Early Feasibility Evaluation of Transmural Systems Transcaval Closure Device (TCD) for Transcaval Access Ports During Transcatheter Aortic Valve Replacement (TAVR)
Phase: NA
Conditions: Aortic Stenosis
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
 
Early feasibility evaluation of Transmural Systems Transcaval Closure Device  
 
 
 
(TCD) for transcaval access ports during transcatheter aortic valve replacement  
 
 
 
(TAVR) 
NCT number: 
 
NCT03432494 
Document Type:  
Protocol with Statistical Analysis Plan   
Document Date: 
February 12, 2018 

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NHLBI DIR Protocol Title: 
 
Early feasibility evaluation of Transmural Systems Transcaval Closure Device (TCD) for transcaval access 
ports during transcatheter aortic valve replacement (TAVR)  
Short title 
Transcaval closure device (TCD) for transcaval TAVR 
Version History 
2017-05-20 
Draft 
2017-06-13 
After NHLBI Branch Review 
2017-11-15 
IDE application  
 
2017-12-14 
FDA interactive IDE review  
2017-12-22 
NHLBI IRB Stipulations  
2018-01-17 
Amendment A-consent amendment only 
2018-02-12 
Amendment B, clarification of time-and-events schedule 
 
Investigational Device Exemption 
G170286 December 15, 2017 
Sponsor-Investigator: 
Robert J. Lederman, MD, Senior Investigator, NHLBI Division of Intramural Research 
 
 

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Key Roles  
Role 
Individual 
Affiliation 
Principal Investigator (NIH) Robert J. Lederman, MD 
NHLBI Division of Intramural Research 
National Co-Principal In-
vestigators 
Toby Rogers, PhD, BM BCh 
Adam B. Greenbaum, MD 
Vasilis C. Babaliaros, MD 
Medstar Washington Hospital Center 
Henry Ford Hospital 
Emory University Hospital 
Study Manager 
Annette M. Stine, RN 
NHLBI Division of Intramural Research 
CT core lab 
Marcus Chen, MD  
NHLBI Division of Intramural Research 
Monitoring service 
TBD 
Harris Contractors or equivalent 
Independent Clinical 
Events Adjudication Com-
mittee 
TBD 
TBD 
Data Safety Monitoring 
Board 
Jamieson M. Bourque, MD, 
MHS  
NHLBI via University of Virginia 
IDE Study Sponsor 
Robert J. Lederman, MD, on 
behalf of NHLBI  
NHLBI Division of Intramural Research 
Data Coordinating Center 
Robert J. Lederman, MD 
NHLBI Division of Intramural Research 
Study Statistician 
Xin Tian, PhD 
NHLBI Office of Biostatistics Research 
Site 1 PI 
Adam B. Greenbaum, MD 
Henry Ford Hospital, Detroit, MI 
Site 2 PI 
Vasilis C. Babaliaros, MD 
Emory University Hospital, Atlanta, GA 
Site 3 PI 
Toby Rogers, PhD, BM BCh 
Medstar Washington Hospital Center 
Site 4 PI 
TBD 
 
 
 

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Study Site: 
Site Principal Investigator: 
National Heart, Lung and Blood 
 Institute, NIH 
FWA #00005897  
(Data Coordinating Center)* 
Robert J. Lederman, MD, Senior Investigator 
National Heart Lung and Blood Institute, 
National Institutes of Health 
Building 10, Room 2c713, MSC 1538 
Bethesda, MD 20892-1538 
Voice: 301-402-6769 
Email: lederman@nih.gov 
 
Statistician: Xin Tian, PhD  
NHLBI Office of Biostatistics Research 
 
NHLBI associate investigators 
Jaffar M. Khan, BM BCh 
Henry Ford Hospital 
FWA#: 00005846 
Adam B. Greenbaum, MD 
Director, Cardiac Catheterization Laboratory 
Henry Ford Hospital, Cardiac Cath Lab K-2 
2799 West Grand Blvd, Detroit, MI. 48202 
Phone: 313-916-3875 
Email: agreenb1@hfhs.org 
 
