Heterotopic Implantation Of the Edwards-Sapien Transcatheter Aortic Valve in the Inferior VEna Cava for the Treatment of Severe Tricuspid Regurgitation HOVER Trial
Phase: PHASE3
Conditions: Tricuspid Regurgitation
Sponsor: Henry Ford Health System

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  V2.3  24 Apr 2020 
  The HOVER Study 
Heterotopic Implantation Of the Sapien 3 Transcatheter Aortic Valve in 
the Inferior VEna cava for the treatment of severe tricuspid 
Regurgitation 
 
 
 
This protocol represents an original investigational device exemption (IDE) for placement of a SAPIEN-XT 
or S3 Transcatheter Heart Valve in the inferior vena cava for treatment of severe tricuspid regurgitation. 
 
Physician-led US Multi-Center IDE Pilot Study - IDE: G-140131-S2 
 
 
Sponsor Investigator: 
 
Brian O’Neill, MD 
 
Henry Ford Hospital 
Center for Structural Heart Disease 
2799 West Grand Blvd. 
Clara Ford Pavilion # 440 
Detroit, MI 48202 
313-970-6483 (p) 
313-916-2819 (f) 
 
Partial financial support provided by: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 
 
Version 2.3   24 Apr 2020 
 
 

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  V2.3  24 Apr 2020 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS……………………………………………………………………………………………..4 
STATEMENT OF INVESTIGATOR…………………………………………………………………………..………6 
PROTOCOL SUMMARY……………………………………………………………………………………………..…7 
STUDY DESIGN SCHEMATIC…………………………………………………………………………………………10 
1.0 BACKGROUND..…………………………………………………………………………………………………….11 
2.0 PROJECT PLAN…………………………………………..………………………………………………………….13 
 
2.1 Rationale For study…………………………………………………………………………………..13 
 
2.2 Design……………………………………………………………………………………………………….13 
 
 
2.2.1 Definition of the Heart Team…………………………………………………..…14 
 
 
2.2.2 Core Lab…………………………………………………………………………………….14 
 
 
2.2.3 Executive Committee…………………………………………………………….…..14 
 
 
2.2.4  Use of Edwards-Sapien Transcatheter Valve……………………….…....15 
 
2.3 Statistical Analysis………………………………………………………………………………………15 
 
2.4 Study Endpoints………………………………………………………………………………………...16 
3.0 STUDY ENROLLMENT AND WITHDRAWAL…………………………………………….……………..….17 
 
3.1 Baseline……………………………………………………………………………………………………...17 
 
3.2 Informed Consent……………………………………………………………………………………….17 
 
3.3 Eligibility Process…………………………………………………………………………………………18 
 
3.4 Participant Inclusion Criteria……………………………………………………………………….18 
 
3.5 Participant Exclusion Criteria…………………………………………………………………….…18 
4.0 RISK AND BENEFIT ANALYSIS …………………………………………………………………………..…...….19 
 
4.1 Efforts to Minimize Procedural Risk………………………………………………………….….20 
 
 
4.1.1.  Site Heart Team and Executive Committee Presentation………..….20 
 
 
4.1.2.  Data Safety Monitoring Board (DSMB)…………………………………….…20 
 
 
4.1.3.  Interim Monitoring and Stopping Rules……………………………….…….20 
 
4.2 Potential Benefits………………………………………………………………………………………..21 
5.0 STUDY PROCEDURES AND SCHEDULE.……………………………………………………………………...22 
 
5.1  Pre-Procedure Assessments…………………………………………………………………….....22 
 
5.2 Procedure Description…………………………………………………………………………….…...23 
 
 
5.2.1 Placement of percutaneous aortic valve in the IVC………………..……..23 
 
5.3 Post-Procedure Assessments………………………………………………………………..………24 
 
5.4 Discharge Assessments……………………………………………………………………..……….…25 
 
5.5 Follow-Up Assessments ……………………………………………………………………………....25 
5.6 Annual Study Visit, Final Study Visit, Premature Discontinuation or 
 Unscheduled Study Visit..………..………………………………………………………………………..26 
 
5.7  Patient Withdrawal……………………………………………………………………………..……...28 
6.0 ADMINISTRATIVE RESPONSIBILITIES………………………………………………………..…………..…..28 
 
6.1 Institutional Review Board (IRB) Information……………………………………………….28 
 
 
6.1.1 Institutional Review Board Approval Letter…………………………..……..28 
 
6.2 Informed Consent………………………………………………………………………….…….……...28 
 
6.3 Confidentiality……………………………………………………………………………….…….………28 
7.0 ADVERSE EVENT REPORTING ……………………………………………………………………………………29 
 
7.1  Adverse events……………………………………………………………………………….…………..29 
7.2  Serious Adverse Events…………………………………………………………………..…………..29 
7.3  Non-Serious Adverse Events…………………………………………………………….…………29 
7.4 Unanticipated Adverse Events…………………………………………………………….…….…29 
7.5  Anticipated Adverse Events……………………………………………………….……………….30 

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7.6  Unanticipated Adverse Device Effects……………………………………………………….30 
7.7  Adverse Event Follow-Up………………………………………………………………………....30 
8.0 DATA MONITORING AND QUALITY CONTROL …………………………………………………….….30 
 
8.1 Case Report Forms (CRFs)…………………………………………………………………..……..30 
8.2 Data Reporting………………………………………………………………………………………..…30 
8.3 Data Review……………………………………………………………………………………..……….30 
8.4 Records……………………………………………………….…………………………….……….…….31 
9.0 ETHICAL AND REGULATORY CONSIDERATIONS .…………………………………………………...32 
 
9.1 Role of the Sponsor investigator………………………………………………………….…..32 
9.2  General Duties………………………………………………………………………………….…….32 
9.3 Selection of Investigators…………………………………………………………………….…..32 
9.4 Monitoring (See also Monitoring Plan)……………………………………………..……..32 
9.5 Supplemental Applications…………………………………………………………………...…32 
 
9.6 Maintaining Records……………………………………………………………………………..…32 
9.7 Submitting Reports……………………………………………………………………………..…..32 
9.8 Informed Consent………………………………………………………………………………..….32 
10.0 STUDY DATA REPORTING AND PROCESSING ………………………………………………….....33 
 
10.1  Data Processing and Quality Control…………………………………………….…..….33 
10.2  Data Entry………………………………………………………………………………….…….….33 
10.3  Data Cleaning…………………………………………………………………………………...…33 
10.4  Data Editing……………………………………………………………………………………..….33 
10.5  Confidentiality and Protection of Study Files……………………………………….33 
10.6  Coordinating Center………………………………………………………………………….…33 
REFERENCES……………………………………………………………………………………………………………..34 
ADVERSE EVENT FORM………………………………………………………………………………………….…37 
UNANTICIPATED ADVERSE DEVICE EFFECT FORM………………………………………………..…..38 
STUDY CONSENT FORM……………………………………………………………………………………….…..39 
APPENDIX A:  HOVER ECHO PROTOCOL......................................................................49 
APPENDIX B:  VARC-2 ENDPOINT DEFINITIONS…………………………………………………….…55 
APPENDIX C:  HOVER CT PROTOCOL AND PATIENT DOSE ESTIMATION………………..…64 
APPENDIX D:  INCLUSION/EXCLUSION CHECKLIST……………………………………………….….66 
APPENDIX E:  HIGH RISK DOCUMENTATION……………………………………………………………70 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ACC 
American College of Cardiology 
ACT 
Activated Clotting Time 
AHA 
American Heart Association 
AST 
Alanine Transaminase 
AST 
Aspartate Transaminase 
BIB 
Balloon in Balloon 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
CAVI 
Caval Valve Implant 
CBC 
Complete Blood Count 
CEC 
Clinical Events Committee 
CKMB 
Creatinine Kinase MB 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
Gy 
Gray 
Hgb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability 
Act 
IDE 
Investigational Device Exemption 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IMA 
Internal Mammary Artery 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IVC 
Inferior Vena Cava 
IVUS 
Intravascular Ultrasound 
KAP 
Kerma Air Product 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LE 
Lower extremity 
LLC 
Limited Liability Corporation 
LMW 
Low molecular weight 
MELD 
Model for End Stage Liver Disease 
mmHg 
Millimeters of mercury 
MRI 
Magnetic resonance imaging 
NYHA 
New York Heart Association 
PA 
Pulmonary Artery 
PAH 
Pulmonary Arterial Hypertension 
PFT 
Pulmonary Function Testing 
Plt 
Platelets 

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  V2.3  24 Apr 2020 
PT 
Prothrombin Time 
 
PTT 
Partial Thromboplastin Time 
RA 
Right Atrium 
RV 
Right Ventricle 
RVEF 
Right ventricular ejection fraction 
SAE 
Serious Adverse Events 
SD 
Standard Deviation 
SRDL 
Substantial Radiation Dose Level 
STS 
Society of Thoracic Surgeons 
SVC 
Superior Vena Cava 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
TAVR 
Transcatheter Aortic Valve Replacement 
TEE 
Transesophageal Echocardiogram 
THV 
Transcatheter Heart Valve 
TIA 
Transient Ischemic Attack 
TR 
Tricuspid Regurgitation 
TTE 
Transthoracic echocardiogram 
TVR 
Tricuspid Valve Replacement 
UADE 
Unanticipated Adverse Device Event 
UF 
Unfractionated 
US 
Ultrasound 
VARC 
Valve Academic Research Consortium 
WBC 
White Blood Cell Count 
WHO 
World Health Organization 
6MWT 
6-Minute Walk Test 
 
 
 

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  V2.3  24 Apr 2020 
Statement of Investigator 
This statement is required to comply with the Investigational Device Exemption regulations contained in 
the 21CFRR 812.43(c) 
Study Title: The HOVER Study: Heterotopic Implantation Of the Sapien 3 Transcatheter Aortic Valve in 
the Inferior VEna cava for the treatment of severe tricuspid Regurgitation  
Protocol Number:   v2.3 24 Apr 2020 
Investigator Name: 
Institution Name: 
Address: 
Telephone Number: 
Email: 
I have read and understood the Clinical Investigational Plan and agree to participate in this trial and 
provide to the Sponsor the required information. 
I certify that I am a(n) __________________ __ (insert medical specialty) qualified by training and 
experience to conduct this trial.  As evidence of my training and experience, I will provide the Sponsor 
with a signed and dated copy of my curriculum vitae. 
I was ____/ I was not ____ involved in an investigation or other research in which my participation was 
terminated by a Sponsor, IRB/IEC or FDA. (If I was, an explanation of the circumstances that led to 
termination is attached to this Agreement.) 
☐I agree to conduct the investigation in accordance with the agreement, the investigational plan, 
Code of Federal Regulations Title 21, Parts 50, 56 and 812, and the conditions of approval imposed 
by the reviewing IRB and FDA. 
☐(For Principal Investigators only) I agree to supervise the handling of the device and its use 
involving human subjects; 
☐N/A (not site Principal Investigator) 
☐I agree to ensure that the requirements for obtaining informed consent are met. 
☐I agree to allow the Sponsor (or approved representative) to monitor the progress of the clinical 
investigation through the review of subject source documentation and study records. 
 
Signature:__________________________ 
 
 
Date:_______________ 

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  V2.3  24 Apr 2020 
HOVER PROTOCOL SUMMARY 
 
Title:   
The HOVER Study:  Heterotopic Implantation Of the Sapien 3 Transcatheter 
Aortic Valve in the Inferior VEna cava for the treatment of severe tricuspid 
Regurgitation 
 
Design: 
This is a prospective multi-center, non-blinded (open label), non-randomized 
safety and feasibility study of the heterotopic implantation of the Sapien 3 valve 
in the inferior vena cava for the treatment of severe tricuspid regurgitation in 
patients who are inoperable or at a very high surgical risk for tricuspid valve 
replacement.  A total of 15 patients will undergo implantation.  Primary 
endpoints will be assessed at 30-days and 6-months.  This study is an off-label 
use of an FDA-approved and commercially available medical device.    
 
Study Objectives:   
#1:  Determine the short term safety (<30 days) of Caval Valve Implant (CAVI) 
#2:  Determine the intermediate term (6 months) efficacy of CAVI on palliation 
of patient symptoms of right heart congestion. 
 
Primary Endpoints: 
#1:  Safety as defined by successful vascular access without unplanned major 
vascular complication as defined by VARC-2, delivery and retrieval of the 
transcatheter valve delivery system, correct position of both the vascular 
stent(s) and transcatheter valve in the IVC, a single valve placed within the IVC, 
and no need for additional surgery or re-intervention (including drainage of 
pericardial effusion) with the patient being alive at 30-days.  
#2:  Efficacy as defined by Improvement of KCCQ score >15, or improvement in 
6-minute walk test (6MWT)>70 meters or improvement of greater than 6% of 
peak Vo2 in cardiopulmonary exercise testing.   
 
Population:   
Patients with severe symptoms (NYHA class III-IV) and signs of peripheral and 
venous congestion (specifically lower extremity edema and abdominal ascites 
requiring diuretics),    resulting from documented severe tricuspid regurgitation.  
These patients may benefit from tricuspid valve repair or replacement, but are 
believed to be at high risk or are deemed inoperable for standard tricuspid valve 
surgery as assessed by at least one cardiac surgeon. 
 
Phase:  
 
1-2 
 
Clinical Sites: 
 
1. 
Henry Ford Hospital, Detroit, Michigan – site PI: Dr. Brian O’Neill 
(Coordinating Center)  
2.  
Temple University Hospital, Philadelphia, Pennsylvania – site PI: 
Vladimir Lakhter, DO 
3. 
University of California San Francisco, San Francisco, California – site PI: 
Dr. Vaikom Mahadevan 
4. 
Baptist Hospital of Miami, Miami, FL – site PI: Dr. Ramon Quasada 
 
 
 
 
 
 

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  V2.3  24 Apr 2020 
Statement:  
This protocol represents an original investigational device exemption (IDE) for 
placement of a SAPIEN XT or S3 Transcatheter Aortic Heart Valve in the inferior 
vena cava for treatment of severe tricuspid regurgitation. 
 
