 
employ two approaches to the analysis of QOL. The first will be to base the analysis on 
longitudinal mixed effects models.  These models would predict outcome from treatment 
group and time. The mixed modeling approach requires an assumption that patient 
dropout is ignorable in that the probability of dropping out at any time is related only to 
previously observed data.  Of course, this assumption may not hold, and moreover it is 

 
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impossible to test robustly from the data at hand.  An alternative approach we will also 
use, not subject to this criticism, will be to separate the data into strata defined by the 
time of death or dropout.  We will then estimate a separate linear model, including a 
treatment effect, for the data in each stratum.  This method, known as pattern-mixture 
modeling, is not sensitive to un-testable assumptions about the dropout mechanism 
because it models the data directly in strata defined by dropout time.  The method of Wu 
and Bailey is an instance of pattern-mixture modeling.  
 
Adverse Events:  Differences in the incidence of individual AEs within 24 months post-
randomization will be compared between randomization arms using Poisson regression. 
Ninety-five percent confidence intervals (based on the Poisson distribution) for the risk 
ratios for individual AEs for treatment with MVS and TV annuloplasty versus MVS 
alone will be computed. 
 
NYHA classification: The distribution of NYHA at 12 and 24 months will be presented 
for each randomization arm and compared using a chi-squared test. 
 
Hospital length of stay and days in Intensive Care:  We will compare hospital LOS and 
days spent in ICU between treatment groups, separately by region (North America and 
Germany). A Wilcoxon Rank-Sum test will be used to test for differences within each 
geographic subgroup. 
 
 
Hospital readmission:  Rates of all-cause hospitalizations and rates of cardiovascular and 
heart failure specific hospitalizations, both within 30 days and within two years will be 
compared using Poisson regression.     
 
Costs and Cost-Effectiveness   
Cost 
Cost will be calculated by converting charges to cost using institution specific Ratio-of-
Cost-to-Charges (RCCs). Institution-specific cost reports will be used to calculate RCCs 
for each major resource category.  Cost data will only be collected in the North American 
sites.  Costing data will be compared by Student’s t test after log transformation.  
Independent predictors of cost, including baseline factors, operative factors and 
postoperative events, will be determined by multivariate regression analysis.  
 
Cost-Effectiveness 
The primary objective of the CEA is to estimate the incremental CE ratio (ICER) of the 
intervention under investigation as compared to the study-defined alternative.  This ratio 
measures the ratio of the difference in costs and outcomes between the two study arms, 
with outcomes measured as quality-adjusted life-years (QALYs).  QALYs reflect an 
individual’s preference for both quantity and QOL in a single measure that facilitates 
comparisons across diverse treatment modalities. We will also compute net health 
benefits (NHB) as an alternative way of looking at cost-effectiveness.   This parameter 
compares the incremental effectiveness of an intervention with the minimum health effect 

 
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that society would demand in return for the investment; i.e., with the health produced by 
investing at the societal ceiling cost-effectiveness ratio (CR).   
 
Costs will be estimated as discounted incremental health care costs, and effectiveness 
will be measured as the discounted increment in quality-adjusted life years.  A secondary 
objective will be to identify disease- and patient-related factors that predict high costs of 
care following the intervention.  All CE ratios will be reported with probability intervals 
to reflect the level of uncertainty in the clinical estimates used in the model and the 
underlying economic assumptions.  We anticipate that the distribution of costs will be 
skewed to the right.  If this violates the assumption of normality, we will modify the 
method using the nonparametric Bayesian bootstrap.  We will use standard discount rates 
for both QALYs and costs.  
 
We will calculate the ICER based on actual trial data and also develop a model to project 
long-term cost-effectiveness.  Sensitivity analyses will be performed to estimate several 
sources of uncertainty, including sampling variation and variations in discount rates. 
 