Robert J. Lederman, MD  
 (will participate in interventional procedures) 
Emory University 
FWA #: 00005792 
Vasilis C. Babaliaros, MD 
Emory University 
1364 Clifton Rd. NE, Suite F606 
Atlanta, GA 30322 
Phone: 678-557-4514 
Fax: 404-712-0884 
Email: vbabali@emory.edu  
Medstar Washington Hospital Cen-
ter 
 FWA#: 00000504 
 
Toby Rogers, PhD, BM BCh 
Medstar Washington Hospital Center 
110 Irving Street, NW 
Suite 4B-1 
Washington, DC 20010  
Site #4 
To be determined 
* No subject enrollment 
Estimated Duration of Study: 
18 months 
Estimated Completion Date of Study: 
June 31, 2019 
 
 

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Subjects of study and sites: 
 
DISCLOSURES 
RJL and TR are co-inventors on patents, assigned to NIH, on the test article. They may be required to re-
ceive royalty payments should the test article advance to commercialization. 
ABG serves as a proctor for Edwards Lifesciences and Abbott Vascular.  
VCB is a consultant for Edwards Lifesciences and for Abbott Vascular, and his employer has research con-
tracts from Edwards Lifesciences, Abbott Vascular, Medtronic, and Boston Scientific. 
ABBREVIATIONS 
CEAC 
Clinical events adjudication committee 
CRF 
Case Report Form 
CT 
Computed tomography 
DSMB 
Data Safety Monitoring Board 
EFS 
Early feasibility study 
eGFR 
Estimated glomerular filtration rate 
IVC 
Inferior vena cava 
LDH 
Lactate dehydrogenase 
MACE 
Major adverse cardiovascular events 
TAVR 
Transcatheter aortic valve implantation 
TCD 
Transcaval closure device 
THV 
Transcatheter heart valve 
VARC-2 
Valve academic research consortium (criteria), second edition 
 
PRÉCIS 
Transcaval access to the abdominal aorta from the neighboring inferior vena cava (IVC) enables transcath-
eter aortic valve replacement (TAVR) in patients not eligible for femoral artery access. Currently the pro-
cedure is performed using devices, off-label, designed and marketed to close holes inside the heart and 
great vessels, manufactured by Abbott St Jude (Amplatzer Duct Occluder and Amplatzer Muscular VSD 
Occluder).  Because these Amplatzer occluders are not designed to close transcaval access sites, they may 
not completely prevent bleeding.   
This is an early feasibility study (EFS) evaluation of a purpose-built closure device for transcaval access.  
The device, the Transcaval closure device (TCD) will be evaluated for safety and performance to close 
transcaval access sites in patients ineligible for femoral artery access for TAVR. 
 
Subjects 
Sex 
Age range 
Sites 
30 consented but not 
treated 
15 treated 
Men & Women  
≥21 years 
Up to 4 