Study Duration:  
84 months from start of enrollment to completion of follow up 
 
Participant Duration: 
60 months  
 
Sponsor Investigator and overall PI: 
Brian O’Neill, MD 
 
 
 
 
 
Henry Ford Hospital 
Center for Structural Heart Disease 
2799 West Grand Blvd. 
Clara Ford Pavilion # 440 
Detroit, MI 48202 
313-970-6483 (p) 
313-916-2819 (f) 
 
 
Sponsor Site Co-Investigators:  
William O’Neill, MD; Marvin Eng, MD; Tiberio Frisoli, MD; Pedro Villablanca, MD; Dimitrios Apostolou, 
MD; Hassan Nemeh, MD; Daizo Tanaka, MD; Gillian Grafton, DO 
 
Sponsor Site Echocardiologists:  Dee Dee Wang, MD; James Lee, MD 
 
Manufacturer Information: 
Edwards LifeSciences LLC 
 
 
 
 
One Edwards Way 
 
 
 
 
Irvine, CA 92614 
 
 
 
 
949-250-2500 (p) 
 
 
 
 
949-250-2525 (f) 
 
 
Scientific Committee & DSMB: 
 
Jesus Gomez-Abraham MD 
 
Surgical Director Lung Transplantation 
 
Cardiac Surgery/MCS/TAH/VAD Surgeon 
 
201 Lyons Avenue Suite G5 
 
Newark, NJ 07112 
 
 
 
Hector R. Cajigas MD 
 
Senior Associate Consultant Pulmonary Hypertension Program Mayo Clinic 
 
Critical Care Medicine, Pleural Disease, Pulmonary Vascular Medicine 
 
Mayo Clinic 200 First Street SW 
Rochester, MN 55905 
Phone: (507) 266-3958 
Fax: (507) 266-4372 
 
Eduardo DeMarchena 
Professor of Medicine and Surgery 

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  V2.3  24 Apr 2020 
University of Miami Medical Group 
1400 NW 10th Avenue Dominion Tower 206 (M-815) 
Miami Fl. 33136 
Phone:  305-243-9200 
Fax:  305-243-2138 
 
 
 
 
Pre-Submission Meetings: The concept of this study was initially proposed to the structural heart 
disease branch of the FDA in a conference call on 4/4/2014.  After that call a preliminary protocol was 
submitted for review to Changfu Wu on 4/24/2014.  Feedback for the initial protocol was provided on 
4/28/2014 by the FDA. Additional correspondence was received and on January 08, 2016 the FDA 
approved the updated protocol to include: 1. The use of either the Sapien XT or the Sapien S3 valve and 
2. Expansion of the study to the 4 additional sites.  
 
 
 

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  V2.3  24 Apr 2020 
SCHEMATIC OF STUDY DESIGN 
Prior To Enrollment 
 
 
 
 
 
 
 
Procedure Date 
 
 
Post-Op and Discharge 
 
 
30-Day Visit 
 
 
6-Month Visit 
 
1-year Visit 
 
 
Annual Visits up to 
5 years 
Obtain informed consent, screen potential patients by inclusion 
and exclusion criteria, evaluation by members of heart team.  
Presentation at local site heart team meeting. 
Conference call with executive committee to review patient case.  
If 2/3 committee agree then patient is enrolled in study. 
Perform baseline assessments as per Table 1.  Caval Valve 
Implantation 
Post procedure and discharge assessments, schedule 30-day visit 
as per Table 1
Follow up assessments.  Safety endpoints evaluated as per Table 
1 
Follow up assessments.  Efficacy endpoints evaluated as per 
Table 1 
Follow up assessments.  Efficacy endpoints evaluated as per 
Table 1 
Follow up assessments and study close out (at year 5). 

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  V2.3  24 Apr 2020 
 
1.0 
BACKGROUND 
Severe tricuspid regurgitation (TR) is an under treated disease state associated with significant morbidity 
and mortality.  Nath and colleagues showed a 1-year mortality of 33.1% in patients diagnosed with 
severe tricuspid regurgitation1.  In the United States alone, 1,600,000 patients are diagnosed with severe 
tricuspid regurgitation each year, while only 8,000 (less than 1%) are treated with tricuspid valve 
surgery2.  The reasons for this are varied, however, many of these patients who are not treated go on to 
exhibit signs of central and peripheral venous congestion, including irreversible hepatic cirrhosis and 
chronic kidney disease.  This creates a vicious spiral, in which those patients who are initially good 
operative candidates may become high risk or inoperable for conventional tricuspid valve surgery.  
Additional therapeutic options are therefore needed for these patients and their treating physicians. 
 
Currently, there are no specifically designed devices for the transcatheter treatment of tricuspid valve 
disease.  As a result, the treatment of these patients to date has relied on the off-label use of 
transcatheter aortic valve technology.  Multiple case reports have shown the feasibility of percutaneous 
transcatheter aortic valve impantation within degenerated tricuspid valve bioprostheses or “valve-in-
valve” 3,4.   The experience is less robust for transcatheter tricuspid replacement within a native tricuspid 
valve5 and is likely limited in part to the annular dilatation which is present in patients with severe TR6.  
Despite this promising experience with transcatheter aortic valve placement directly within the tricuspid 
valve, long term data is lacking, and recent reports have demonstrated early valve failure in patients 
using this technique7. 
 
Recently, caval valve implant of the Edwards Sapien Transcatheter valve for treatment of severe 
tricuspid regurgitation has shown promise as an additional therapy for patients with severe TR who are 
high risk or inoperable.  Placement of a valve in the right atrial (RA)/caval junction would in theory 
prevent the massive reflux of blood into the IVC, thereby protecting the hepatic, renal, and lower 
extremity veins from volume overload.  Santhanakrishnan and colleagues evaluated the effects of 
placing a unidirectional valve in the IVC in a bench model simulating a Fontan procedure, in which the 
SVC and IVC are directly anastomosed to the right and left pulmonary artery in those patients with one 
ventricle.  Although short term effects of this procedure are favorable, long term patients go on to 
develop elevation in the systemic venous pressure from retrograde flow in expiration, particularly to the 
hepatic veins.  In their study, the authors created a flexible wall model to simulate the IVC/SVC/PA 
connections.  Using a Medtronic melody valve placed in the IVC in a sub-diaphragmatic position, they 
demonstrated a significant decrease in hepatic venous pressure through 20% of the cardiac cycle, with 
minimal gradient across the valve.  They concluded this therapy may have potential for lowering hepatic 
venous pressure by arresting retrograde flow occurring in the IVC 8. 
 
The first in-vivo animal experience of this procedure was by Corno and colleagues in 20039.  In their 
study, bovine jugular xenografts were mounted on self-expanding nitinol stents and placed in the IVC of 
5 adult pigs.  Animals were anesthetized and the diameter and length of the IVC was measured using 
Intravascular ultrasound (IVUS).  After placement of the valve, pressures were measured proximal and 
distal to assess for any gradients.  IVUS showed partial opening and closing of the valve, with complete 
closure occurring during deep breaths.  Autopsy showed adequate positioning of the valve stent without 
any deformation, with the proximal most portion of the valve 2cm proximal to the right atrial junction 
without any deformation of the valved stent.   Sochmann et al performed twin valve caval stenting in a 
series of studies of three sheep and one swine.  In their series, severe TR and reflux into the SVC and IVC 
was induced through papillary muscle avulsion in sheep, while the swine served as a control.  Self-
designed stents were placed in the caval veins through a 12-French sheath.  5-French pigtail catheters 

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  V2.3  24 Apr 2020 
were introduced into the femoral and jugular veins so that bicaval venography could be performed.  In 
the swine, the valve functioned well for 3 hours without a position change and remained stable on 
necropsy.  In 3 sheep, after placement of the stents, right ventricular (RV) angiography demonstrated 
retrograde filling of the SVC and IVC to the valves but not beyond10.  At necropsy, the valve position 
remained stable.   
 
Contemporary animal models have confirmed and expounded on these early results.  Lauten and 
colleagues created acute severe TR in a sheep model via papillary muscle and chordae avulsion11.  
Successful creation of TR was verified by a prominent ventricular (v) wave which was present in the 
central venous pressure tracing.  Self-expanding nitinol stents containing a porcine pulmonary valve 
were placed in the superior vena cava (SVC) and inferior vena cava (IVC).  In both an acute group (n=9) 
and chronic group (n=4), a significant decrease in the v-wave was demonstrated post-implant with an 
accompanying increase in cardiac output.  At autopsy in the chronic group, the stents were covered with 
fibrous tissue and adhered strongly to the vessel wall.  In one animal in the acute group, the SVC valve 
embolized into the right atrium with resultant hemodynamic instability.  This did not cause immediate 
death.  Autopsy showed correct device position in all successfully treated animals. 
 
 
The effectiveness of this therapy in animals has also translated to humans.  In the first-in-man report, a 
79 year old woman with a history of severe TR who was declined for traditional tricuspid valve surgery 
had been experiencing worsening symptoms of right ventricular (RV) congestion for several years.  After 
institutional review board (IRB) approval the patient underwent the procedure.  Reflux into the caval 
and hepatic veins were confirmed by angiography.  After careful position guiding by fluoroscopy and 
echocardiography, the valve, a self-made nitinol stent frame porcine pericardial valve, was placed in the 
IVC.  Transesophagehal echo (TEE) performed immediately after the procedure and repeated every 2 
weeks demonstrated stable position and valve function.  At 8 weeks of follow-up, CT-angiogram 
confirmed the absence of regurgitation into the IVC.  The patient had clinical improvements in New York 
Heart Association Functional Class (NYHA), and improvement in both peripheral edema and ascites.  
Sadly, 3 months later, the patient was admitted with an intracranial hemorrhage and expired.  Autopsy 
revealed stable position of the valve, with fibrous tissue covering the valve helping to anchor it in 
position 12.  The same authors describe a second case of an 83 year-old woman with severe TR also with 
symptoms of chronic right heart failure.  Caval valve implant was performed as part of a compassionate 
treatment.  Valves were again individually designed with the upper segment of the IVC valve to lay in the 
right atrium above the diaphragm to avoid backflow into the IVC, with a funnel shape to the SVC valve.   
After deployment of both valves, both the IVC and SVC mean pressures decreased with a stable mean 
right atrial (RA) pressure.  Clinical follow up of the patient demonstrated complete resolution of ascites 
and peripheral edema, with normalization of synthetic liver function.  Echo and CT confirmed stable 
valve position without paravalvular regurgitation13.  In the largest series to date, Laule et al report on 
three patients who underwent caval valve implant for severe TR.  Each of these patients had recurrent 
right heart failure despite optimal medical therapy.  2 of these patients underwent stenting to the IVC 
alone.  These investigators employed a novel technique of pre-stenting the IVC with placement of an 
Edwards-Sapien XT (29mm) valve within the stent.  Follow up at 30-days showed no adverse events 
according to valve academic research consortium criterium (VARC).  In addition, all patients improved by 
at least 1 NYHA class, symptoms of right heart congestion, and improvements in indices of RV function.  
Longer term follow up of these patients is forthcoming. 
 
An unanswered question with this technique is the effects of redirection of blood flow from the IVC to 
the right atrium, and the clinical impact on increased volume load do the right atrium and SVC. 

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  V2.3  24 Apr 2020 
The initial animal studies by Lauten demonstrated an increase in RA pressure with the creation of severe 
TR, with minimal increases in RA pressure after the implantation of the IVC valve 11.  In addition, there 
were increases in cardiac output noted.  In the 12-Month follow up of a patient undergoing bicaval valve 
implant, RA pressure was noted to decrease from 21-16mmHG at 3-month follow up 13.  This suggests a 
chronic decrease in right ventricular volume load from effective diuresis of the patient, as demonstrated 
by a 9kg body weight loss the patient was noted to have at follow-up.  These findings are also 
demonstrated in follow up from a patient in the HOVER trial.  In this patient, mean RA pressure was 
noted to decrease from 12-10mmHG immediately post-implantation.  At 6-month follow up there was a 
further decrease in mean RA pressure noted to 5mmHg14.   These decreases in RA pressures were again 
accompanied by increasing cardiac output.  Although these observations will require further study, 
these reports suggest that this re-directed flow is well tolerated by the right heart, and may improve 
overall hemodynamics through diuresis and augmentation of cardiac output.  We hope to evaluate the 
effects of this, as well as clinical improvement in symptoms of right heart congestion with this study. 
 
 
2.0 PROJECT PLAN 
 
2.1  Rationale for Study 
Severe TR is characterized by right heart congestion and volume overload15.  Non-surgical treatment for 
TR relies on the administration of increasing doses of diuretic therapy to promote diuresis and volume 
contraction.  However, many patients go on to become refractory to chronic diuretics over time.  This is 
in part to the effects on chronic right heart congestion on the kidney.  Based on previous studies, we 
believe that protection of the hepatic and renal veins with a one-way valve from the transmitted TR will 
allow for continued diuresis, and improvement in symptoms.  Although CAVI has shown improvements 
in right heart congestion in a small series of patients, several questions remain.  Previous studies have 
not clearly excluded TR that can occur with pulmonary arterial hypertension (PAH.)  As 2/3 of the 
regurgitant flow from tricuspid regurgitation is directed to the IVC, the effects of redirection of this flow 
to the SVC are unknown.  The degree of TR can be sensitive to changes in pre-load.  It remains unclear if 
improvement in right heart congestion may therefore also affect degree of TR and indices of right 
ventricular (RV) function.  Finally, the durability of the procedure beyond the intermediate term (6 
months) is not well characterized.  To help clarify these issues, we have created the Heterotopic 
Implantation Of the Edwards Sapien 3 Transcatheter Aortic Valve in the Inferior VEna cava for the 
treatment of severe Tricuspid Regurgitation study. 
 
2.2 Design: 
This is a prospective multi-center, non-blinded (open label), non-randomized safety and feasibility study 
of the heterotopic implantation of the Edwards Sapien 3 valve in the inferior vena cava for the 
treatment of severe tricuspid regurgitation in patients who are inoperable or at a very high surgical risk 
for tricuspid valve replacement.  Patients enrolled will have severe TR and cardiac symptoms of right 
heart congestion in whom conventional tricuspid valve surgery (TVR) would be associated with high risk.  
Severe TR is defined by a vena contracta width > 7mm OR evidence of systolic hepatic vein flow reversal 
OR visible tricuspid valve coaptation defect + dense/triangular continuous wave with early peaking as 
assessed by continuous wave signal AND  a very large central jet or eccentric wall impinging jet as 
assessed by color flow. 16.  All patients must be on diuretics with documented evidence of continued 
venous congestion, such as lower extremity or abdominal wall edema.   
 

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  V2.3  24 Apr 2020 
All patients will be evaluated by at least one cardiac surgeon.  The cardiac surgeon must agree that 
based on his assessment the patient is high risk or inoperable for TVR as per the surgical office note and 
attached (appendix E).    Most inoperable patients have elevated STS risk scores including one or more 
STS risk elements that exceed thresholds considered safe for operation. A common example is 
respiratory disease, for which the STS risk-scoring threshold usually signals increased risk in operable 
patients, but which may be severe enough in a given patient to explain inoperability.  In trials of TAVR, 
oxygen dependency in particular, has been independently associated with increased one-year mortality 
17.  Other "inoperable" patients, regardless of STS score, are rendered inoperable by severe co-
morbidities of the low-prevalence, high-heterogeneity variety that are difficult to represent statistically 
and are not part of the STS risk model. Common examples include liver disease, porcelain aorta, chest 
wall abnormalities, and frailty.  Chest wall abnormalities may include prior chest irradiation, a graft close 
to the sternum, or an absent or reconstructed sternum 18,19.  It must be acknowledged that "inoperable" 
is frequently an integration of multiple dimensions of an individual patient in whom no simple, single-
factor quantifiable line can be drawn between operable and "inoperable."  Factors which make a patient 
high risk or inoperable will be clearly de-lineated in the patient’s surgical evaluation.   The “operable” 
patient will have characteristics which include a normal RVEF, normal creatinine, no previous open heart 
surgeries, preserved left ventricular ejection fraction.  As the STS is undefined for these patients, should 
a patient have no other characteristics which make them high risk, an STS score for a simulated mitral 
valve procedure of <5 can also be considered in declaring a patient operable.   
 