Crossovers 
Crossovers (patients who after randomization switch from the allocated treatment to the 
non-allocated treatment) are expected to be few in this trial.  Patients randomized to TV 
annuloplasty who do not receive it during the trial can be considered crossovers.  In 
addition, patients who are randomized to no annuloplasty but receive it during the index 
procedure are considered to have crossed over.  As the primary analysis is by intention to 
treat, crossovers will be analyzed as belonging to the group to which they were 
randomized. Given the short duration between randomization and surgery, crossovers are 
assumed to be rare (no more than 3%).  
 
ORGANIZATION OF THE STUDY 
This section describes the overall study organization.  The study will be conducted at up 
to 50 sites in the CTSN sponsored by NHLBI, in collaboration with NINDS and CIHR, 
and the DZHK supported DGTHG.  The following committees and institutions will be 
involved in the administration of the study.     
 
Event Adjudication Committee  
The charge of the EAC is to review source documents and adjudicate all AEs, causes of 
mortality and cardiovascular and heart failure related readmissions. The individuals who 
will serve on the committee are unaffiliated with the conduct of the clinical trial or the 
DCC.  The committee will consist of experienced clinicians with expertise in 
cardiothoracic surgery, cardiology, infectious disease and neurology. Additional specialty 
clinicians can be added as deemed necessary. The EAC will meet every 2-4 months or as 
needed to review outcomes data for each subject enrolled.  
 
 
 
Data and Safety Monitoring Board   
To meet the study's ethical responsibility to its subjects, an independent DSMB will 
monitor results during the study.  The board consists of physicians, biostatisticians, 

 
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ethicists, neurologists and bioengineers who have no formal involvement or conflict of 
interest with the subjects, the investigators, the DCC, or the clinical sites and will be 
appointed by the NHLBI. The DSMB will act in a senior advisory capacity to the DCC 
and the NHLBI regarding data and safety matters throughout the duration of the study. In 
addition, the DSMB will review interim summary results of the accumulating data from 
the EAC every 6 months.  These data include AEs and mortality.  They will communicate 
their findings directly with the DCC and the NHLBI.  The clinical centers will have no 
contact with the members of DSMB, and no voting member of the committee may 
participate in the study as an investigator. 
 
Data and Clinical Coordinating Center    
A university-based DCC (InCHOIR) will collaborate with the Network Investigators. The 
DCC will coordinate and monitor the trial and will administrate the DSMB and EAC.  It 
bears responsibility for monitoring interim data and analyzing the study's results in 
conjunction with the investigators and the sponsor.   
 
Echocardiography Core Laboratory 
All echocardiograms will be performed according to a standardized protocol and will be 
centrally analyzed by the Network Echo Core Lab directed by Judy W. Hung, MD, 
located at the Massachusetts General Hospital, Boston, MA. 
 
Network Steering Committee 
The Network Steering Committee (with the assistance of the protocol development 
committee) will provide the overall scientific direction for the study.  The responsibilities 
of the Steering Committee are to: (a) maintain contact with study investigators to ensure 
high quality data collection; (b) approve and implement major protocol changes in 
response to advice from the DSMB; (c) collaborate in data analysis, interpretation, and 
publication; (d) establish criteria for authorship on all manuscripts, publications and 
presentations that arise from the study. 
 

 
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predictors of persistent or recurrent heart failure in patients with mitral prosthetic valves. 
J Thorac Cardiovasc Surg. 2004 Aug; 128(2):278-83. 
 
Sagie A, Freitas N, Chen MH, Marshall JE, Weyman AE, Levine RA. Echocardiographic 
assessment of mitral stenosis and its associated valvular lesions in 205 patients and lack 
of association with mitral valve prolapse.  Am Soc Echocardiogr. 1997 Mar;10(2):141-8. 
 
Taramasso M, Vanermen H, Maisano F, Guidotti A, La Canna G, Alfieri O. The growing 
clinical importance of secondary tricuspid regurgitation.  J Am Coll Cardiol. 2012 Feb 
21;59(8):703-10.  
 