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Table of Contents 
1.0 
OBJECTIVE ......................................................................................................................................... 6 
2.0 
BACKGROUND ................................................................................................................................... 6 
3.0 
CLINICAL AND SCIENTIFIC JUSTIFICATION ........................................................................................ 6 
3.1 
Preclinical testing ............................................................................................................. 7 
4.0 
TREATMENT OPTIONS ....................................................................................................................... 7 
5.0 
STUDY DESIGN .................................................................................................................................. 8 
5.1 
Schematic of study design ............................................................................................... 8 
5.2 
Overview of study design ................................................................................................ 8 
5.3 
Transcaval TAVR Procedure ............................................................................................. 9 
5.4 
Time and Events Schedule ............................................................................................. 10 
5.5 
Blood tests ..................................................................................................................... 11 
6.0 
ELIGIBILITY ASSESSMENT ................................................................................................................ 11 
6.1 
Inclusion Criteria ............................................................................................................ 11 
6.2 
Exclusion criteria ............................................................................................................ 12 
6.3 
Rationale for selection criteria ...................................................................................... 12 
7.0 
STRATEGIES FOR RECRUITMENT ..................................................................................................... 12 
8.0 
SAMPLE COLLECTION, STORAGE AND TRACKING PLAN ................................................................. 13 
8.1 
Data transfer to collaborators ....................................................................................... 13 
9.0 
BIOSTATISTICAL AND ANALYTICAL CONSIDERATIONS .................................................................... 13 
9.1 
Sample Size .................................................................................................................... 13 
9.2 
Study Analysis and Endpoints ........................................................................................ 13 
9.3 
Core Laboratory ............................................................................................................. 16 
9.4 
Data Safety Monitoring ................................................................................................. 16 
9.5 
Off study criteria ............................................................................................................ 18 
10.0 
ADVERSE EVENT REPORTING .......................................................................................................... 18 
10.1 
Definitions ...................................................................................................................... 18 
10.2 
Adverse event management: ........................................................................................ 21 
10.3 
Scheduled reporting to FDA .......................................................................................... 23 
11.0 
HUMAN SUBJECTS PROTECTION .................................................................................................... 23 
11.1 
Rationale for Subject Selection ...................................................................................... 23 
11.2 
Risks and Discomforts .................................................................................................... 23 
12.0 
TEST ARTICLES and INDICATIONS FOR USE ..................................................................................... 24 
12.1 
Indications for use ......................................................................................................... 24 
13.0 
INVESTIGATOR ADMINISTRATIVE REQUIREMENTS ........................................................................ 24 
13.1 
Good Clinical Practice .................................................................................................... 24 
13.2 
IRB Submissions ............................................................................................................. 25 
13.3 
Subject Information and Informed Consent .................................................................. 25 
13.4 
Study Eligibility Committee............................................................................................ 25 
13.5 
Protocol Compliance ...................................................................................................... 25 
13.6 
Investigational Device Accountability ............................................................................ 26 
13.7 
Data monitoring plan ..................................................................................................... 26 
13.8 
Publication and Presentation of Study Findings and Use of Information ..................... 27 
14.0 
SPONSOR REGULATORY REQUIREMENTS ....................................................................................... 27 
14.1 
Role of Sponsor .............................................................................................................. 27 
14.2 
General Duties ............................................................................................................... 28 
14.3 
Research Monitoring Plan ............................................................................................. 28 
14.4 
Site Selection and Training ............................................................................................ 28 