2.2.1 Definition of the Heart Team 
When a potential subject is identified in the clinical practice of a participating site, the subject will be 
referred to the site heart team.  The goal of the heart team is to optimize patient selection and improve 
procedural success.  Originally intended for transcatheter aortic valve replacement (TAVR) decision 
making, the concept of the heart team has expanded to involve patients with structural or complex 
coronary artery disease in whom the participation of multiple physicians from differing areas of 
expertise is beneficial 20 21.  Ideally, this team is comprised of an interventional cardiologist and cardiac 
surgeon at the core, with other expertise from advanced imaging, cardiac anesthesia, and heart failure 
as important adjuncts.  Patients are seen individually by physicians, or, as part of a dedicated visit to 
multiple specialties in the form of a valve “clinic.”  After patients are evaluated, the members of the 
heart team will discuss the patient’s case at a weekly conference.  Here, a patient’s clinical history and 
clinical data are reviewed, and a group recommendation is made.  If after evaluation by an 
interventional cardiologist, heart failure specialist, and cardiac surgeon, as well as presentation at the 
local heart team conference, a patient is deemed a suitable candidate for the trial, they will be 
presented to the executive committee of the trial.  The credentialing of heart team members will be the 
responsibility of the local heart team site. 
 
2.2.2 Core Lab 
Either concomitantly or after decision by the local heart site to presentation to the executive 
committee, baseline echocardiograms and CT scans will be reviewed by the coordinating center (Henry 
Ford Hospital) to confirm severe TR and anatomic suitability for implant. 
 
2.2.3  The Executive Committee 
The purpose of presentation of patients to the executive committee is to provide additional consultation 
from experts to further review and approve the selection prior to the patient being enrolled in the trial.  
The executive team will be comprised of the site PI from each site.  The presentation will occur in the 
form of a conference call which is open to any member of the individual sites included in the HOVER 
trial.  During the executive committee conference call, the local site will verify that the patient meets the 

15 
  V2.3  24 Apr 2020 
inclusion, and is free from exclusion criteria for the trial.  The local site will present the patient’s case for 
committee review.  Any questions the executive committee may have regarding the case will be 
addressed during this call.    If after the case presentation, 2/3 of the executive committee agree the 
patient is suitable for CAVI, the patient will be enrolled in the trial and an implantation date will be set.  
Documentation of approval for the trial of the patient by the executive committee will be added to the 
patient’s chart. If all members of the executive committee are unable to convene on one conference 
call, the case will be presented individually to members of the committee in separate phone calls. 
 
2.2.4  Use of Edwards-Sapien Transcatheter Valve 
This trial represents the off-label use of an approved medical device.  The on-label indications are as 
follows: 
 
The Edwards SAPIEN 3 transcatheter heart valve (THV), model 9600TFX, and accessories are indicated 
for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic 
stenosis who are judged by a heart team, including a cardiac surgeon, to be appropriate for the 
transcatheter heart valve replacement therapy. 
 
 
2.3 Statistical Analysis 
A total of up to 15 patients will be enrolled.  Due to the lack of preliminary data as well as exploratory 
nature of the study, no sample size and power analyses were performed. We expect to screen 
approximately 45 patients to enroll up to 15 eligible patients into this trial. 
 
All clinically relevant baseline and follow-up data will be tabulated. Means (SDs), medians (ranges), and 
95% confidence intervals will be reported for continuous variables and frequencies, percentages, and 
95% confidence intervals for categorical variables. Specifically, each of the two primary endpoints (the 
procedural success at 30-days and the composite binary response variable at 6-months) will be 
summarized using both a point estimate and its exact confidence interval based on a binomial 
distribution. Other binary safety and efficacy secondary endpoints will be analyzed similarly. Continuous 
secondary endpoints (e.g., hemodynamics data) will be reported using descriptive summary statistics as 
well as a point estimate and its confidence interval based on a normal distribution assumption. The 
changes from baseline to each follow-up timepoint will additionally be evaluated using the McNemar 
matched pairs test for dichotomous variables and the t-test for continuous variables. In the presence of 
distributional non-normality, the Wilcoxon signed rank test will be used instead of the t-test. Data 
transformations such as log or square-root may also be considered. The analyses of NYHA functional 
classification will involve comparison of the baseline and post-operative (at each timepoint) functional 
class and determination of the percentages of patients improving, not changing, or worsening at each 
postoperative timepoint. The same principle will be applied to quality of life score (KCCQ) and 6-minute 
walk distance.  Although this is an exploratory analysis, we anticipate 50% of patients will demonstrate 
improvement in one of the three pre-specified components of the primary efficacy outcome. 
 
The time-to-event approach may be considered to analyze some of safety and efficacy endpoints (e.g., 
time to treatment failure, event-free survival, and overall survival) while taking censoring into account in 
data analyses. Such endpoints will be summarized using the Kaplan-Meier method. Confidence intervals 
for the medians and survival rates at different time points will be constructed, when appropriate. For a 
continuous endpoint measured repeatedly over time, a mixed-effects regression model may be 
employed to study its over-time trajectory or change patterns. All these results will be reported 
descriptively. 

16 
  V2.3  24 Apr 2020 
The intent-to-treat approach will be used for data analyses of this trial. That means all enrolled patients 
will be included in the interim and final data analyses regardless of their eligibility or subsequent events. 
Patients who are lost to follow-up or drop out of study prior to their scheduled follow-up evaluation 
time due to any reason will be treated as a treatment failure for response determination and censored 
for time-to-event type of endpoints at the time of their last follow-up if no relevant event has occurred 
by then. A secondary analysis that includes only all eligible patients may be conducted in addition to the 
primary analysis described above at the discretion of the trial PI and study biostatistician. However, such 
analysis may not serve as the basis for drawing conclusions concerning treatment safety or efficacy, and 
the reasons for excluding patients from the analysis should be clearly reported. 
 
All enrolled patients will be evaluable for adverse events from the time of their protocol treatment. 
Adverse events will be tabulated by type and severity according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0. 
 
During the entire study period, adverse events will be closely monitored by the trial PI and clinical trial 
coordinator of this study, working along with the study DSMB. In particular, formal stopping rules on the 
6-month mortality are stipulated in this protocol (please refer to section 4.1 “Efforts to minimize 
procedure risks”).  In addition, in the event that other adverse events (e.g., surgical complications) are 
thought to be excessive for the study patient population at any point of the trial, the patient accrual to 
the trial will be suspended immediately, pending a review of all adverse events data. A final decision will 
be made by the trial PI and DSMB as to whether the trial should be amended, terminated or continue 
accrual. Such decision should be filed with and pre-approved by the institutional IRB. 
 
 
2.4 Study Endpoints: 
The primary safety endpoint is procedural success at 30-days.  Procedural success will include: 
• 
Successful vascular access without unplanned major vascular complication as defined by VARC-
2, delivery and retrieval of the transcatheter valve delivery system, correct position of both the 
vascular stent(s) and transcatheter valve in the IVC, a single valve placed within the IVC, and no 
need for additional surgery or re-intervention (including drainage of pericardial effusion) with 
the patient being alive at 30-days.  
   
The primary efficacy endpoint will be improvement in one of three variables assessed from baseline to 
6-months.     
• 
Improvement of KCCQ score >15.  This has been shown to correlate with improvement in quality 
of life with heart failure patients22.   
• 
Improvement in 6-minute walk test (6MWT)>70 meters.  This has been shown to provide 
prognostic information in patients with congestive heart failure after an intervention23.   
• 
Improvement of greater than 6% of peak Vo2 in cardiopulmonary exercise testing.  In a heart 
failure population, this has been shown to help assess prognosis in patients who were instituted 
in an exercise program 24.   
 
Secondary endpoints will be evaluated at several timepoints and will be divided into safety and efficacy:  
The first in the acute setting which will be out to 30 days or hospital discharge whichever being longer; 
additional time points will be at midterm (6 months post-procedure), long term (1 year and annually up 
to 5-years post-procedurally.)   
Secondary safety endpoints include: 

17 
  V2.3  24 Apr 2020 
• 
All stroke and TIA (VARC-2) 
• 
Mortality (VARC-2) 
• 
Myocardial infarction (VARC-2) 
• 
Acute Kidney Injury (VARC-2) 
• 
Major Vascular Complication (VARC-2) 
Secondary efficacy endpoints include: 
• 
Assessment of improvement of LE edema by the Villalta Score25.  A 3.1 point improvement 
in this scale was associated with improved quality of life26.   
 
Besides the above formal secondary endpoints, we will monitor for the following throughout the trial:   
• 
Deep Vein/IVC thrombosis or pulmonary embolism 
• 
Improvement in grades of tricuspid regurgitation as assessed by echocardiogram  
• 
Changes in TAPSE by echocardiogram for RV function 
• 
Pleural effusions   
• 
Additional quality questionnaires to assess for changes in ascites (EORTC QLQ-C30 27 and ESAS-
AM 28).  A 10-point change in mean score in the QLQ-C30 has been shown to be a meaningful 
response (O’Connor R. Measuring Quality of Life in Health Churchill Livingstone: Philadelphia; 
2004).  A decrease of 1.25 points in the ESAS-AM has been shown to correlate with symptom 
improvement after paracentesis28. 
 
3.0 STUDY ENROLLMENT AND WITHDRAWAL 
 
3.1. Baseline 
The screening phase of the trial is designed to meet two objectives: 
1. Patient Consent. 
2. Determine study patient eligibility and access site for the procedure. 
 
3.2. Informed Consent 
Informed Consent will be obtained from all prospective subjects prior to beginning any study activities. 
All aspects of the trial including that participation is voluntary, will be explained and the patient will 
have the opportunity to have their questions answered before deciding whether to participate.  Patients 
who agree to participate and sign the informed consent document will be given a copy of their signed 
consent to take home with them. 
 
Upon completion of the screening process, the patient’s case will be presented to the site heart team.  If 
after presentation to the site heart team it is agreed by the members the patient is a suitable candidate, 
the patient will be presented to the executive committee of the trial.  If after the conference call 2/3 of 
the executive committee members agree, the patient is enrolled in the trial. 
 
3.3  Eligibility Process 
All patients with severe tricuspid regurgitation and symptoms who are high risk or inoperable will be 
screened for study inclusion.  Patients must have all inclusion criteria, and be free from all exclusion 
criteria.  Screening and enrollment logs will be maintained.  Reasons for screen failures will be 
documented.  The full description and timing of screening tests can be found in Table 1.  
 
 

18 
  V2.3  24 Apr 2020 
3.4  Participant Inclusion Criteria: 
In order to be eligible to participate in this study, an individual must meet all of the following criteria 
1. Patients must be at least 21 years old.  
2.  The patient must have severe, symptomatic (ACC/AHA Stage D symptoms) tricuspid regurgitation 
(TR) as assessed by 2D echocardiogram with evidence of peripheral and central venous congestion 
(specifically lower extremity edema and abdominal ascites requiring diuretics.)    
3.  The patient must be evaluated by a “heart team” of physicians including an interventional 
cardiologist, cardiothoracic surgeon, heart failure specialist, and imaging specialist, and presented for 
review at a local multi-disciplinary conference.  By consensus, the heart team must agree (and verify in 
the case review process) that valve implantation will likely benefit the patient. 
4. The heart team must agree that medical factors preclude operation, based on a conclusion that the 
probability of death or serious, irreversible morbidity exceeds the probability of meaningful 
improvement.  Also, other factors which may increase the patients perceived surgical risk for inclusion in 
the trial will be clearly delineated if they are present.  These include, but are not limited to the following 
as defined by VARC 2:  Frailty, Hostile chest, porcelain aorta, IMA or other critical conduit crossing the 
midline or adherent to the posterior table of sternum, severe right ventricular (RV) dysfunction.  The 
surgeons' consultation notes shall specify the medical or anatomic factors leading to that conclusion.  At 
least one of the cardiac surgeon assessors must have interviewed and examined the patient.  
5. The study patient provides informed consent and agrees to comply with all required post-procedure 
follow-up visits, including annual visits up to 5 years. 
6.  Mean diameter of the IVC at the right atrial junction or superior most hepatic vein ≤30.5mm 
 
3.5  Participant Exclusion Criteria: 
Patient or Subject will be excluded from the study if any of the following conditions are present: 
1. Heart Team assessment of operability (the heart team considers the patient to be a good surgical 
candidate). 
2. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before the intended treatment 
[defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB ≥ twice normal in the 
presence of MB elevation and/or troponin level elevation (WHO definition)]. 
3.  Untreated, severe, left sided valvular heart disease including mitral regurgitation or stenosis, and 
aortic regurgitation or stenosis. 
4.  Mean pulmonary artery pressures ≥40mmHG and PVR >4 woods units as assessed by right heart 
catheterization. 
5. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 
30 days of the index procedure.  Examples of permanent implant would include any new heart valve.  
Implantation of a permanent pacemaker is excluded. 
6. Patients with planned concomitant surgical or transcatheter ablation for Atrial Fibrillation. 
7. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt < 50,000 
cell/mL). 
8. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or 
mechanical heart assistance within 30 days of screening evaluation. 
9. Need for emergency surgery for any reason. 
10. Left ventricular ejection fraction <40%.  
11. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. 
12. Active upper GI bleeding within 3 months (90 days) prior to procedure. 
13. A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be 
anticoagulated for the study procedure. 

19 
  V2.3  24 Apr 2020 
14. Recent CVA clinically confirmed (by neurologist) or neuroimaging confirmed stroke or transient 
ischemic attack (TIA) within 6 months (180 days) of the procedure. 
15. Estimated life expectancy < 1 year from conditions other than TR. 
16. Expectation that patient will not improve despite treatment of tricuspid regurgitation 
17. Currently participating in another investigational cardiac device study or any other clinical trial, 
including drugs or biologics. Note: Trials requiring extended follow-up for products that were 
investigational, but have since become commercially available, are not considered investigational trials. 
18. Active bacterial endocarditis within 6 months (180 days) of procedure. 
19.  Patients with signs or symptoms of SVC syndrome, or hepatic cirrhosis not felt due to passive 
congestion from TR. 
20: Subject unable to personally provide informed consent  
21.  FEV1<30% of predicted29 
22.  Model for End State Liver Disease (MELD) score ≥21 (calculated per reference study 30) for patients 
not on blood thinners 
 
 
4.0 RISK AND BENEFIT ANALYSIS 
 
There are potential risks associated with transcatheter heart valve implantation. There are risks related 
to the overall procedures (complications associated with standard cardiac catheterization which include 
bleeding, infection, stroke, death, cardiac arrest, pacemaker implantation, allergic reactions, emergency 
open heart surgery, and emergency blood transfusion, prolonged hospital stay, renal failure, groin 
lymphocele, limb ischemia, myocardial infarction, injury to adjacent structures including nerves, blood 
vessels, or other structures.)  In addition, there are also risks associated with the valve itself which 
include valve embolization and/or migration and the emergent need for open heart surgery and possibly 
death, as well as valve thrombosis which can lead to death, stroke, pulmonary embolism, or venous 
thrombosis.  Structural valve deterioration may also occur in the form of wear, fracture, calcification, 
leaflet tear/tearing from the stent posts, leaflet retraction, suture line disruption of components of a 
prosthetic valve, thickening, stenosis.  
 