Van de Veire NR, Braun J, Delgado V, Versteegh MI, Dion RA, Klautz RJ, Bax JJ.  
Tricuspid annuloplasty prevents right ventricular dilatation and progression of tricuspid 
regurgitation in patients with tricuspid annular dilatation undergoing mitral valve repair.  
J Thorac Cardiovasc Surg. 2011 Jun;141(6):1431-9.  
 

 
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CONFIDENTIAL 
 
Vargas Abello LM, Klein AL, Marwick TH, et al.  Understanding right ventricular 
dysfunction and functional tricuspid regurgitation accompanying mitral valve disease.  J 
Thorac Cardiovasc Surg. 2013 May;145(5):1234-1241.e5. 
 
Yilmaz O, Suri RM, Dearani JA, Sundt TM 3rd, Daly RC, Burkhart HM, Li Z, Enriquez-
Sarano M, Schaff HV.  Functional tricuspid regurgitation at the time of mitral valve 
repair for degenerative leaflet prolapse: the case for a selective approach. J Thorac 
Cardiovasc Surg. 2011 Sep;142(3):608-13.  
 
 
 
 

 
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CONFIDENTIAL 
 
Appendix I:  Moderate Tricuspid Regurgitation Trial Echocardiographic Image 
Acquisition Protocol 
 
General Considerations: 
 
 For the echocardiogram, the patient will be positioned in left lateral recumbency 
or in the position that permits optimal imaging.  All images should be acquired 
during quiet respiration unless otherwise specified. 
 
 At least 3 and no more than 5 cardiac cycles are requested for two-dimensional 
imaging unless otherwise specified. At least 5 cardiac cycles are required for 
spectral pulsed wave (PW) and continuous wave (CW) Doppler. For patients in 
atrial fibrillation, a minimum of 2 captures of 5 consecutive cardiac cycles are 
required. Unless otherwise specified, depth should be adjusted to maximize the 
image while including all necessary structures. Harmonic imaging should be 
employed to optimize visualization of endocardial borders. 
 
 All PW, CW Doppler and m-mode recordings will be performed at a sweep speed 
of 100 mm/sec.  Gain should be adjusted to reduce excess noise. Color Doppler 
Nyquist limits will be adjusted to the range of 50-70 cm/sec, unless otherwise 
specified. The following protocol is required however additional images should 
be obtained at the discretion of the sonographer/physician. 
 
I. Protocol for Transthoracic Echocardiogram (TTE) pre and post-surgery 
 
1. Parasternal long axis  
 
2D image  
 
Color Doppler across aortic and mitral valves 
 
Zoom image of LVOT 
 
Zoom image of vena contracta  
 
 
2. Parasternal right ventricular inflow view of the tricuspid valve  
 2D image include RV and RA (optimize endocardium) 
 Color Doppler across tricuspid valve (TV) including distal jet into RA 
 Zoom view of TV annulus (for measurement of TV annulus) 
 Zoom view of vena contracta proximal jet of TR  
 Zoom view of the proximal flow convergence region of the TR jet after 
baseline shifted downward (same direction as TR jet flow) to a Nyquist of 
25-35 cm/s 
   
 Continuous wave Doppler across TV valve to estimate TV gradient. 
 
3. Parasternal outflow view of the pulmonic valve  
 
2D  
 
Color Doppler across PV  

 
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 
Pulse wave Doppler  
 
CW of the pulmonary valve  
 
Zoom 2D image of pulmonary valve annulus for measurement of 
the pulmonary annular diameter. 
 
 
4. Basal PSAX (at the aortic valve level) 
 
2D image include TV, short axis of aortic valve and RVOT  
 
Color Doppler of TV include distal jet into right atrium 
 
Zoom view of Color Doppler view of vena contracta of TR  
 
Zoom view of the proximal flow convergence region of the TR jet 
after baseline shifted downward (same direction as TR jet flow) to 
a Nyquist of 25-35 cm/s 
   
 
Pulsed Doppler sample of pulmonary flow at the level of the 
pulmonary valve to measure pulmonary velocity time interval 
(VTI) opening and closing transients of the pulmonary valve 
should be recorded. 
 