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15.0 
Appendix A: Risk Analysis ............................................................................................................... 31 
1.0 OBJECTIVE 
The objective of this study is to evaluate the safety and early feasibility of closure of transcaval aortic ac-
cess sites using the TCD after transcatheter aortic valve replacement (TAVR). 
2.0 BACKGROUND 
Transcatheter aortic valve implantation (TAVR) avoids the morbidity and mortality of surgical aortic valve 
replacement in high and intermediate risk patients 1-5.  
Transthoracic (transapical and transaortic) access is inferior 
to femoral-artery access5.  Discomfort and morbidity are 
more pronounced from transthoracic access for TAVR, prob-
ably because of invasiveness and pulmonary insults.  Opera-
tor ergonomics are more favorable for transfemoral than for 
non-transfemoral access, and these human factors may im-
pact procedure outcomes. An alternative transfemoral ac-
cess approach to TAVR might be desirable in these patients 
to reduce the hazards and discomfort of transthoracic ac-
cess and because of the superior operator ergonomics. 
3.0 CLINICAL AND SCIENTIFIC JUSTIFICATION 
We developed a technique of transfemoral venous access 
for retrograde TAVR by entering the abdominal aorta 
through the adjoining inferior vena cava, called transcaval 
access 6 (Figure 1).  The procedure relies on the observation 
that interstitial pressure always exceeds venous pressure.  Animals tolerate the resulting acute aorto-
caval fistula even without repair, because the retroperitoneal space appears to pressurize and cause aor-
tic blood to return immediately through the corresponding 
hole in the vena cava (Figure 2).  Patients tolerate transcaval 
access after nitinol cardiac occluders are implanted to close 
the aortic entry site.  Transcaval access and closure was uni-
formly successful in the first 19 patients, all of whom had no 
good TAVR access options7. Thereafter, we performed a 
multi-center trial of transcaval TAVR in 100 patients (STS 
predicted risk of mortality 9.6±6.3%) ineligible for transfem-
oral and high or prohibitive risk for transthoracic access. 
Transcaval access was successful in 99/100. Device success 
(access and closure with a nitinol cardiac occluder without 
death or emergency surgical rescue) was 98/99. Inpatient 
survival was 96% and 30-day survival was 92%. Transcaval-
related life-threatening bleeding was 7%. Transcaval access enabled TAVR in patients who were not good 
candidates for transthoracic access. Bleeding and vascular complications were common but acceptable in 
this high-risk cohort.   
Currently transcaval access sites are closed using Amplatzer Duct Occluders and Amplatzer Muscular VSD 
Occluders (Abbott St Jude Medical), off-label.  These polyester-seeded self-expanding nitinol devices are 
designed to close intravascular communications between the aorta and pulmonary artery or between the 
 
Figure 1. Illustration of transcaval access 
and closure. 
 
Figure 2. Interstitial pressure exceeds ve-
nous pressure and drives decompression of 
aortic bleeding. 

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left and right ventricles, and are by-design tolerant of post-procedure blood flow.  As a result, the Am-
platzer devices are not immediately hemostatic. While the majority of patients experience and tolerate 
residual aorto-caval fistula through Amplatzer occluder devices, a minority do not tolerate the acute left-
to-right cardiovascular shunt because of severe cardiomyopathy and require adjunctive covered stent im-
plantation. In addition, Amplatzer devices are also designed to elongate during delivery when tension is 
applied, which risks intra-procedure pull-through and mal-deployment.  As a result, closure with Am-
platzer devices requires special operator skill for deployment 8. 
The Transmural Systems Transcaval Closure Device (TCD) is purpose-built for this application. It was de-
signed in collaboration by NHLBI investigators and Transmural Systems, Incorporated.  The preclinical de-
velopment was funded by a SBIR contract from NHLBI to Transmural Systems.   The TCD is designed to fa-
cilitate rapid hemostasis and fistula occlusion by virtue of polyester covering.  The TCD is also designed to 
resist pull-through because of an incorporated spring that flattens the aortic disc. As a result of these de-
sign features, the TCD is expected to exhibit hemostasis, fistula occlusion, and ease-of-use compared with 
the Amplatzer devices that had been used off-label to close transcaval access sites. 
3.1 Preclinical testing 
Extensive preclinical testing has been performed on the TCD System.  The TCD has been evaluated 
through a series of bench tests to verify that the design met specification both as-manufactured as well as 
after exposure to representative shipping and environmental conditioning.  All studies were completed, 
and results passed prospective endpoint criteria. 
In addition to extensive bench testing, an in vivo GLP study assessed key safety and performance charac-
teristics of the TCD. Nine (9) swine were implanted with the TCD and followed for 30- and 90-day end-
points to evaluate device placement, ability to achieve hemostasis, and chronic device integrity.  The re-
sults of the study demonstrate that the TCD can be advanced, repositioned, retrieved, and deployed with-
out safety or performance events.  Immediate hemostasis was achieved in all implanted devices, and no 
acute or chronic aorto-caval fistulae were observed. 
In addition, the chronic histopathology found acceptable fibrosis and inflammation, which was reduced 
compared with non-GLP histopathologic evaluation of the Amplatzer Duct Occluder that has been used in 
hundreds of patients to date. End organ analysis including, kidney, liver, spleen, heart, and coronary 
bands in the legs showed no thromboemboli.  In addition, the Implant and delivery system passed all ISO-
10993 requirements. 
The results of the preclinical bench and in-vivo testing justify the use of the TCD in human subjects. 
4.0 TREATMENT OPTIONS 
Several “alternative access” approaches are available for patients ineligible for transfemoral artery access 
for TAVR.  Trans-apical and trans-aortic access, both of which are “trans-thoracic” approaches, require 
open chest surgery and confer the pulmonary and other risks of operative morbidity and mortality.   In 
the only independently adjudicated study of the Sapien 3 THV5, life-threatening bleeding occurred in 
22.6% of intermediate-risk patients after transthoracic TAVR and 6.7% after transfemoral TAVR, compared 
with 12% after transcaval TAVR closed with Amplatzer devices in a separate NHLBI IDE study.  It is note-
worthy that the operative risk score of subjects in the PARTNER-II study were higher (mean STS predicted 
risk of mortality score 9.6%) than in the NHLBI IDE study (mean STS score 5.8%) 