There are risks associated with stenting of the IVC for valve implantation.  These include migration of the 
stent and injury to the vessels of the heart or the heart itself, as well as venous thrombosis and stroke.  
Although these risks are present, the potential of a new therapy which improves the quality of life in 
those patients who are otherwise ineligible for surgery outweighs these potential risks. 
 
Pleural effusions may occur either immediately post-operatively, or at follow up.  It is recommended 
that a trial of diuretic therapy, as well as attempts at diagnosis of the effusion (exudative vs. 
transudative) be attempted if the patient becomes symptomatic.  If diuretic therapy fails, a 
thoracentesis should be considered for symptomatic relief.  If the effusion reoccurs, additional 
thoracenteses may be considered.  Alternatively, the placement of a permanent drainage catheter, or 
pleuredesis may be another option in patients with continued fluid accumulation who remain 
symptomatic. 
 
4.1 Efforts to minimize procedure risks 
Efforts to minimize procedural risks will be addressed in the following manner. 
 
4.1.1.  Site Heart Team and Executive Committee Presentation 

20 
  V2.3  24 Apr 2020 
All possible patients will be presented at a site heart team conference.  There the data will be reviewed, 
including any aspects which may or may not affect the possible success of the procedure.  After this 
step, patients will be presented to a panel of experienced operators outside of the local heart team 
institution, the executive committee.  There, the data will be reviewed a second time prior to 
enrollment in the trial.   
 
4.1.2.  Data Safety Monitoring Board (DSMB) 
A DMSB will be established.  The DSMB is independent from the Sponsor, the investigators, or anyone 
involved in the medical care of the study subjects. Members will not have scientific, financial, or other 
conflict of interest related to the Sponsor or the investigators. The committee will be selected by the 
overall Principal Investigator and managed independently. 
The members must have the following characteristics: 
• working professionally as physicians or statisticians; 
• at least one member with specific expertise in cardiothoracic surgery clinical trials; 
• no relevant conflicts of interest; 
• they will not be involved in the conduct of this trial in any other capacity, such as principal 
investigators, sub-principal investigators; 
• they will not be engaged in any simultaneously occurring competitive trials; 
• they should not be on the NIDPOE or debarred list of investigators. 
Members will not serve on the DSMB, Clinical Event Adjudication Committee (CEC) or Operating 
Committee of a competing device trial. Members will not have any affiliation with the core laboratories, 
the data coordinating center, or the principal investigator of the trial. The DSMB committee will review 
all safety data from the HOVER Trial and make recommendations based upon the safety analyses. The 
frequency of the DSMB meetings will be determined prior to study commencement; however, the DSMB 
may call a meeting at any time if there is reason to suspect safety is an issue. DSMB oversight for this 
trial is expected to be rigorous with frequent review of all essential safety data. The DSMB chairperson 
will notify the principal investigator of any safety or compliance issues. They will also provide 
confidential recommendations, when necessary, of study termination. All DSMB reports will remain 
strictly confidential, but will be made available to regulatory authorities. The principal investigator will 
notify the FDA if any member of the DSMB advises to terminate the study due to safety concerns. 
 
 
4.1.3.  Interim Monitoring and Stopping Rules 
The interim monitoring and stopping rules will focus on the 6-month mortality. Based on current 
literature, it is reasonable to assume a 6-month mortality of at least 30% for the high risk patients 
targeted in this clinical trial 31.   For the purpose of this trial, we will focus on device-related mortality. 
  The interim monitoring will be implemented with stopping rules when 3, 6, and 9 patients have been 
enrolled and treated with the protocol device. The proposed stopping rules are: 
Number of patients on 
trial: 
When number of 6-month 
deaths ≥: 
Probability of stopping the trial early 
when the true 6-month mortality is 30%: 
3 
2 
0.216 
6 
3 
0.105 
9 
4 
0.064 
15 
6 
0.064 
 
As it can be seen from the above table, the probability of stopping the trial early is very small (≤10.5%) 
assuming the true 6-month mortality rate is no more than 30% when there are at least 6 patients 

21 
  V2.3  24 Apr 2020 
enrolled and treated on the clinical trial. When there are only 3 patients enrolled, we are only stopping 
the trial early when two (or more) out of the first three patients died within 6 months on trial due to a 
device-related death. This probability is reasonably small as well (21.6%). 
In addition to mortality, should valve thrombosis occur in ≥30% of patients at 6-months, the trial will be 
paused to evaluate if any additional precautions are required. 
 
The trial PI (Dr. Brian O’Neill, MD), working along with the study DSMB, will monitor other safety 
parameters such as significant surgery complications, one-year mortality, overall survival, and event-free 
survival at least biannually (every 6 months) as well in an effort to make certain that the patients on trial 
are not inadvertently harmed by the proposed protocol treatment. 
 
 
4.2 Potential Benefits 
Implantation of the transcatheter heart valve into the IVC may have immediate and long term benefits.  
In the immediate term, patients may notice stability to the amount of edema they have in their 
abdomen and legs.  In the long term, with protection of the renal veins from the TR, patients may notice 
improvement in central and peripheral venous congestion, improvement in end organ function including 
liver and kidneys, and improvement in overall quality of life. 
 
 
 
 

22 
  V2.3  24 Apr 2020 
5.0 STUDY PROCEDURES AND SCHEDULE 
The study procedures and schedule are listed below.  If patients are unable to perform examinations for 
any reason, justification of this must be provided by the study site PI. 
 
5.1  Pre-Procedure Assessments 
The following will be collected in all patients at baseline (within 90 days of procedure, except for 
Informed Consent which will be obtained prior to beginning screening). Items in bold font are required 
to determine eligibility and must be performed prior to the Heart Team and Executive Committee 
meetings. 
• 
Informed Consent 
• 
Medical history.  This will include past medical and surgical history, social history, family history. 
• 
Physical Exam.  This will include vital signs and weight, head, ears, eyes, nose and throat 
(HEENT), neck, lungs, cardiovascular, abdomen, genitourinary, gastrointestinal, musculoskeletal, 
neurological 
• 
NYHA functional Class as per The Criteria Committee of the New York Heart Association. 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. 
Boston, Mass: Little, Brown & Co; 1994:253-256 
• 
Diuretic types and doses 
• 
Surgical note documenting high risk/inoperable status. 
Laboratory Measurements 
• 
CBC with differential (During 6 months of screening and within 21 days of procedure) 
• 
Cardiac Enzymes (Troponin I and/or CK and CKMB) (≤72 hours before the procedure) 
• 
Comprehensive metabolic panel (within 90 days of procedure) 
• 
Lactate Dehydrogenase (LDH) 
• 
ACT (within 21 days of procedure) 
• 
aPTT  (within 21 days of procedure) 
• 
PT/INR (within 90 days of procedure) 
• 
Brain Natriuretic Peptide (BNP) (within 21 days of procedure) 
Non-Invasive Tests 
• 
ECG (within 21 days of procedure) 
• 
Chest X-ray (portable or PA and lateral) (within 21 days of procedure) 
• 
Echocardiogram (Transthoracic)  (within 90 days of procedure) 
• 
Chest and Abdominal CT (within 90 days of procedure) 
• 
Cardiopulmonary Exercise Stress test 32  (within 90 days of procedure) 
• 
Venous Lower Extremity Duplex Study (within 21 days of procedure) 
• 
Pulmonary Function Testing (PFT) (within 90 days of procedure) 
Functional Assessments 
• 
6-minute walk test 33 (within 90 days of procedure) 
• 
Villalta Scale 25,26 (within 21 days of procedure) 
• 
EORTC QLQ-C30 27 (within 21 days of procedure) 
• 
ESAS-AM 28 (within 21 days of procedure) 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 22 (within 21 days of procedure) 
Invasive Tests 
• 
Left Heart Catheterization with or without LV gram and IVUS. (Within one year of baseline) 
• 
Right Heart Catheterization (within 90 days of procedure) 

23 
  V2.3  24 Apr 2020 
5.2 PROCEDURE Description 
 
Procedure Assessments  
The following tests and assessments will be performed on the day of or during the procedure: 
Total procedure time is defined as the time from skin incision to the time of skin incision access closure. 
The following invasive hemodynamic data must be collected pre and post implant: 
 
• 
Echo assessments of severity of tricuspid regurgitation and RV function 
• 
Fluoroscopic imaging of the implanted valve 
• 
Medications given for cardiovascular effect including anti-platelet/anti-thrombins 
• 
Event assessment 
 
5.2.1 Placement of percutaneous aortic valve in the inferior vena cava 
 
The procedure will be performed in the cath lab/ hybrid Cath Lab/OR under general anesthesia and 
transesophageal echocardiographic as well as fluoroscopic guidance. 
 
Measurements obtained prior to the procedure 
The diameter of the IVC at the RA/IVC junction will be measured prior to the procedure by contrast CT 
or rotational cine fluoroscopy to determine sizing of the stent which will be placed in the IVC.  In order 
to avoid compromise of the hepatic veins with the valve skirt, distances from the RA/IVC junction to the 
hepatic veins will be measured by contrast CT. 
 
Procedure 
The procedure will be performed through the right or left femoral vein using standard technique.  We 
will use fluoroscopic and ultrasonographic landmarks to locate the right femoral vein and using a 
micropuncture needle for initial access, and then will place an 8F sheath in the right Common Femoral 
vein. We will than perform a cavogram using a Omniflush catheter.  The Edwards expandable sheath and 
delivery system will be placed into the right femoral vein.  A 5-French sheath will be placed in the right 
or left radial femoral artery to monitor arterial pressure and secure arterial access throughout the 
procedure, and a catheter may or may not be placed in the right internal jugular vein.  Heparin will be 
administered to achieve an activated clotting time (ACT) between 250-300s.  To achieve stable position 
of the valve in the IVC, we will perform pre-stenting of the IVC with with either a balloon expandable or 
self-expandable stent according to standard technique.  A repeat cavogram with an Omniflush catheter 
will be done to delineate the takeoff of the hepatic veins prior to valve implantation.    When positioning 
is confirmed the Edwards or balloon in balloon (BIB) delivery system will be deployed into the 
suprahepatic segment of the IVC by standard technique.  Right ventricular (RV) angiography from IJ 
access and echocardiogram will be performed to confirm intact valve function and any evidence of 
regurgitation.  At the end of the procedure, the venous sheath will be removed and perclose devices will 
be deployed or a figure of 8 suture will be used to achieve adequate hemostasis.  The arterial sheath will 
be removed with closure devices or with direct manual pressure. 
 
Anticoagulation Regimen: 
Pre-procedure: Patients in atrial fibrillation on warfarin may be bridged with LMW or UF heparin prior to 
the procedure.  During the procedure: IV heparin will be given to maintain ACT > 250 sec.  Patients may 
be bridged to a therapeutic INR with either heparin or Lovenox post-procedurally. 
 
 

24 
  V2.3  24 Apr 2020 
Recommended Antiplatelet/Anticoagulation Regimen  
Aspirin 81 mg p.o. daily indefinitely plus warfarin therapy to maintain an INR between 2-3.  In those 
patients with severe hepatic dysfunction whom have elevated INR at baseline, ASA 81mg will be 
continued and the level of additional anti-coagulation will be decided on a case by case basis. 
 
Radiation precautions: 
Radiation exposure will be documented at each study visit in the CRF, with options to record whether 
chest x-ray, including additional plain x-rays, CT scans and all fluoroscopy procedures were performed. 
In the event that a dose isn’t recorded; such as a plain X-ray, an average dose will be assigned for each 
applicable test. A trigger will be applied in the database such that when the cumulative estimated 
radiation exposure calculation exceeds 150 to 250 Gy/cm2. 
Additional precautions: for any study patient, the site coordinator and investigator will be notified and a 
follow-up visit advised to assess patient for skin reaction. Substantial radiation dose level (SRDL) - The 
operator should be notified promptly if SRDL was exceeded. The SRDL is a trigger level to initiate follow-
up of a radiation dose that might produce a clinically relevant injury in an average patient. Some 
suggested values for the SRDL are a skin dose of 3 Gy, a KAP of 500 Gy/cm2, or an air kerma at the 
interventional reference point of 5 Gy (NCRP 2010). For cardiology procedures, a level greater than 2Gy 
will be noted and close follow up will be performed to evaluate for skin toxicity. 
 The operator should write an appropriate note in the patient's medical record, stating that a substantial 
radiation dose has been administered, and indicating the reason. This information may be included in 
the post procedure notes. Patients with reported KAP between 150 and 250 Gy/cm2 must be further 
evaluated for radiation injury and the event must be reported as a serious adverse event in the case 
report form.  
Acute evaluation - When the SRDL has been exceeded, clinical follow-up essential for early detection 
and management of skin injuries. The patient should be advised of the possibility of a skin injury due to 
a tissue reaction, and should be told to examine the beam entrance site at 2-4 weeks after the 
procedure. The operator should be notified if any skin changes are seen. Patients who have not 
previously notified the operator should be contacted by telephone at approximately 30 days after the 
procedure, in order to ensure that a skin injury is not missed. 
Long-term evaluation - If a skin injury is suspected, the interventionalist should see the patient at an 
office visit, and should arrange for appropriate follow-up care. The physician responsible for the 
patient's care should be informed of the possibility of radiation effects. 
 
5.3 Post-Procedure assessments: 
Study patients will be continuously monitored clinically, hemodynamically, and electrocardiographically 
during catheterization for all local, systemic side effects and complications. After completion of the 
procedure, patients will be admitted to the hospital for further monitoring.     
• 
Physical Exam.  This will include vital signs and weight, head, ears, eyes, nose and throat 
(HEENT), neck, lungs, cardiovascular, abdomen, genitourinary, gastrointestinal, musculoskeletal, 
neurological 
• 
NYHA functional Class as per The Criteria Committee of the New York Heart Association. 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. 
Boston, Mass: Little, Brown & Co; 1994:253-256 
• 
Diuretic types and doses 
• 
Event assessment as per VARC-2 19. 
 