 
5. PSAX of ventricles: ensure on-axis views and include right ventricle 
 Level of the mitral valve when both anterior and posterior leaflets are 
visualized. 
 
Mid-papillary muscle level. 
 
Level of the apex 
 
 
6. Apical 4-chamber view  
 Full sector to include all four chambers 
 Focus on right heart: 2D to Include RV and RA, making sure to include 
lateral wall of  RV (often requires a slight medial tilt of transducer) 
 Zoom view of RV only (include base of RV/TV annulus and optimize RV 
endocardium) 
 Color Doppler across TV one including right atrium to capture the distal 
jet taking care to include wall-impinging eccentric jets in the region of 
interest. 
 Zoom view of TV annulus (for measurement of TV annulus) 
 Zoom view of Color Doppler across TV to image the vena contracta of the 
TR jet  
 Zoom view of the proximal flow convergence region of the TR jet after 
baseline shifted downward (same direction as TR jet flow) to a Nyquist of 
25-35 cm/s 
 PW of TV at leaflet tips and at level of TV annulus 
 CW of TV for estimation of pulmonary artery systolic pressure 
 M-mode across lateral tricuspid annulus (for TAPSE measurement) 
 Tissue Doppler of lateral tricuspid annulus (to measure peak annular 
velocity)   
 
 
Focus on left heart:  

 
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o 2D include both LV and LA 
o Zoom view of LV only (avoid foreshortening of LV apex) 
o Color Doppler across MV one including left atrium to capture the 
distal jet taking care to include wall-impinging eccentric jets in the 
region of interest. 
o Zoom view of MV annulus (for measurement of MV annulus) 
o -Zoom view of the proximal flow convergence region of the MR jet 
after baseline shifted downward (same direction as MR jet flow) to a 
Nyquist of 30-40 cm/s 
o PW of MV at leaflet tips and at level of MV annulus 
o PW Doppler of right pulmonary vein flow. The sample volume should 
be placed at least 1 cm within the pulmonary vein  
o CW of MV  
o Tissue Doppler of lateral and septal mitral annulus  
 
 
7. Apical 5-Chamber view  
 Color flow Doppler across LVOT/Aortic valve  
 PW Doppler in left ventricular outflow tract positioned such that closing 
artifact but not opening artifact of the valve is visible. 
 CW Doppler through the LVOT/aortic valve. 
 
 
8. Apical 2-chamber view 
 
2D image include left ventricle and left atrium 
 
Zoom view to include LV only (avoid foreshortening of LV apex) 
 
Color Doppler cross mitral valve including distal jet into left 
atrium 
 
 
 
 
9. Apical 3-chamber view (aka apical long-axis view) 
 
2D image include left ventricle and left atrium 
 
Color Doppler cross mitral valve including distal jet into left 
atrium 
 
PW Doppler in left ventricular outflow tract  
 
CW Doppler through the LVOT/aortic valve. 
 
 
 
10. Subcostal imaging 
 
2D of Inferior vena cava with and without a “sniff” (5-10 beat 
loop). 
 
Pulse wave of hepatic vein flow 
 
Color Doppler of IVC and RA junction 
 
Color Doppler of inter-atrial septum to interrogate presence of 
SD. 
 
4-chamber view showing RV, RA LA and LV 
 
Color Doppler of TV and MV in 4 chamber subcostal view 

 
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 
SAX views (particularly if parasternal evaluation was limited). 
 
 
11. Contrast will be used for endocardial border delineation when less than 80% 
of the endocardium can be visualized on the harmonic image.  
 
 
Note: Addition of any non-standard imaging will be coordinated in collaboration 
with the selected Core Laboratory under a protocol amendment and should be obtained at 
the discretion of the sonographer/physician. 
 