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There are several extra-thoracic alternative access approaches, including trans-carotid, mediastinal, and 
trans-subclavian approaches. These also generally require operative exposure and confer operative mor-
bidity and vascular complications. 
Medical therapy, or balloon aortic valvuloplasty, of severe aortic valve disease is considered an unsatisfac-
tory strategy with high mortality. 
5.0 STUDY DESIGN 
5.1 Schematic of study design 
TAVR is indicated, 
unsuitable for femoral 
artery access appears
Clinically indicated 
abdomen/pelvis CT 
indicates transcaval 
access is feasible
Central eligibility review 
(PI and Sponsor)
Informed Consent 
and Baseline 
assessment
Adverse 
events are 
assessed at 
time of 
discharge
30 day 
follow-up 
with CT 
when 
feasible
Participation 
begins when 
transcaval access is 
attempted.  TCD 
device is 
implanted.
6 month 
contact
12-month 
follow-up and 
CT
Study 
concludes
 
5.2 Overview of study design 
This is an early feasibility study of the TCD.  It is a prospective, open-label, single-arm, multi-center, inves-
tigator-initiated, and independently-adjudicated investigation of the TCD in patients undergoing TAVR 
who are not eligible for standard transfemoral artery access. 
Candidates will be identified by the participating structural heart disease programs.  Standard TAVR plan-
ning includes contrast-enhanced abdomen and pelvis CT, typically during the same contrast exposure as 
the cardiac CT.  Eligibility will be reviewed and proposed by the local multidisciplinary heart teams.  Ana-
tomic eligibility will be confirmed by the core CT analysis laboratory using the clinically indicated CT.  Can-
didates will then undergo central eligibility review by the Study Eligibility Committee.  If deemed eligible, 
candidates will be offered participation in the study.  
Once enrolled, subjects will undergo protocol baseline assessment. If eligible, subjects will be admitted to 
the hospital and undergo transcaval TAVR under this protocol.  The transcaval access site will be closed 
with the TCD.  They will undergo follow-up testing including CT scan at 30 days and 12 months. 