 
 

25 
  V2.3  24 Apr 2020 
Laboratory Measurements 
• 
CBC with differential 
• 
Cardiac Enzymes (Troponin I and/or CK and CKMB) every 8 hours x3 
• 
Comprehensive metabolic panel 
• 
 Lactate Dehydrogenase (LDH)  
• 
ACT (optional) 
• 
PT/INR 
• 
Brain Natriuretic Peptide (BNP) 
Non-Invasive Tests 
• 
ECG 
• 
Echocardiogram (Transthoracic) 
 
 
5.4 Discharge Procedures 
The following data will be collected for all study patients as close to the date of discharge as possible.  A 
post-procedure echocardiogram will also be performed prior to discharge.  If a patient is discharged over 
a weekend or holiday, the discharge tests may be completed on the last weekday prior to discharge. 
Systems: 
• 
Physical Exam.  This will include vital signs and weight, head, ears, eyes, nose and throat 
(HEENT), neck, lungs, cardiovascular, abdomen, genitourinary, gastrointestinal, musculoskeletal, 
neurological 
• 
NYHA functional Class as per The Criteria Committee of the New York Heart Association. 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. 
Boston, Mass: Little, Brown & Co; 1994:253-256 
• 
Diuretic types and doses 
• 
Event assessment as per VARC-2 19. 
Laboratory Measurements 
• 
CBC with differential 
• 
Comprehensive metabolic panel 
• 
Brain Natriuretic Peptide (BNP) 
• 
Haptoglobin 
• 
 Lactate dehydrogenase (LDH) 
 
 
5.5 Follow-Up Procedures 
Patients will follow up at 1, 6 and 12 months with a member of the study team.  The following 
information will be collected at follow up visits. 
Systems: 
• 
Physical Exam.  This will include vital signs and weight, head, ears, eyes, nose and throat 
(HEENT), neck, lungs, cardiovascular, abdomen, genitourinary, gastrointestinal, musculoskeletal, 
neurological 
• 
NYHA functional Class as per The Criteria Committee of the New York Heart Association. 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. 
Boston, Mass: Little, Brown & Co; 1994:253-256 
• 
Diuretic types and doses 
• 
Event assessment as per VARC-2 19. 
 

26 
  V2.3  24 Apr 2020 
Laboratory Measurements 
• 
CBC with differential 
• 
Comprehensive metabolic panel 
• 
Brain Natriuretic Peptide (BNP) 
• 
Haptoglobin 
• 
 Lactate Dehydrogenase  (LDH) 
Non-Invasive Tests 
• 
ECG 
• 
Chest X-ray (portable or PA and lateral) 
• 
Echocardiogram (Transthoracic) 
• 
Chest and Abdominal CT (6-months only) 
• 
Cardiopulmonary Exercise Stress test 32 (6-months only) 
Functional Assessments 
• 
6-minute walk test 33 
• 
Villalta Scale 25,26 
• 
EORTC QLQ-C30 27 
• 
ESAS-AM 28 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 22 
Invasive studies 
• 
Right heart catheterization (6-months only) 
 
5.6 Annual Study Visit, Final Study Visit, premature discontinuation or unscheduled study visit 
The following variables will be collected for the above parameters. 
• 
Physical Exam.  This will include vital signs and weight, head, ears, eyes, nose and throat 
(HEENT), neck, lungs, cardiovascular, abdomen, genitourinary, gastrointestinal, musculoskeletal, 
neurological 
• 
NYHA functional Class as per The Criteria Committee of the New York Heart Association. 
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. 
Boston, Mass: Little, Brown & Co; 1994:253-256 
• 
Diuretic types and doses 
• 
Event assessment as per VARC-2 19. 
 
Table 1:  Summary Schedule of Procedure and Follow-Up 
Baseline 
During the 
procedure 
 
24 hrs. after the 
procedure 
7 days after 
procedure or at 
discharge 
At 30 days 
(+/- 7 days) 
At 6 months 
(+/- 14 days) 
At 1 yr 
(+/- 21 days) 
Annually up to 5 
years (+/- 21 day) 
Premature 
discontinuation or 
unscheduled visit 
Informed Consent 
Xb† 
 
 
 
 
 
 
 
 
Medical History 
Xb† 
 
 
 
 
 
 
 
 
Physical Exam (incl. Vital 
signs) 
Xb† 
 
X 
X 
X 
X 
X 
X 
X 
NYHA Class 
Xb† 
 
X 
X 
X 
X 
X 
X 
X 
Diuretic types and doses 
Xb† 
 
X 
X 
X 
X 
X 
X 
X 
Event Assessment 
Xb 
 
X 
X 
X 
X 
X 
X 
X 
Surgical note 
documenting high 
risk/inoperable status 
Xb† 
 
 
 
 
 
 
 
 

27 
  V2.3  24 Apr 2020 
Laboratory 
Measurements 
 
 
 
 
 
 
 
 
 
CBC with Differential 
Xd 
 
x 
X 
 
X 
X 
 
 
Cardiac Enzymes 
(Troponin I and/or CK and 
CK-MB) 
Xe 
 
X (every 
8 hours 
x 3) 
 
 
 
 
 
 
Comprehensive Metabolic 
Panel 
Xb† 
 
X 
X 
X 
X 
X 
 
 
 LDH  (to assess 
hemolysis) 
Xc 
 
X 
X 
X 
X 
X 
 
 
ACT^ 
 
X* 
X* 
 
 
 
 
 
 
aPTT  
Xc 
X* 
 
 
 
 
 
 
 
PT/ INR  
Xb† 
 
X 
 
 
 
 
 
 
Brain Natriuretic Peptide 
(BNP) 
Xc 
 
x 
X 
X 
X 
X 
 
 
Haptoglobin 
Xc 
 
 
X 
X 
X 
X 
 
 
Non-Invasive Tests 
 
 
 
 
 
 
 
 
 
ECG 
Xc 
 
X 
 
X 
X 
X 
 
 
Chest X-ray 
Xc 
 
 
 
X 
X 
X 
 
 
Echocardiogram - TTE or 
TEE 
Xb† 
X 
X 
 
X 
X 
X 
 
 
Chest and/or Abdominal 
CT 
Xa† 
 
 
 
 
X 
 
 
 
Cardiopulmonary Exercise 
Stress test 
Xb 
 
 
 
 
X 
 
 
 
Venous Lower Extremity 
Duplex Study 
Xc 
 
 
 
 
 
 
 
 
Pulmonary Function Test 
(PFT) 
Xb† 
 
 
 
 
 
 
 
 
Functional Assessments 
 
 
 
 
 
 
 
 
 
6-Minute Walk Test 
Xb 
 
 
 
X 
X 
X 
 
 
Quality of Life (Kansas 
City Cardiomyopathy 
Questionnaire (KCCQ) 
Xc 
 
 
 
X 
X 
X 
 
 
Villalta Scale 
Xc 
 
 
 
X 
X 
X 
 
 
EORTC QLQ-C30  
Xc 
 
 
 
X 
X 
X 
 
 
ESAS-AM 
Xc 
 
 
 
X 
X 
X 
 
 
Invasive Tests 
 
 
 
 
 
 
 
 
 
Left Heart Catheterization 
w/wo LV gram and IVUSa 
Xa† 
X* 
 
 
 
 
 
 
 
Right Heart 
Catheterization 
Xb† 
X 
 
 
 
X 
 
 
 
 
a.        The following assessment will be collected within one year of procedure day.   
b. 
The following assessments will be completed within 90 days before the procedure day  
c. 
The following assessments will be completed within 21 days before the procedure. 
d. 
The following assessment needs to be done during the 6 months screening and within 21 days 
               before the procedure.    
e. 
CK/CKMB and/or Troponins ≤ 72 hours before the procedure 
f.             Right heart catheterization only 
*             Optional 
† 
Required prior to Heart Team and Executive Committee meetings to determine eligibility 
 
 

28 
  V2.3  24 Apr 2020 
5.7  Patient Withdrawal 
All study patients are required to complete clinical follow-up for all designated study visits. A careful 
review of these requirements must be communicated to the patient and family members prior to 
obtaining the study consent. Patients who cannot make study visits due to physical or geographical 
constraints should be encouraged to complete as many assessments within the planned visit as possible. 
A study patient that has been withdrawn from the study will not be replaced and may impact the ITT 
analysis. 
 
Every patient should be encouraged to remain in the study until they have completed the protocol 
required follow-up period. If the patient discontinues prematurely from the study, the reason for 
discontinuation must be documented. Possible reasons for premature discontinuation may include, but 
are not limited to the following: 
• Withdrawal of consent: Patient decides to withdraw from the study. 
• Lost to follow-up: All patients should be encouraged to return to the clinic for evaluation during long 
term follow-up. The patient will be considered lost to follow-up if this communication is unsuccessful. 
Patients who discontinue prematurely will be included in the analysis of results, and will not be 
replaced. 
• Death registries: In the event of a patient withdrawal or lost to follow-up, the sponsor may opt to 
obtain the death certificate, search the Social Security Death Index and/or other death registries to 
obtain survival information. 
 
 
6.0 ADMINISTRATIVE RESPONSIBILITIES 
 
6.1 Institutional Review Board (IRB) Information 
This protocol and the informed consent must be reviewed and approved by the appropriate IRB before 
enrollment of patients.  All changes to the protocol must be approved in writing by the IRB before the 
change is implemented. 
 
6.1.1 Institutional Review Board Approval Letter 
Institutional Review Board (IRB) approval to participate in this trial is required from each institution 
participating in this investigation. Prior to patient enrollment, a signed copy of the IRB approval letter 
must be submitted to the sponsor investigator certifying trial approval. Investigators are responsible for 
submitting and obtaining initial and continuing review of the trial at least annually unless otherwise 
directed by their IRB. 
 
6.2 Informed Consent 
Informed consent is mandatory and must be obtained from all study patients prior to their participation 
in this trial.  Any modifications to the Informed Consent Form must be approved by the IRB. A copy of 
the IRB approved Informed Consent Form along with a copy of each patient’s signed consent form must 
be maintained by each investigator in a designated clinical trial administrative file. A signed copy of the 
consent form must be given to each patient. 
 
6.3 Confidentiality 
All information and data collected in this trial will be considered confidential.  Only authorized data 
management center personnel will have access to these confidential files. Authorized personnel from 
the regulatory authorities have the right to inspect and copy all records pertinent to this trial. All data 
used in the analysis and reporting of this evaluation will be without identifiable reference to the patient. 

29 
  V2.3  24 Apr 2020 
7.0 ADVERSE EVENT REPORTING 
 
7.1  Adverse events: 
An adverse event (AE) is any untoward medical event in a patient and does not necessarily have a causal 
relationship with the use of the device.  Symptoms or medically significant laboratory or instrumental 
abnormalities of a preexisting disease, such as hypertension or other disease, should not be considered 
adverse events but must be documented in the medical history if clinically significant. New symptoms or 
laboratory abnormalities, however, as well as worsening of existing ones, are considered adverse 
events.  Study device causality for adverse events will be graded as unlikely, possible or probably.  
 
7.2  Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that: 
• results in death 
• is life-threatening, i.e., an event that, in the view of the investigator, places the subject at immediate 
risk of death from the event as it occurred (it does not include an event that could have caused death if 
it had been more severe) 
• requires inpatient hospitalization or prolongs the existing hospitalization 
• results in persistent or significant disability or incapacity, where disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions, either reported or defined as per clinical 
judgment 
• is a congenital anomaly or birth defect (if exposure to product just before conception or during 
pregnancy resulted in an adverse outcome in the child) 
 
All investigators will be responsible for reporting serious adverse events to the sponsor and their 
reviewing IRBs in accordance with local guidelines. In addition, all SAEs will be reviewed by an 
independent Data Safety Monitoring Board (DSMB) in accordance with their charter. (An SAE will be 
reported to the Sponsor and DSMB Chair within 24 hours from when the event was discovered and the 
SAE CRF will be submitted no later than ten (10) days after the SAE was discovered)  Study device 
causality for SAE’s will be graded as unlikely, possible or probably. 
 
7.3  Non-Serious Adverse Events  
A non-serious adverse event is any AE that does not meet the criteria listed above for a serious adverse 
event, or the outcome (subject treatment, life-threatening condition, hospitalization, recovery) cannot 
be determined with the information provided. Non-serious AEs will be documented on the AE log and 
will be reported to IRB per local regulations. 
 
7.4 Unanticipated Adverse Events 
An unanticipated adverse event is an AE for which the nature or severity are not consistent with the 
applicable product information (refer to IFU and on-label use).  Unanticipated adverse events are to be 
reported to the study sponsor, each reviewing IRB, and the FDA, no later than ten (10) days after the 
date the adverse event was discovered. The coordinating center will be responsible for the 
communication with the regulatory bodies.  
 
7.5  Anticipated Adverse Events 
An anticipated adverse event is an AE for which the nature and severity are consistent with the 
applicable product information (e.g. Package insert/summary of product characteristics for an approved 
product). This term relates only to the treatment, not the patient’s underlying condition. 
 

30 
  V2.3  24 Apr 2020 
7.6  Unanticipated Adverse Device Effects 
Unanticipated adverse device effects (UADE) are defined as any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
study patients. 
 
All UADEs must be reported to the FDA immediately upon the Investigator’s awareness of the event. The 
AE Forms of the CRF must be completed with 7 working days for all UADEs. The Investigator is also 
responsible for notifying his/her IRB of all UADEs occurring at his/her site no later than 10 days after the 
investigator first learns of the effect (and any additional information as required by EC/IRB or local 
regulations). All UADE adverse events must be followed until resolution or until a stable clinical endpoint 
is reached. All required treatments and outcomes of the UADE adverse event must be recorded. 
 
 
7.7  Adverse Event Follow-up 
All adverse events occurring within the follow-up period (whether serious, non-serious, unanticipated, 
or anticipated) will be monitored and documented according to the follow-up. To be compliant with 
ethical and regulatory principles, treatment-related SAEs that occur after follow-up is completed 
(outside the protocol) and are assessed by the investigator as “unanticipated” must be updated to the 
FDA via the MAUDE reporting system in accordance with FDA regulations 
 
 
8.0 DATA MONITORING AND QUALITY CONTROL 
 
8.1 Case Report Forms (CRFs) 
Case report forms (CRFs, see addendum) will be generated, based on the investigational plan. An 
electronic clinical trial management system (RedCap, Vanderbilt U, TN) will be used to collect all patient 
data during the trial by the data coordinators or their designee.  Data will be collected in a paper form or 
in electronic format and entered into the electronic clinical trial management system.  Paper forms will 
be kept in a secure location and only accessible to the data coordinator or investigator. 
 
8.2 Data Reporting 
The Investigator or his/her designee is responsible for recording all data from the trial onto the CRFs. 
Completed CRFs will be reviewed at regular intervals throughout the trial. To this end, the Investigator 
must permit inspection of the trial paper files and patient CRFs by such representatives and/or 
responsible government agencies including the FDA or DMSB.  
 
 
 
8.3 Data Review 
All CRFs will be thoroughly reviewed and all missing or unclear data will be adjudicated by the 
investigator or his designee throughout the study.  Any data which has not been collected or is 
unavailable will also be noted. For purposes of safety review the DMSB will have access to all necessary 
safety and event data. 
 