II. Protocol for Intra-operative Transesophageal Echocardiogram (TEE) 
 
Intra-operative TEE imaging will be performed on all specified index operative 
procedures in the CTSN clinical trials, consistent with standard clinical care. For the 
purposes of the CTSN trials, the clinically indicated TEE’s will be performed according 
to the standardized protocol below. The echos will be over-read by the echo core lab. 
 
Valvular evaluation should always include Color Doppler and Pulsed/Continuous Wave 
Doppler as appropriate.  A comprehensive intra-operative multiplane TEE as defined by 
the ASE/SCA Guidelines (Shanewise JS et al. J Am Soc Echocardiogr 1999; 12:884-900) 
should be performed. 
 
Pre-Procedure Imaging 
The following checklist may be used with appropriate Doppler performed for valvular 
assessment: 
 
1. Mid and High esophageal views  
 4 Ch view (of entire LV/RV); maximize endocardial definition.  
 Tricuspid Valve/Right Ventricle/right atrium/Interatrial Septum 
o 4 Chamber view angled to focus on right heart –both include RA and 
RV  
o Focus on TV including right atrium by changing depth to and obtain 2D 
image and color Doppler at 0, 60, 90 and 120-140 degrees; please 
include entire TV annulus 
o Interatrial septum (IAS) at (50 to70 degrees-with aortic rim in view) and 
bicaval view (90-110°)  2D and Color Doppler across IAS    
o (if 3D available) 3D TEE image of TV and RV at 0 degrees and 60 
degrees (Full volume acquisitions-1 beat and either  4 beat or HVR 
mode-please hold respiration for latter) 
o (if 3D available) 3D color Doppler TEE of TR jet at 0 and 90 degrees 
(Full volume acquisition-1 beat and either 4 beat or HVR mode-please 
hold respiration for latter) 
 
2. Mitral Valve: (lower depth to maximize visualization of the valve but include 
chordal attachments to the papillary muscle level). Please obtain 2D and color 

 
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Doppler images of the mitral valve and chordal structures.  For color Doppler 
assessment: Please adjust color Doppler settings to optimize visualization of 
MR jet area and vena contracta (Nyquist between 50-70 cm/s).  Please also 
obtain in at least one view: baseline shifting (in direction of MR jet flow) to 
Nyquist of 0.3 to 0.4 m/s) with Zoom mode on the proximal flow region. This 
is for PISA calculation.  
 
Please obtain views of the mitral valve in the following planes: 
 Transverse Plane (0°)  
o Change depth to image entire LV as well; maximize endocardial 
definition)  
 Commissural View (60°)  
o Change depth to image entire LV as well; maximize endocardial 
definition.  
 Two-chamber View (90°)  
 Three-chamber View (120-140°)  
 Record CW of MR in at least one plane 
 Record PISA region after baseline shifting Nyquist upward (in direction of 
flow) to 40 cm/s.  Please record 3-5 beats and not a single frame  
 
3. LVOT/AV/Aorta  
 Long-axis view (120-140°) 2D and with color Doppler  
 Ascending aorta (mid to high esophageal view) (90° to 110)  
 Ascending aorta SAX views (0°, high esophageal)  
 AV SAX (30°, mid esophageal) with color Doppler  
 
4. Main PA/PV  
 Bifurcation view (0-30°, high esophageal)  
 RVOT view (70°, mid esophageal)  
 
5. Left atrial appendage 
 2D at 45, 75, and 120-135 degrees.   
 
6. Pulmonary vein pulse wave Doppler: Sample volume placed in the vein, 1 cm 
from the orifice. 
 One left and one right PV 
 
7. Transgastric views  
 Three 2D short axis views are requested  
o Mitral valve level  
o Mid papillary muscle  
o Apical level.  
 Short axis images of the right ventricle and tricuspid valve (0 degrees) 
o Long axis of right ventricle and tricuspid valve (60-100 degrees) 