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5.3 Transcaval TAVR Procedure 
The transcaval TAVR procedure is planned from a CT of the abdomen and pelvis, preferably with thin-slice 
<1.5mm reconstructions, and preferably with contrast enhancement9. The goal is to select a crossing tar-
get free of significant calcium or interposed structures, far from visceral branches that might be compro-
mised by the closure device or by bailout covered stent implantation. 
The procedure is performed under general anesthesia or under moderate sedation at the discretion of the 
institutional heart team. Prophylactic antimicrobials are administered according to institutional routine. 
Participation in the investigational protocol (for follow-up and surveillance) begins only when transcaval 
access is attempted. We select this timepoint lest physicians successfully undertake transfemoral artery 
access in patients who have consented but who have “borderline” femoral artery access vessels. If there is 
any intent or attempt to perform transcaval access, the candidate is treated as enrolled. 
The technique of transcaval access is described in detail elsewhere8. Percutaneous right femoral vein ac-
cess is obtained for the transcaval sheath, and percutaneous femoral artery access is obtained for thoracic 
and abdominal aortography, for the required intravascular snare, for adjunctive balloon aortic tamponade 
if necessary, and for bailout covered stent implantation if necessary.  Separate vascular access is obtained 
according to operator routine for temporary transvenous pacing.  Heparin is the recommended TAVR anti-
coagulant because it is amenable to pharmacologic reversal with protamine before closing the transcaval 
access port. 
Typically baseline abdominal aortography is performed to register the fluoroscopy with the baseline CT 
plan.  Coaxial crossing catheters (such as a renal length guiding catheter, 0.035” braided microcatheter, 
Piggyback 0.014-to-0.035” polymer jacket exchange catheter, and 0.014” Astato-XS-20 guidewire) are po-
sitioned at the crossing target in the IVC and aimed at an aortic snare catheter.  The guidewire is electri-
fied briefly at 30-50W, by connecting to a standard monopolar electrosurgery generator, during advance-
ment from the IVC into the aorta.   The ensnared guidewire is then used in turn to advance the exchange 
catheter, microcatheter, and rigid guidewire all to allow advancement of the THV introducer sheath from 
the femoral vein into the abdominal aorta.  The sheath is secured with suture. 
Next the transfemoral TAVR procedure is performed according to operator preference and institutional 
routine. 
At the conclusion of the TAVR procedure, heparin anticoagulation is reversed with protamine.  Hemody-
namics are recorded.  The TCD delivery system is positioned over a 0.014” guidewire though the THV in-
troducer sheath into the abdominal aorta, and the appropriate orientation confirmed.   The THV intro-
ducer sheath is withdrawn fully from the aorta into the lower IVC.  The TCD aortic disc is exposed and the 
appropriate orientation again confirmed.   The TCD aortic disc is retracted against the endoluminal wall of 
the aorta, and position confirmed by angiography.  The TCD body is then withdrawn outside the aorta to 
occupy the iatrogenic aortocaval tract.  The hemostatic (against extravasation) and occlusive (against fis-
tula) performance of the TCD is assessed by serial angiography and instantaneous hemodynamics.  If nec-
essary, the TCD is recaptured into the delivery system and repositioned.  After satisfactory positioning, 
the TCD may be released, and the 0.014” guidewire removed.   
If necessary, balloon aortic tamponade is performed according to standard transcaval technique and op-
erator preference, using a balloon size selected from baseline CT.  Use of the balloon aortic tamponade 
technique is recorded, but is not considered a device or procedure failure.  

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Covered stent implantation is performed at the discretion of the operator for unsatisfactory performance 
of the TCD, at the discretion of the operator, and the indications are recorded.  
Completion angiography is performed using digital subtraction angiography and the immediate hemo-
static performance (against extravasation) and occlusive performance (against fistula) are assessed. Per-
cutaneous vascular site hemostasis is obtained according to usual techniques. 
Should the TCD fail, treatment contingencies include balloon aortic tamponade, covered stent implanta-
tion, and closure using an Amplatzer closure device. 
Before discharge, changes in hemoglobin and blood transfusions are recorded carefully to determine 
VARC-2 bleeding scores.  Other pre-discharge blood tests are obtained to measure hemolysis and infec-
tion.  Post-procedure antiplatelet and anticoagulation regimens are selected according to physician pref-
erence.  
Unscheduled abdomen/pelvic CT are analyzed if they are available. 
Contrast-enhanced abdominal/pelvic CT is obtained in follow-up after 30 days, when permitted by renal 
function, as determined by the local physician. 
A follow-up encounter (telephone or in-person) is performed at 6 months to assess interval adverse 
events. 
A final study-mandated in-person visit is performed at 12 months, with contrast-enhanced abdomen/pel-
vic CT, when permitted by renal function, as determined by the local physician. 
5.4 Time and Events Schedule 
 