 

31 
  V2.3  24 Apr 2020 
8.4 Records 
Records to be maintained by the site investigator include: 
• 
Correspondence 
o IRB Correspondence (incl. IRB approval) 
o Sponsor correspondence 
o General correspondence 
• 
Study documents 
o Clinical protocol including all amendments 
o Informed consent and HIPAA authorization 
o Sample case report form (database) 
o Instruction for use (device) 
o Statement of investigator 
o Laboratory certifications 
o Laboratory reference ranges 
• 
Study tracking logs  
o Subject logs 
o Adverse events and unanticipated adverse device effects log 
o Device accountability log 
o Monitoring log 
• 
Research personnel 
o PI (site PI): 
 
curriculum vitae 
 
current medical license 
 
human subject protection training document 
 
conflict of interest or financial disclosure form(s) 
o Sub-PI: 
 
curriculum vitae 
 
current medical license 
 
human subject protection training document 
 
conflict of interest or financial disclosure form(s) 
o Signature and delegation of responsibility log 
• 
For sites that are using a local IRB 
o IRB compliance document (FWA) 
• 
Bi-annual reports to the FDA 
 
The following records must be maintained for each patient enrolled in the trial: 
• Signed Patient Informed Consent Form; 
• All completed CRFs; 
• Supporting documentation of any complications or serious adverse events.  
 
 
Investigator’s Final Report 
Upon completion or termination of the HOVER study, the overall Principal Investigator must submit a 
final written report to the FDA and the IRB. The report must be submitted within 3 months (90 days) of 
completion or termination of the trial. 
 
 

32 
  V2.3  24 Apr 2020 
Protocol Deviations/Violations  
The investigator will not deviate from the protocol without the prior written approval of the IRB except 
where necessary to eliminate an apparent immediate hazard. 
 
9.0 ETHICAL AND REGULATORY CONSIDERATIONS 
 
9.1 Role of the Sponsor investigator 
The sponsor investigator has the overall responsibility for the conduct of the study, including assurance 
that the study meets the regulatory requirements of the appropriate regulatory bodies. In this study, the 
sponsor will have certain direct responsibilities and may delegate other responsibilities to the study 
coordinator or other investigators. 
 
9.2  General Duties 
The Sponsor's general duties consist of submitting the appropriate regulatory applications, obtaining IRB 
or Ethics Committee approval, selecting investigators, ensuring proper clinical site monitoring and 
ensuring study patient informed consent is obtained.  Based on data collected from the study, the 
sponsor will prepare written progress reports and a final report.  
 
9.3 Selection of Investigators 
The Sponsor will select qualified investigators, obtain a signed Investigator’s Agreement and provide the 
investigators with the information necessary to conduct the study. 
 
9.4 Monitoring (See also Monitoring Plan) 
The Sponsor or its designee, will monitor the study to ensure compliance with the protocol and the 
Investigator’s Agreement.  The sponsor will evaluate circumstances where an investigator deviates from 
the clinical protocol and will retain the right to remove the investigator from the study. The Sponsor will 
review significant new information, including unanticipated adverse events and ensure that such 
information is provided to the DMSB, study investigators and to all reviewing IRB/ECs. 
 
9.5 Supplemental Applications 
As appropriate, the principal investigator will submit changes in the Investigational Plan to the 
regulatory authority. The principal investigator will submit all changes in the Investigational Plan to 
investigators to obtain IRB re-approval.   
 
9.6 Maintaining Records 
 
The Sponsor will maintain copies of correspondence, all data, adverse device effects and other records 
related to the clinical trial as appropriate.  
 
9.7 Submitting Reports 
The Sponsor will submit all reports required by the appropriate regulatory authorities, including 
unanticipated adverse device effects, withdrawal of IRB approval, current investigators list, annual 
progress reports, final reports protocol violations.  
 
9.8 Informed Consent 
All study patients must personally provide written informed consent.  Copies of the informed consent 
form must be maintained for the duration of the study. One copy will reside in the medical chart, one 
copy will be provided to the patient, and the original resides in the regulatory binder on site. The IRB 
approval letter for the study will also be maintained. The study patient has been informed of the nature 

33 
  V2.3  24 Apr 2020 
of the study, agrees to its provisions and has provided written informed consent as approved by the 
Institutional Review Board (IRB) of the respective clinical site. 
 
10.0  STUDY DATA REPORTING AND PROCESSING 
 
10.1  Data Processing and Quality Control 
The online database will reside on a central server accessible through the Internet.  It will be password 
protected and available only the investigators and study personnel.   The database will be protected by 
whole disk encryption. 
 
10.2  Data Entry 
The data entry is performed by study personnel on a secured and dedicated website. All data entered is 
subjected to data type verification.  
 
10.3  Data Cleaning 
All CRFs will be subjected to initial inspection for omitted data, data inconsistencies, and deviations. The 
resolution of data inconsistencies will be done by the investigators or other data management 
specialists. 
 
10.4  Data Editing 
Corrections to the CRFs will be made by the research coordinator, and approved by the investigator or 
designee. 
 
10.5  Confidentiality and Protection of Study Files 
Passwords will be issued to appropriate data management personnel to ensure confidentiality and 
protection of the data by allowing variable levels of access to the computer system. 
 
10.6  Coordinating Center 
Henry Ford Hospital, Detroit, MI will serve as the coordinating center, providing administrative, 
regulatory, and statistical support for the trial.  Henry Ford Hospital staff will coordinate activities across 
the HOVER sites and will perform the following functions: 
• 
Participate in study start-up site inservicing and training; 
• 
Ongoing site monitoring to assure compliance with federal regulations and GCP; 
• 
Oversight of compliance with IRB requirements, including initial and continuing review 
approvals, modifications and Serious Adverse Event submissions; 
• 
Coordination of DSMB meetings and communications; 
• 
Registration and updates on clinicaltrials.gov; 
• 
Oversee data collection and verification via RedCap; 
• 
Perform statistical analyses; 
• 
Perform study close out activities; 
• 
Execute and administer contractual/financial agreements between Henry Ford Hospital and the 
other sites; 
• 
Liaison between investigator, FDA, IRB, DSMB and study sites. 

34 
  V2.3  24 Apr 2020 
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Passantino A, Lagioia R, Mastropasqua F, Scrutinio D. Short-term change in distance walked in 6 
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of the American College of Cardiology. 2006;48(1):99-105. 
24. 
Swank AM, Horton J, Fleg JL, et al. Modest increase in peak VO2 is related to better clinical 
outcomes in chronic heart failure patients: results from heart failure and a controlled trial to 
investigate outcomes of exercise training. Circ Heart Fail. 2012;5(5):579-585. 
25. 
Kahn SR. Measurement properties of the Villalta scale to define and classify the severity of the 
post-thrombotic syndrome. J Thromb Haemost. 2009;7(5):884-888. 
26. 
O'Donnell MJ, McRae S, Kahn SR, et al. Evaluation of a venous-return assist device to treat 
severe post-thrombotic syndrome (VENOPTS). A randomized controlled trial. Thromb Haemost. 
2008;99(3):623-629. 
27. 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst. 1993;85(5):365-376. 
28. 
Easson AM, Bezjak A, Ross S, Wright JG. The ability of existing questionnaires to measure 
symptom change after paracentesis for symptomatic ascites. Ann Surg Oncol. 2007;14(8):2348-
2357. 
29. 
Schunemann HJ, Dorn J, Grant BJ, Winkelstein W, Jr., Trevisan M. Pulmonary function is a long-
term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health 
Study. Chest. 2000;118(3):656-664. 
30. 
Dunn W, Jamil LH, Brown LS, et al. MELD accurately predicts mortality in patients with alcoholic 
hepatitis. Hepatology. 2005;41(2):353-358. 
31. 
Iscan ZH, Vural KM, Bahar I, Mavioglu L, Saritas A. What to expect after tricuspid valve 
replacement? Long-term results. European journal of cardio-thoracic surgery : official journal of 
the European Association for Cardio-thoracic Surgery. 2007;32(2):296-300. 

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32. 
American Thoracic S, American College of Chest P. ATS/ACCP Statement on cardiopulmonary 
exercise testing. Am J Respir Crit Care Med. 2003;167(2):211-277. 
33. 
Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. Am J Respir 
Crit Care Med. 2002;166(1):111-117. 
 
 
 

39 
  V2.3  24 Apr 2020 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE OF RESEARCH STUDY: The HOVER Study:  Heterotopic Implantation Of the Sapien 3 Transcatheter 
Aortic Valve in the Inferior VEna cava for the treatment of severe tricuspid Regurgitation.  
 
PROTOCOL NO:  Version 2.3 
WIRB® Protocol #20161648 
 
SPONSOR: Henry Ford Hospital 
 
LEAD INVESTIGATOR and SITE:  
Brian O’Neill, MD 
Henry Ford Hospital 
Center for Structural Heart Disease 
2799 West Grand Blvd. 
Clara Ford Pavilion # 440 
Detroit, MI 48202 
313-970-6483 (p) 
313-916-2819 (f) 
 
 
LOCAL INVESTIGATOR/study doctor:  {First, Last Name, Degree} 
 
LOCAL SITE: { Name, Department, and Address where patients will be seen} 
 
LOCAL STUDY-RELATED PHONE NUMBER(S): 
         DAYTIME PHONE NUMBER: 
         24-HOUR EMERGENCY PHONE NUMBER: 
 
 
 
Why you are being invited to take part in a research study 
Your tricuspid valve is very leaky. This leakiness is causing symptoms, such as shortness of breath, and 
swelling in your legs or stomach. This leakiness may be affecting the other organs in your body. If the 
valve is not fixed, you will continue to have these problems. 
 
The current standard treatment is to repair or replace the leaking valve with an artificial valve using 
open heart surgery. However, you are at a very high risk of experiencing serious complications from this 
treatment. Because of this, we invite you to take part in a research study investigating a way to replace 
the function of the tricuspid valve without using open heart surgery. Instead, the valve is replaced 
during a cardiac catheterization where an artificial valve is inserted through a large vein in your body. 
Your old tricuspid valve will not be replaced as is the normal practice with surgery.  Instead, a valve will 
be inserted into your body which will assist your leaky valve with its function.  The valve used in this 
research study is FDA-approved to replace the aortic valve. It is designed to replace the aortic valve, not 
the tricuspid valve. It is also designed to be inserted through an artery, not a vein. It is not FDA approved 
to use as a replacement for function of the tricuspid valve. Therefore, use of this valve in this research is 
experimental and investigational. 

40 
  V2.3  24 Apr 2020 
 
Who can I talk to? 
{Non-Henry Ford sites replace information in bolded italics with site-specific information} 
If you have questions, concerns, or complaints, or think the research has hurt you, contact the research 
team at Phone: 313-970-6483 or send a letter to 
 
Brian O’Neill, MD 
Henry Ford Hospital 
Center for Structural Heart Disease 
2799 West Grand Blvd. 
Clara Ford Pavilion # 440 
Detroit, MI 48202 
 
 
This research has been reviewed and approved by Western Institutional Review Board. You may talk to 
them at 1-800-562-4789 or 360-252-2500, 1019 39th Avenue SE Suite 120, Puyallup Washington 98374-
2115, or e-mail them at: Help@wirb.com for any of the following: 
 
• 
Your questions, concerns, or complaints are not being answered by the research team. 
• 
You cannot reach the research team. 
• 
You want to talk to someone besides the research team. 
• 
You have questions about your rights as a research subject. 
• 
You want to get information or provide input about this research. 
 
WIRB is a group of people who perform independent review of research. 
 
WIRB will not be able to answer some study-specific questions, such as questions about appointment 
times.  However, you may contact WIRB if the research staff cannot be reached or if you wish to talk to 
someone other than the research staff. 
 
Disclosure Of Potential Conflict Of Interest 
In addition to serving as the principal investigator (PI) on the study, Dr. Brian O’Neill also serves as a 
consultant for Edwards Lifesciences LLC. In this position he receives funding from Edwards for his 
expertise. Edwards is providing partial financial support for this study in form of a research grant. 
Involvement as a consultant is independent of this study and has no financial relationship to the 
enrollment or conduct of this study. Although none of the Henry Ford Health System doctors are 
supposed to let his/her financial interests affect the study, this may not always be possible. 
The investigator(s) in this study are also healthcare providers. They are interested in the knowledge to 
be gained from this study and are interested in your well-being. Henry Ford Health System receives 
funding from Edwards in form of a research grant to support this research study. However, investigators 
do not receive salary or other financial support from Edwards in exchange for conducting this study.  
 
 
 

41 
  V2.3  24 Apr 2020 
Why are we doing this research? 
Blood that flows between different chambers of your heart must flow through a heart valve. These 
valves open up enough so that blood can flow through. They then close, keeping blood from flowing 
backward. 
 
The tricuspid valve separates the right lower heart chamber (the right ventricle) from the right upper 
heart chamber (right atrium). 
 
Tricuspid regurgitation is a disorder in which this valve does not close tightly enough. This problem 
causes blood to flow backward into the right upper heart chamber (atrium) when the right lower heart 
chamber (ventricle) contracts. 
 
 
 
 
The current standard treatment is to repair or replace the leaking valve with an artificial value using 
open heart surgery. However, some patients are too sick to undergo surgery. 

42 
  V2.3  24 Apr 2020 
 
A few years ago, the FDA approved a new method to treat seriously diseased aortic valves. This 
procedure repairs the aortic valve without removing the old, damaged valve. Instead, it wedges a 
replacement valve into the aortic valve’s place. The procedure is called a transcatheter aortic valve 
replacement (TAVR) or transcatheter aortic valve implantation (TAVI). 
 
Transcatheter aortic valve replacement involves threading a catheter through an artery into the heart 
and then threading a collapsed replacement valve to the valve site through a catheter. Once the new 
valve is expanded, it pushes the old valve out of the way and the replacement valve takes over the job of 
regulating blood flow. 
 
The Edwards SAPIEN 3TM (S3) Transcatheter Heart Valve are valves that are FDA-approved for 
transcatheter aortic valve replacement. The Edwards SAPIEN 3TM Transcatheter Heart Valve is not FDA 
approved to surgically implant to replace the function of the tricuspid valve.  Therefore, use of the The 
Edwards SAPIEN 3TM Transcatheter Heart Valve in this research is experimental and investigational. 
 