 
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o Pulse wave of hepatic vein flow 
 Deep Gastric views  
o 5Ch view Aortic valve (with color, PW and CW Doppler)  
 
8. Aorta  
 Thoracic aorta (short axis views) 
 Aortic arch (SAX and LAX views) 
 
Post-procedure Imaging  
A full post-procedure TEE should be obtained if time permits. Otherwise, the study 
should be tailored to the procedure performed, including a minimum of the following:  
 
1. Tricuspid Valve/right ventricle 
 
 Right heart –both include RA and RV at 0 and 60, 90 degree view  
 2D and color Doppler (for jet area and vena contracta) at 0, 60, 90 and 120-
140 degrees; please include entire TV annulus  
 Pulse and continuous wave across tricuspid valve 
 (If 3D TEE available-3D TEE image of RA and RV at 0 degree (Full volume 
acquisitions-1 beat and either  4 beat or HVR mode-please hold respiration 
for latter) 
 (if 3D available)-3D TEE image of TV and RV at 0 degrees and 60 degrees 
(Full volume acquisitions-1 beat and either  4 beat or HVR mode-please hold 
respiration for latter) 
 (if 3D available)-3D color Doppler TEE of TR jet at 0 and 90 degrees (Full 
volume acquisition-1 beat and either 4 beat or HVR mode-please hold 
respiration for latter) 
 
 
2. Mitral valve  
 2D and color Doppler of mitral valve at 0, 60, 90, and 120 degrees   
  
(include MR jet area and vena contracta for color Doppler views) 
 Zoom of PISA region (if MR is >mild by semi-qualitative assessment) with 
baseline shift to 40 cm/s 
 Continuous wave Doppler to assess post-procedure gradients and MR jet 
velocity 
 Pulmonary vein (one left and one right PV) pulse wave Doppler: Sample 
volume placed in the vein, 1 cm from the orifice.  
 
3. Left ventricle 
 Mid-Esophageal views of LV at 0 and 60 degrees  
 

 
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CONFIDENTIAL 
 
III. Moderate TR: Echocardiographic Measurements 
The degree of tricuspid valve regurgitation will be categorized according to American 
Society of Echocardiography guidelines as none/mild/moderate/severe (J Am Soc 
Echocardiogr 2003; 16:777-802).   
  
 
 
A. Tricuspid Valve/Right atrium and right ventricle  
The following variables will be measured: 
1.  Degree of tricuspid regurgitation categorized as: 
a) None/Trace   
b) Mild 
c) Moderate 
d) Severe 
2. Jet area of TR 
3. Vena contracta 
4. EROA by PISA    
5. TV annulus dimension (Apical 4 Chamber) 
6. TV: Mechanism of TR: Primary  vs secondary 
7. RA volume (ml) 
8.  RV function categorized as: 
 
a)  Normal 
 
b)  Mildly impaired 
 
c)  Moderately impaired 
 
d)  Severely impaired 
9. Tricuspid annular peak systolic excursion (TAPSE) 
10. Peak tricuspid annular velocity (PTAV) 

 
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11. RV fractional area change (%) 
12. RV size categorized as 
 
 
a)  Normal 
 
b)  Mildly dilated 
 
c)  Dilated 
13. RV dimension (apical 4 chamber view) 
14. RVSP 
 
B. LV Measures 
1. Interventricular septum (mm) 
2. Posterior wall thickness 
3. LVID end-diastole 
4. LVID end-systole 
5. ESV 
6. EDV 
7. LVEF 
 
 
C. Mitral Valve 
1. Degree of MR (Trace/none, mild, moderate, severe) 
2. Mechanism of MR 
 
D. Aortic Valve 
1. Aortic stenosis (y/n) 
2. Aortic Regurgitation (None, trace, mild, moderate or severe) 
 
 