 
Screening (-30 to 0D) 
Baseline 
Day 0 
Inpatient 
30 d (±14d) FU 
6 mo (± 3 wk) 
12 mo (± 4 wk)  FU  
Baseline informed consent 
 
X 
 
 
 
 
 
Multidisciplinary heart team eligibility determination 
 
X 
 
 
 
 
 
Baseline clinical assessment 
 
X 
 
 
 
 
 
Blood tests 
 
X 
 
X 
X 
 
X 
Vital signs and in-person visit 
 
X 
 
 
X 
 
X 
Abdomen/pelvis CT (contrast-enhanced) analyzed by core lab 
X 
 
 
 
X 
 
X 
Study eligibility committee concordance 
X 
 
 
 
 
 
 
Transcaval TAVR with implantation of transcaval closure device (TCD) 
 
 
X 
 
 
 
 
Vital status and adverse event assessment 
 
 
 
X 
X 
X 
X 
Subjects will receive continuing care from their primary physicians with consultant input as requested 
from the structural heart disease program. 

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For subjects who die, necropsy evaluation is requested to examine the abdominal aorta and cava en bloc 
at NIH. 
5.5 Blood tests 
Blood test 
Rationale 
Schedule 
Lactate dehydrogenase (LDH) 
Haptoglobin 
A combination of low or undetectable plasma 
haptoglobin (≤25 mg/dL) and elevated LDH 
(above institutional normal limit) will screen 
for hemolysis after the procedure 10.  A posi-
tive combination of these tests will prompt 
confirmatory evaluation by peripheral red 
blood cell smear and reticulocyte test. 
Baseline 
Pre-discharge 
30-day 
12-month 
Complete blood count including  
- Hemoglobin 
- Platelet count 
- White blood cell count and differen-
tial 
Test for hemoglobin 
Test for low platelets 
Screen for infection related inflammation 
Baseline 
Pre-discharge 
30-day 
12-month 
Creatinine and estimated glomerular 
filtration rate (eGFR) 
Test of renal excretory function 
Baseline 
Pre-discharge 
30-day 
12-month 
 
6.0 ELIGIBILITY ASSESSMENT 
6.1 Inclusion Criteria  
• 
Consents to participate in this study and all related clinical follow-up procedures 
• 
Adults age ≥ 21 years 
• 
Undergoing transcatheter aortic valve replacement (TAVR) based on the clinical assessment of the 
multidisciplinary heart team 
• 
Ineligible for femoral artery access for the selected transcatheter heart valve (THV) according to 
the THV manufacturer instructions for use.  
[Note Corevalve Evolut R: ≥5mm; Evolut PRO 23, 26, 29 mm valves and Evolut R 34 mm: ≥ 5.5 mm; 
Edwards Sapien 3, 23-26mm: 5.5 mm; Edwards Sapien 3, 29mm: 6.0mm;  
Anatomic ineligibility also considers patient-specific pattern of iliofemoral calcium and tortuosity.] 
• 
Eligible for transcaval access based on Core Lab analysis of the baseline abdomen/pelvis CT indi-
cating a calcium-free target window on the abdominal aorta; a target ≥ 15mm from the lowest 
main renal artery or aorto-iliac bifurcation; no important interposed structures; a projected intra-
vascular centerline distance from the lower femoral head to the target at least 5cm less than the 
intended THV introducer sheath; patent celiac or superior mesenteric artery;  