The purpose of this research is to try using the The Edwards SAPIEN 3TM Transcatheter Heart Valve as an 
implant to replace the function of the triscuspid valve. The Edwards SAPIEN 3TM Transcatheter Heart 
Valve is designed to replace the aortic valve, not the tricuspid valve. It is also designed to be inserted 
through an artery, not a vein. This research will place the valve at the junction of the inferior vena cava 
(large vein that drains the lower body) and the heart to prevent blood from the heart from flowing 
backwards to the lower body. This research will be the first time the safety and effectiveness of using 
the The Edwards SAPIEN 3TM Transcatheter Heart Valve as a replacement for the function of the 
tricuspid valve is tested in humans as part of a clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
There is very limited experience with surgically implanting the The Edwards SAPIEN 3TM (S3) 
Transcatheter Heart Valve to replace the function of the tricuspid valve with fewer than thirty patients 
reported in the literature. The research team at the lead investigative site has used this valve to replace 
the aortic valve. However, before starting this research study, Dr. O’Neill, who is also the lead principal 
investigator, has performed research into the field of transcatheter valve replacement.  In preparation 
for this research protocol, Dr. O’Neill performed extensive research into the field including a review of 
all the literature available.  He has spoken with physicians who are performing this procedure in 
Germany, and also participated in the first procedure which was performed in the United States.  Dr. 
O’Neill has worked closely with your doctors participating in this study along with an excellent team of 
cardiothoracic surgeons who have performed hundreds of tricuspid valve replacements over the years, 
and who will be involved in all parts of your workup and procedure.   
 
 

43 
  V2.3  24 Apr 2020 
How long will the research last? 
We expect that you will be in this research study for up to 5 years. You will have a visit with one of the 
doctors involved in the research study at 30-days, 6-months, and 1 year, and then annually after that for 
up to 5 years. In addition to scheduled visits, you may also be contacted via the telephone in-between 
visits to see how you are doing and schedule your follow–up visits. 
 
How many people will be studied? 
This study will take place at several institutions. We expect up to 15 people in total to be enrolled in the 
research study.   Up to 10 patients will be enrolled at this institution. 
 
Do I have to participate? 
Your participation in this study is voluntary.  You may decide not to participate or you may leave the 
study at any time.  Your decision will not result in any penalty or loss of benefits to which you are 
entitled. 
 
Your participation in this study may be stopped at any time by the study doctor or the sponsor without your 
consent for any reason, including: 
• 
if it is in your best interest; 
• 
If you do not consent to continue in the study after being told of changes in the research that may 
affect you. 
 
What happens if I say yes, I want to be in this research? 
If you choose to be included in the study, you will have the following studies performed if they have not 
already been done as part of your regular clinical care, to determine if you would meet the criteria for 
inclusion in the study. 
 
 
Prior to the Procedure 
o Physical Exam including vital signs 
o NYHA classification 
o 12-Lead Electrocardiogram (EKG) 
o Chest X-ray 
o Echocardiogram (heart ultrasound) 
o CT scan (computed axial tomography) of your chest, abdomen, and pelvis 
o Cardiopulmonary exercise stress test (VO2) 
o Lower extremity venous dopplers 
o 6-minute walk test 
o Right heart catheterization, intravascular ultrasound of the inferior vena cava and right 
ventriculogram 
o Left heart catheterization 
o Quality of Life Assessment (Kansas City Cardiomyopathy Questionnaire KCCQ) 
o ESAS:AM and EORTC QLQ-C30 questionnaire 
o Formal Frailty Assessment 
o Villalta Scale 
 
Clinical laboratory tests including 
o Comprehensive metabolic panel 
o CBC with differential and platelet count 

44 
  V2.3  24 Apr 2020 
o Liver panel including AST and ALT 
o Albumin 
o B-type natriuretic peptide (BNP) 
o  LDH 
o Haptoglobin 
o PTT or PT/INR 
o CK/CKMB and/or Troponins ≤ 72 hours before the procedure 
 
At your subsequent follow up visits 
o NYHA classification 
o Standard 12-lead ECG 
o Comprehensive transthoracic echocardiogram (TTE) 
o Clinical laboratory tests (see above) 
o Functional Assessments: 
o 6-minute walk test 
o Quality of Life Assessment (Kansas City Cardiomyopathy Questionnaire KCCQ) 
o Chest X-ray examination 
o CT scan (at 6-month visit only) 
o ESAS:AM and EORTC QLQ-C30 questionnaires 
 
• 
Finally, you will have doctors’ visits during enrollment with a heart failure specialist, an 
interventional cardiologist, and a cardiothoracic surgeon. You will see some, if not all of these 
doctors at subsequent follow up visits. 
• 
During the procedure you will be put to sleep by the anesthesia team using medications that will 
make you sleep and prevent you from having any pain. You will also be given heparin which is a 
medication that will thin your blood during the procedure. 
• 
A metal stent will be placed in the vein leading to your heart which will allow the heart valve to 
remain implanted. After the procedure you will remain in the hospital for several days while the 
doctors work to ensure that the valve is functioning properly. 
• 
After you leave the hospital you will be seen at 30-days, 6 months, 1-year, and then annually up 
to 5 years. If you are not feeling well you may be seen on a more frequent basis by members of 
the study team or your primary care physician. 
• 
These doctor visits should only take up to 1 hour based on how you are feeling. 
• 
A total of up to 50mL of blood will be drawn from you at your follow up visits, but most likely 
less than this. 
• 
At your visits you will speak with the members of the study team and research coordinator. 
• 
It is important to understand that although studies have shown this is a safe procedure to 
perform in humans, it has not been studied extensively in a large trial which is why at this time 
the procedure is experimental. The valve which will be implanted has been studied in large scale 
clinical trials which have proved it is safe, although it has not been implanted in the position in 
which we plan for you. 
• 
After the invasive procedure is performed there are no additional invasive planned procedures 
as part of the study protocol. You will undergo routine lab testing and ultrasound as part of the 
protocol. However, if any additional invasive procedures are required, they will be explained to 
you and your consent for them will be obtained on a different form. 
• 
As there currently are no long term studies to tell us how you will improve with this procedure, 
as well as how the valve will function in the part of your body in which it will be placed, we will 

45 
  V2.3  24 Apr 2020 
be performing laboratory testing, ultrasound, and questionnaires to see how you are feeling, to 
see how your body responds to the valve, and to ensure the valve functions properly in its 
position. 
• 
If you choose not to be included in the procedure, you will continue to have follow up 
appointments with your doctors which will likely include blood testing and ultrasound, although 
this will be decided between you and your doctor. 
 
Once you decide to participate in this trial, and if you qualify, you will be treated with the valve. If there 
are any unexpected findings from this procedure, for example a change in the way the valve functions, 
you will be notified in a timely manner and counseled regarding any additional procedures which may or 
may not need to be performed. 
 
What are my responsibilities if I take part in this research? 
If you take part in this research: 
1. You will need to follow up with the study doctors as outlined in the consent form. 
2. You will need to agree to have the follow up blood testing and other follow up testing 
performed. 
3. You will need to notify your study doctors if there is a change in how you feel to determine if 
this is due to the placement of the valve.   
4. You will need to notify the doctors if you are admitted to the hospital for any reason. 
 
This valve can form blood clots that can lead to serious life-threatening side effects. During the 
procedure you will be given drugs that will stop your blood from clotting. After the procedure you will 
need to take medicine to prevent blood clots for the rest of your life.  
 
If you expire during study participation, your family/next-of-kin will be asked to allow an autopsy. 
 
What happens if I say no, I do not want to be in this research? 
You may decide not to take part in the research and it will not be held against you. It will in no way 
affect your relationship with the study doctor. Instead of being in this research study, your choices may 
include: The continuation of your medicines for your condition, finding a surgeon who would agree to 
valve surgery and re-consideration of valve surgery if your condition should improve in the future. 
 
What happens if I say yes, but I change my mind later? 
If you agree to take part in the research now and if you decide to stop at any time, it will not be held 
against you. Again, it will in no way affect your relationship with the study doctor. 
 
If you decide to leave the research, then you may not undergo the recommended follow up to make 
sure that your body is functioning properly with the device in place. In addition, any changes in the valve 
that may affect your health may not be noticed. 
 
If you decide to leave the research, contact the investigator so that the investigator can make note of 
this and notify the proper officials who are also involved with the monitoring of the trial. 
 
If you stop being in the research, already collected data may not be removed from the study database. 
You will be asked whether the investigator can collect data from your routine medical care. If you agree, 
this data will be handled the same as research data. 
 

46 
  V2.3  24 Apr 2020 
Is there any way being in this study could be bad for me? 
We have limited knowledge about the risks of using the SAPIEN 3 Transcatheter Valve for replacement 
of the tricuspid valve. 
 
The known risks of the valve replacement procedures in general include bleeding, infection, stroke, 
death, cardiac arrest, pacemaker implantation, allergic reactions, emergency open heart surgery,  
emergency blood transfusion, prolonged hospital stay, renal failure, groin lymphocele, limb ischemia, 
myocardial infarction, and injury to adjacent structures including nerves, blood vessels, or other 
structures. 
 
Pleural effusions (excess fluid that accumulates in the space that surrounds the lungs) may occur either 
immediately post-operatively, or at follow up. 
 
There are risks associated with stenting of the vessel for valve implantation. These include migration of 
the stent and injury to the vessels of the heart or the heart itself, as well as venous thrombosis and 
stroke. 
 
You may need surgery to remove the valve. 
 
Although it is impossible to predict which, if any, of the above risks may occur with your procedure, 
based on our experience of using the Edwards SAPIEN 3TM Transcatheter Valve to replace the aortic 
valve, the likelihood of each of these risks can be best estimated as follows: 
 
Occasional: Bleeding, infection, pacemaker implantation, allergic reactions, prolonged hospital stay, 
renal failure 
 
Rare: Emergency blood transfusion, groin lymphocele, limb ischemia, myocardial infarction, injury to 
adjacent structures including nerves, blood vessels, stroke, death, cardiac arrest, emergency open heart 
surgery. 
   
The risks of using the Edwards SAPIEN 3TM Transcatheter Valve to replace the tricuspid valve may be 
different than the risks of using the Edwards SAPIEN 3TM Transcatheter Valve to replace the aortic valve. 
Because of the extremely limited experience with this procedure, the exact side effects, their severity, 
and their frequency are essentially unknown.  
 
There is a risk that the procedure may not work and may make your heart condition worse. 
 
With any new procedure, physicians get better over time. Since the physicians have no prior experience 
in performing this procedure in humans to replace the tricuspid valve, risks may occur more often or be 
more severe than when physicians have more experience in performing this procedure. 
 
Because this treatment is experimental, there may be risks that are currently unknown. These risks may 
be a minor inconvenience or severe enough to cause disability and death. 
 
The tests that you undergo in preparation for the procedure may also have risks. The known risks 
associated with each test will be explained to you. . The risks may include but are not limited to: 
bleeding, infection, stroke, death, cardiac arrest, pacemaker implantation, allergic reactions, emergency 
open heart surgery, emergency blood transfusion, prolonged hospital stay, renal failure, groin 

47 
  V2.3  24 Apr 2020 
lymphocele, limb ischemia, myocardial infarction, injury to adjacent structures including nerves, blood 
vessels, or other structures. 
 
In addition to the risks which may occur during the procedure, the following risks may be encountered 
during your workup for the procedure. 
 
• 
CT scan: There is a small risk you may have an allergic reaction with the contrast which is given 
to you during this test. This reaction can be very serious in some cases and cause death. In 
addition, there is also a risk that the contrast given to you may cause problems to your kidneys 
and you may require dialysis. 
• 
Cardiopulmonary exercise stress test: You will be monitored closely during this procedure. 
However, in rare circumstances you may suffer abnormal beating of the heart which may 
threaten your life and cause death or permanent disability. 
• 
Echocardiogram: In certain circumstances, a contrast agent may be required to evaluate your 
heart function. In rare circumstances, you may develop an allergic reaction to this contrast 
which could cause death or permanent disability. 
• 
Right and left heart catheterization: You may experience bleeding, infection, stroke, death, 
cardiac arrest, pacemaker implantation, allergic reactions, emergency open heart surgery,  
emergency blood transfusion, prolonged hospital stay, renal failure, groin lymphocele, limb 
ischemia, myocardial infarction, and injury to adjacent structures including nerves, blood 
vessels, or other structures. 
 
Although it is impossible to predict which, if any, of the aforementioned risks may occur with your 
procedure, the likelihood of each of these risks can be best estimated as follows. 
 
Being a part of this study while pregnant may expose the unborn child to significant risks as you will be 
exposed to radiation during the initial procedure, CT scan of the chest and body and chest x-ray. If you 
are a woman capable of having children, you must use a medically acceptable form of birth control. 
Medically acceptable contraceptives include: surgical sterilization (such as a tubal ligation or 
hysterectomy), approved hormonal contraceptives (such as birth control pills, patches, implants or 
injections), barrier methods (such as a condom or diaphragm) used with a spermicide, or an intrauterine 
device (IUD). Contraceptive measures such as Plan B sold for emergency use after unprotected sex is not 
an acceptable method for routine use. If you do become pregnant or have unprotected sex any time 
after signing the consent form, you must notify the study physician immediately. 
 
If you take part in this research, you will be exposed to radiation from fluoroscopy needed for the 
implantation of the experimental Edwards SAPIEN 3TM Transcatheter Valve, 3  catheterization 
procedures to prepare for implantation, a ventriculography procedure if the physician is unable to 
adequately assess your condition by echocardiogram as well as radiation from 2 chest and abdomen CT 
scans and 4 chest x-rays for stent sizing and implant follow-up. Not all parts of your body receive the 
same amount of radiation from this experimental valve implant procedure and your heart and breast 
individually receive a larger amount. Based on current scientific understanding, there is a small risk of 
causing cancer from this amount of radiation exposure. The radiation dose we have discussed is what 
you will receive from this study only and does not include any exposure you may have received or will 
receive from other tests or treatments. The additional radiation exposure is a minimal risk except for the 
fluoroscopy guidance placement where skin injury could result. 
 
 

48 
  V2.3  24 Apr 2020 
Are there costs involved with participating in this research? 
 
The investigational drug/device will not be provided by the sponsor. The cost of the device, the 
procedure to implant the device, and all supporting medical care will be billed to your insurance. Your 
insurance may not cover some or all of these procedures, in which case, the costs will be billed to you. 
Before you agree to be in the study, the research team will talk to your insurance provider and 
determine what costs are likely to be billed to you. In some cases, insurance will not pay for services 
ordinarily covered because these services were performed in a research study. 
 
You and your insurance company will be charged for the health care services that you would ordinarily 
be responsible to pay. In some cases, insurance will not pay for services ordinarily covered because 
these services were performed in a research study. You should check with your insurance to see what 
services will be covered by your insurance and what you will be responsible to pay. 
 
You will not be paid for being in this study. 
 
Will being in this study help me anyway? 
We cannot promise any benefits to you or others from taking part in this research. However, possible 
benefits include improvement in your level of energy, breathing, functioning of vital organs, functioning 
of your heart, and decreases in the amount of fluid that may have been built up in your stomach, legs, 
chest and lungs. 
 
What happens to the information we collect? 
Efforts will be made to limit your personal information, including research study and medical records, to 
people who have a need to review this information. We cannot promise complete secrecy. For example, 
though the study team has put in safeguards to protect your information, there is always a potential risk 
of loss of confidentiality. 
 
Organizations that may inspect and copy your information include the IRB, Henry Ford Hospital, Henry 
Ford Health System and its affiliates, and other representatives of these organizations, and the Food and 
Drug Administration (FDA). 
 