 
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CONFIDENTIAL 
 
Appendix II:  Moderate Tricuspid Regurgitation Trial Echocardiographic Image 
Acquisition Protocol: 3D Image Echo Protocol  
General Considerations: 
Optimize ECG tracing, avoid stitching artifacts. 
Maximize frame rate-minimum frame rate needed 10 Hz but the higher the better. 
Only Full Volume Datasets; Do not acquire in Live 3D or 3D Zoom modes 
 
a. Focused RV Apical 4 Chamber view: 
-Full volume 3D data set in modified AP4 view focused on RV and RA. This view is 
obtained in apical 4 chamber window with probe positioned LATERALLY and tilted 
ANTERIORLY to include the RVOT. If biplane or x-plane imaging is available, 
visualization of RVOT can be confirmed (see figure). Obtain a FV 4 beat acquisition 
(with breath hold), HVR mode (if available) and one beat acquisition; repeat x 1 
-Full volume 3D color Doppler dataset across tricuspid valve: 4 beat acquisition with 
breath hold and one beat acquisition 
 
b. Standard apical 4 chamber view: Optimize depth and sector image to obtain standard 
apical 4 chamber including both ventricles and atria 
-Full volume 3D data set in AP4 view- 4 beat acquisition (with breath hold), HVR mode 
and one beat acquisition; repeat x1 
c. Full volume 3D data set of RV outflow view (parasternal window)-4 beat acquisition 
(with breath hold), HVR mode and one beat acquisition; repeat x 1  
 

 
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CONFIDENTIAL 
 
Appendix III: New York Heart Association Classification (NYHA) 
 
 
 
 
Class 
Patient Symptoms 
Class I (Asymptomatic) 
No limitation of physical activity. Ordinary physical activity 
does not cause undue fatigue, palpitation, or dyspnea 
(shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or 
dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, 
but less than ordinary activity causes fatigue, palpitation, or 
dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical 
activity is undertaken, discomfort is increased. 
 
 

 
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Appendix IV:  Six-Minute Walk Test Instructions 
 
The walking test will be conducted in an enclosed corridor (preferably free of 
distractions) on a course that is 60 feet long (Guyatt, 19853).  The corridor will be divided 
into 5-foot sections using a method unnoticeable to the patient.  Chairs will be placed at 
either end of the 60-foot course markers.  The distance covered during the preceding 
walk test will not be revealed to the patient during the study. 
 
Before the test, the patient will sit quietly for 10 minutes.  These instructions will be read 
verbatim to the patient: 
 
 
THE PURPOSE OF THIS TEST IS TO FIND OUT HOW FAR YOU CAN WALK 
IN SIX-MINUTES.  YOU WILL START FROM THIS POINT AND FOLLOW 
THE HALLWAY TO THE CHAIR AT THE END, THEN TURN AROUND AND 
WALK BACK.  WHEN YOU ARRIVE BACK AT THE STARTING POINT, YOU 
WILL GO BACK AND FORTH AGAIN.  YOU WILL GO BACK AND FORTH 
AS MANY TIMES AS YOU CAN IN THE SIX-MINUTE PERIOD.  IF YOU 
NEED TO, YOU MAY STOP AND REST.  JUST REMAIN WHERE YOU ARE 
UNTIL YOU CAN GO ON AGAIN.  HOWEVER, THE MOST IMPORTANT 
THING ABOUT THE TEST IS THAT YOU COVER AS MUCH GROUND AS 
YOU POSSIBLY CAN DURING THE SIX MINUTES. I WILL TELL YOU THE 
TIME, AND I WILL LET YOU KNOW WHEN THE SIX MINUTES ARE UP.  
WHEN I SAY STOP, PLEASE STAND RIGHT WHERE YOU ARE. 
 
DO YOU HAVE ANY QUESTIONS ABOUT THE TEST? 
 
PLEASE EXPLAIN TO ME WHAT YOU ARE GOING TO DO. 
 
 
Repeat the entire instructions if the patient does not seem to understand. 
 