The, monitors, auditors, the IRB, and the Food and Drug Administration will be granted direct access to 
the portion of your medical records which are related to this research study for verification of the 
research procedures and date. You will need to sign a separate “Authorization to use and disclose your 
protected health information” to be a part of this research study. 
 
We may publish the results of this research. However, we will keep your name and other identifying 
information confidential. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
Federal law provides additional protections of your personal information. These are described in an 
attached Authorization document referred to above. 
 
 

49 
  V2.3  24 Apr 2020 
Can I be removed from the research without my permission? 
The person in charge of the research study or the sponsor can remove you from the research study 
without your approval. Possible reasons for removal include if the research being conducted is no longer 
in your best interest. The sponsor can also end the research study early. 
 
We will tell you about any new information that may affect your health, welfare, or choice to stay in the 
research. 
 
What if I am injured because of taking part in this research? 
{Non-Temple sites replace information in bolded italics with site-specific information} 
If you are injured as a result of taking part in this research, immediately notify the research team and 
they will arrange for you to get immediate medical care. There is no commitment by Henry Ford 
Hospital, Henry Ford Health System or its subsidiaries to provide monetary compensation or free 
medical care to you in the event of a research-related injury. If you have a research-related injury, 
please contact Dr. O’Neill at (313) 970-6483 during regular hours and at (313) 916-2600 after hours and 
on weekends and holidays. 
The study patient has been informed of the nature of the study, agrees to its provisions, and has 
provided consent as approved by the Institutional Review Board (IRB) of the respective clinical site. 
 
Signature Block for Adult Subject Capable of Consent 
 
Your signature documents your permission to take part in this research. 
 
 
 
 
Signature of subject 
 
Date and Time 
 
 
Printed name of subject 
 
 
 
Signature of person obtaining consent 
 
Date and Time 
 
 
 
Printed name of person obtaining consent 
 
 
 
 
 

50 
  V2.3  24 Apr 2020 
APPENDIX A:  HOVER ECHO PROTOCOL 
-left parasternal long axis 
 
-Coronary sinus dimension 
 
-proximal RVOT dimension 
 
 
 
-left parasternal RV inflow 
-2D: distinguish functional vs. degenerative/rheumatic/carcinoid TR etiologies 
 
-Color Doppler: 
 
 
-identify TR etiology 
 
 
-help identify TR severity 
 
-Vena contracta: >7 mm is in favor of severe TR; <6mm -  non-severe TR 
 
-Continuous wave Doppler  
-assess density/contour of TR signal 
-measure RVSP 
 
-left parasternal RV outflow 
 
-distal RVOT dimension 
 
-pulsed wave/continuous Doppler of RVOT (RVOT VTI) 
 
-RV stroke volume 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

51 
  V2.3  24 Apr 2020 
 
 
 
-left parasternal short axis 
-2D: distinguish functional vs. degenerative/rheumatic/carcinoid TR etiologies 
-2D: proximal/distal RVOT dimension 
 
 
-Color Doppler: 
 
 
-identify TR etiology 
 
 
-help identify TR severity 
 
-Continuous wave Doppler 
-assess density/contour of TR signal 
-measure RVSP 
 
- pulsed wave/continuous Doppler of RVOT (RVOT VTI) 
 
-RV stroke volume 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

52 
  V2.3  24 Apr 2020 
 
-Apical 4 chamber 
 
 
 
-2D: distinguish functional vs. degenerative/rheumatic/carcinoid TR etiologies 
-2D: Measure tenting area and coaptation distance 
-Coronary sinus dimension (apical 4 chamber tilted inferiorly) 
-RV TAPSE (*obtained from whichever apical view with best alignment) 
 
-Color Doppler: 
 
 
-identify TR etiology 
 
 
-help identify TR severity 
 
-PISA:  
 
 
-lower Nyquist limit to 15-40 cm/s 
-EROA >= 40 mm2 or Regurgitant Volume >= 45 mL suggestive of severe TR 
 
-Pulsed Doppler of TV inflow 
-get E/A with sample volume at TV tips; E >= 1 m/s suggests severe TR 
 
-Continuous wave Doppler 
-assess density/contour of TR signal 
-measure RVSP 
 
-RV dp/dt (from best TR signal) 
 
 
-RV lateral tricuspid annulus tissue Doppler (*obtained from whichever apical view 
with best alignment) 
 
 
 
 
 
 
 
 

53 
  V2.3  24 Apr 2020 
 
-RV Tei index (tissue Doppler) (*obtained from whichever apical view with best 
alignment) 
 
 
 
-RA volume index (via area-length or method of discs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-RV-focused apical 4-chamber 
 

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-RV basal and mid dimensions 
 
-RVEF (2D planimetry of end-sys and end-dias area)  *consider contrast 
microbubble contrast 
 
-
 
 
 
-RV global longitudinal strain 
 
 
 
 
 
-RV modified apical 4-chamber 

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-subcostal views with IVC/SVC  and R/L hepatic vein visualization 
 
-hepatic vein flow reversal 
 
-Bubble study – looking at reflux in hepatic veins 
 
-measure IVC flow and hepatic vein dimension 
 
-measure SVC flow and dimensions 
 
-measure distance between hepatic vein os and IVC-RA junction 
 
-measure RV free wall thickness 
 
-(post CAVI) identify position of Edwards-Sapien valve in relation to hepatic vein os 
and IVC-RA junction 
 
-3D TTE of TV (obtained in any view with greatest TV visualization) 
-distinguish functional vs. degenerative/rheumatic/carcinoid TR etiologies 
-Measure tenting area and coaptation distance 
-Color Doppler: 
 
 
-identify TR etiology 
 
 
-help identify TR severity 
 
-Vena contracta: EROA > 75 mm2 by 3D Color – severe TR 
 
-3D TTE of RV 
 
-quantify RV volume with full volume acquisition 
 
 
References: 
 
Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An 
Update from the American Society of Echocardiography and the European Association of 
Cardiovascular Imaging, JASE Jan 2015; 28:1-39. 
 
 
European Association of Echocardiography recommendations for the assessment of 
valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease) 
European Journal of Echocardiography (2010) 11, 307-332 
 
 
 
 
 

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APPENDIX B:  VARC-2 ENDPOINT DEFINITIONS 
 

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=
 

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APPENDIX C:  HOVER CT PROTOCOL AND PATIENT DOSE 
ESTIMATION 
 
 
Scanner:  Philips iCT 256 
 
Dose estimation for an average adult (BMI < 30 and equivalent to 32 cm. diameter water equivalent 
phantom)  
 
I. 
CT Protocol: 
 
Scan 1:  Topogram     
 
Dual projection – Cardiac chest and upper abdomen 
Centered around the diaphragm 
 
Scan 2:  Spiral Retrospectively ECG Gated acquisition  
 
Single Post-contrast phase 
FOV: Z –Axis: Superior cardiac margin down to T12 vertebra  (~10-12 cm) 
 
kVp    
 
  
-  100 kVp for BMI < 30; 120 kVp for BMI > 30 
mAs (mA)  
   
-  400(242) @ 100 kVp 
Beam collimation  
-  0.6 x 128 mm 
Pitch   
  
-  0.2 
Gantry speed 
  
-  0.27 s 
   
Contrast: Omnipaque 350 IV,  60 cc @ 5 cc/s followed by saline 30 cc @ 5 cc/s. 
Bolus track in MPA; 150 HU threshold; Minimum scan delay 
 
 
 
 
 
 
Reconstruction: 
 
Iterative reconstruction (iDose (L3) / IMR (L1) as required)  
Phases:  20%, 30%, 40% R-R interval 
Multiphase:  0 – 90%  
Axial slice thickness/overlap – 0.8 mm/50% 
COR & SAG Reconstruction 1 mm. 
Axial slice thickness 3 mm (ST Kernel) 
 
II. 
Patient Dose estimation: 
 

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Scan 
mAs2 
kV2 
CTDI vol 
mGy 
DLP 
mGy*cm. 
Z axis FOV 
cm. 
Topogram 
30 
120 
0.01 
1.5 
30 cm. 
Spiral 
400 
100 
15.4 
265 
12 cm1. 
 
Total DLP ( 1.5 + 265 ) = 266.5  mGy-cm. 
Estimated Effective Dose = 271.5  mGy-cm. x 0.015 = ~ 3.8 mSv (3.5 - 4.5 mSv) 
 
1. Z axis FOV for spiral scanning will be superior cardiac margin down to T12 vertebra.   
2. Exposure factors will be adjusted depending on the patient’s BMI (i.e. smaller than normal BMI < 20 
and larger than normal BMI > 30).  Automatic Exposure Control (Cardiac DoseRight) will be utilized as 
appropriate. 
3. Effective dose conversion factor based on European guidelines on quality criteria for computed 
tomography EUR 16262. 
 
All studies are supervised by a Board certified Radiologist.  
 
 

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APPENDIX D:  INCLUSION/EXCLUSION CHECKLIST 
I. Study Information 
 
Protocol Title: 
Heterotopic Implantation Of the Edwards-Sapien 3 Transcatheter 
Aortic Valve in the Inferior Vena cava for the treatment of severe 
tricuspid Regurgitation 
IRB Number: 
 
Principal Investigator: 
Brian O’Neill, MD 
 
 
II. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB-approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. Patients must be at least 21 years old 
 
 
      
2. The patient must have severe, 
symptomatic (ACC/AHA Stage D 
symptoms) tricuspid regurgitation (TR) 
as assessed by 2D echocardiogram with 
evidence of peripheral and central 
venous congestion (specifically lower 
extremity edema and abdominal 
ascites requiring diuretics.)    
 
 
      
3. The patient must be evaluated by a 
“heart team” of physicians including an 
interventional cardiologist, 
cardiothoracic surgeon, heart failure 
specialist, and imaging specialist, and 
presented for review at a local multi-
disciplinary conference.  By consensus, 
the heart team must agree (and verify 
in the case review process) that valve 
implantation will likely benefit the 
patient. 
 
 
      

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4. 4. The heart team must agree that 
medical factors preclude operation, 
based on a conclusion that the 
probability of death or serious, 
irreversible morbidity exceeds the 
probability of meaningful 
improvement.  Also, other factors 
which may increase the patients 
perceived surgical risk for inclusion in 
the trial will be clearly delineated if 
they are present.  These include, but 
are not limited to the following as 
defined by VARC 2:  Frailty, Hostile 
chest, porcelain aorta, IMA or other 
critical conduit crossing the midline or 
adherent to the posterior table of 
sternum, severe right ventricular (RV) 
dysfunction.  The surgeons' 
consultation notes shall specify the 
medical or anatomic factors leading to 
that conclusion.  At least one of the 
cardiac surgeon assessors must have 
interviewed and examined the patient. 
 
 
      
 
 
 
5. The study patient provides informed 
consent and agrees to comply with all 
required post-procedure follow-up 
visits, including annual visits up to 5 
years 
 
 
      
Exclusion Criteria 
(From IRB-approved protocol) 
 
1. Heart Team assessment of operability 
(the heart team considers the patient 
to be a good surgical candidate) 
 
 
      
2. Evidence of an acute myocardial 
infarction ≤ 1 month (30 days) before 
the intended treatment [defined as: Q 
wave MI, or non-Q wave MI with total 
CK elevation of CK-MB ≥ twice normal 
in the presence of MB elevation and/or 
troponin level elevation (WHO 
definition)] 
 
 
      
3. Untreated, severe, left sided valvular 
heart disease including mitral 
regurgitation or stenosis, and aortic 
regurgitation or stenosis 
 
 
      

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4. Mean pulmonary artery pressures 
≥40mmHG and PVR >4 woods units as 
assessed by right heart 
catheterization      
 
 
      
5. Any therapeutic invasive cardiac 
procedure resulting in a permanent 
implant that is performed within 30 
days of the index procedure.  Examples 
of permanent implant would include 
any new heart valve.  Implantation of a 
permanent pacemaker is excluded. 
 
 
      
6. Patients with planned concomitant 
surgical or transcatheter ablation for 
Atrial Fibrillation 
 
 
      
7. Leukopenia (WBC < 3000 cell/mL), 
acute anemia (Hgb < 9 g/dL), 
Thrombocytopenia (Plt < 50,000 
cell/mL) 
 
 
      
8. Hemodynamic or respiratory instability 
requiring inotropic support, mechanical 
ventilation or mechanical heart 
assistance within 30 days of screening 
evaluation      
 
 
      
9. Need for emergency surgery for any 
reason 
 
 
 
10. Left ventricular ejection fraction <40% 
 
 
 
11. Echocardiographic evidence of intra-
cardiac mass, thrombus or vegetation 
 
 
 
12. Active upper GI bleeding within 3 
months (90 days) prior to procedure 
 
 
 
13. A known contraindication or 
hypersensitivity to all anticoagulation 
regimens, or inability to be 
anticoagulated for the study procedure 
 
 
 
14. Recent CVA clinically confirmed (by 
neurologist) or neuroimaging 
confirmed stroke or transient ischemic 
attack (TIA) within 6 months (180 days) 
of the procedure 
 
 
 
15. Estimated life expectancy < 1 year 
 
 
 

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16. Expectation that patient will not 
improve despite treatment of tricuspid 
regurgitation 
 
 
 
17. Currently participating in another 
investigational cardiac device study or 
any other clinical trial, including drugs 
or biologics. Note: Trials requiring 
extended follow-up for products that 
were investigational, but have since 
become commercially available, are not 
considered investigational trials 
 
 
 
18. Active bacterial endocarditis within 6 
months (180 days) of procedure 
 
 
 
19. Patients with signs or symptoms of SVC 
syndrome, or hepatic cirrhosis not felt 
due to passive congestion from TR 
 
 
 
20. Subject unable to personally provide 
informed consent 
 
 
 
21. FEV1<30% of predicted  
 
 
 
22. MELD score >21 
 
 
 
 
 
*All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, and medical 
record review.   
 
III. Statement of Eligibility 
 
This subject is  
 eligible / 
 ineligible for participation in the study. 
 
 
Signature: 
Date: 
Printed Name: 
 
 
 

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APPENDIX E:  HIGH RISK DOCUMENTATION 
 
 
 
Documentation of High Risk/Inoperability  
 
Subject ID#____________ was evaluated by the heart team on (date) ____________ and is unsuitable 
for surgery due to: 
☐Probability of death or serious, irreversible morbidity exceeds the probability of meaningful 
improvement (specifically, the probability of death or serious, irreversible morbidity is ≥ 50%).  
☐The subject was interviewed and examined by the heart failure physician (name) 
__________________, MD on (date): __________________ 
☐The subject was interviewed and examined by the cardiac surgeon (name) __________________, MD 
on (date): __________________ 
☐Other factors, which would elevate the patient’s surgical risk which are unique to this patient and not 
reflected in the risk score calculation include*: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
*The cardiac surgeon’s consultations note must specify the medical or anatomic factors leading to this 
conclusion. 
______________________________ 
 
________________________ 
Signature of Site Investigator 
 
 
Date