Repeat the sentence: 
 
 
THE MOST IMPORTANT THING ABOUT THE TEST IS THAT YOU COVER 
AS MUCH GROUND AS YOU POSSIBLY CAN DURING THE SIX MINUTES. 
 
ARE YOU READY? 
 
START WHEN I SAY "GO" 
 
                                                 
3 Kirshner, B, Guyatt, G. (1985) A methodological framework for assessing health 
indices. Journal of Chronic Diseases 38: 27–36. 
 

 
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During the test, the walking pace of the patient should not be influenced. The test 
supervisor must walk behind the patient - not walk with, rush up behind, or rush past the 
patient. 
 
While walking, the patient will be encouraged every 30 seconds with the following 
phrases: 
 
0-3 minutes: 
THAT'S IT; YOU'VE GOT THE IDEA. 
 
 
YOU'RE DOING WELL. 
 
 
KEEP IT UP NOW. 
 
3-6 minutes: 
 
 
REMEMBER, AS FAR AS YOU CAN GO. 
 
 
WE'LL WANT YOU TO GO AS FAR AS YOU POSSIBLY CAN. 
 
 
THAT'S IT; KEEP WORKING AT IT. 
 
 
COME ON; KEEP GOING. 
 
The patient should be spoken to only at the 30-second encouragements and no response 
should be made to the patient's questions about the time and distance elapsed.  If the 
patient is not concentrating on the walking, the patient can be reminded at a 30-second 
mark: 
 
THIS IS A WALKING TEST.  TALKING WILL UTILIZE YOUR ENERGY 
RESERVE AND INTERFERE WITH YOUR PERFORMANCE. 
 
Encouragement phrases can be repeated as needed.  For example, if the patient is slowing 
down and expresses that he/she wants to stop, say: 
 
REMEMBER, IF YOU NEED TO, YOU MAY REST.  JUST REMAIN WHERE 
YOU ARE UNTIL YOU CAN GO ON AGAIN. 
 
If necessary, the patient may rest in a course marker chair although he/she should not be 
encouraged to do so. 
 
The patient will be told the time elapsed at 2 and 4 minutes, i.e.: 
 
YOU HAVE COMPLETED 2 MINUTES 
And 
YOU HAVE COMPLETED 4 MINUTES 
 
At the end of the test, the patient should not move from where he/she was told to "STOP" 
until the distance walked (measured to the nearest foot) has been recorded.   
 
Record the DISTANCE WALKED during the six-minute test. 

 
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Appendix V: Frailty Assessment – Gait Speed Test Instructions 
 
The addition of the Gait Speed test to assess frailty offers a quantifiable way to capture 
frailty in this trial population.  Other approaches to assessing frailty were reviewed, but 
the Gait Speed test serves as the simplest and most effective test in measuring frailty.  
The assessment is an average of three 5 meter walks. 
The test can be performed on any patient able to walk 5 meters using the guidelines 
below.   
 
Accompany the patient to the designated area – well lit, unobstructed, and containing 
clearly indicated markings at 0 and 5 meters.   
 
Position patient with feet behind, but just touching the 0 meter start line. 
 
Instruct the patient to “walk at a comfortable pace” until a few steps past the 5 meter 
mark.  Note, the patient should not slow down before the 5 meter mark. 
 
Begin each trial with the word “Go.” 
 
Start the timer at the first footfall after the 0 meter line.  
 
Stop the timer at the first footfall after the 5 meter line.   
 
Repeat the 5 meter walk three times, allowing for sufficient time for recuperation 
between trials.   
 
Record the times, in seconds, it takes to complete each trial, on the data collection form 
and calculate the average speed.  
 
Note: A patient can use a walking aid (cane, walker).  For patients receiving an IV drip, 
that test should be performed without the IV only if it can be interrupted temporarily 
without any potential risk to the patient.  If not, it can be performed with the patient 
pushing the IV pole.