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• 
Aorta diameter ≥ 11mm at the target crossing site 
• 
Concordance of the study eligibility committee 
6.2 Exclusion criteria 
• 
High risk features on baseline CT including porcelain aorta (confluent calcification); pedunculated 
aortic atheroma; or leftward aortic angle ≥ 20o with regard to vertical;  
• 
Renal dysfunction limiting follow-up contrast-enhanced CT (estimated glomerular filtration rate, 
eGFR < 30 mL/min/1.73m2 if not already on renal replacement therapy) 
• 
Pregnancy or intent to become pregnant prior to completion of all protocol follow-up procedures 
6.3 Rationale for selection criteria 
The selection criteria allow enrollment of the intended population with little anticipated selection bias. 
The main selection criteria are ineligibility for standard transfemoral artery access, and anatomic eligibility 
for transcaval access as published9.  Patients are excluded if there are high risk features such as high risk 
of atheroembolism. Preclinical data are limited supporting application of the TCD in aortas smaller than 
11mm, and therefore such subjects are excluded. 
Contrast-enhanced CT during follow-up risks acute and chronic renal failure in patients with baseline renal 
dysfunction if they are not already on renal replacement therapy.  Therefore candidates are excluded if 
they are not on renal replacement therapy and have eGFR < 30 mL/min/1.73m2. 
No patient will be excluded from participation based on sex, gender, race or ethnicity.  There is no biologi-
cal rationale or evidence for sex-specific risk for complications of transcaval TAVR or TCD closure.   
The inclusive selection criteria and geographic extent of enrolling sites are expected to allow recruitment 
of a diverse economic, ethnic, and racial mix of patients that reflects the incident disease, despite the 
small sample size.  Specifically, the results are expected to be generalizable to Medicare and Medicaid 
beneficiaries because of age and disease-related disability. 
A study eligibility committee led by the NHLBI sponsor is convened to assure each subject meets selection 
criteria before treatment (see section 13.4), and that at least one member has no actual or perceived fi-
nancial conflict of interest. 
7.0 STRATEGIES FOR RECRUITMENT  
Subjects will be recruited from the Structural Heart Disease clinical programs of the participating hospi-
tals.   
The distribution of planned enrolling sites assures accessibility of the trial to ethnically, racially, and eco-
nomically diverse populations.  The study will track sex, age, ethnicity, and racial background of subjects. 
Once recruited, subject retention rate is expected to be high because follow-up activities are not onerous 
and are timed to correspond with routine follow-up medical care, without prohibitively expensive follow-
up testing. 

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8.0 SAMPLE COLLECTION, STORAGE AND TRACKING PLAN 
Imaging data (from angiography and CT) constitute the only specimens to be collected.  CT examinations 
performed for clinical evaluation prior to signing informed consent may be used as the baseline scan, and 
will be analyzed using patient identifiers to assure no misidentification. 
CT and Angiography data will be analyzed at the NHLBI Imaging Core Laboratory.    These data will be 
transmitted on electronic media such as a DVD via carrier or using secure file transfer mechanisms abiding 
HIPAA and local institutional standards (such as https://secureemail.nih.gov).  
Imaging data are stored at a central facility (NHLBI) using secure HIPAA compliant methods and are stored 
in a secure Picture Archive Computer System (PACS), known as NHLBIPACS. 
Necropsy specimens will be handled according to local institutional medical standards and will be dis-
posed accordingly. 
8.1 Data transfer to collaborators 
De-identified and de-linked data and images will be transferred to collaborators at Transmural Systems 
LLC, the manufacturers of the test article.  The de-identification assures individual subjects cannot be 
identified. 
Transcatheter valve registry is a nationwide CMS-mandated registry of patients undergoing TAVR.  All 
sites are encouraged to enroll subjects into the TVT registry.  TVT registry numbers will be collected and 
used for collaboration with the TVT registry and TAVR device manufacturers such as Edwards Lifesciences. 
These TVT registry numbers are linking codes that do not identify subjects. De-identified and de-linked 
data may be transferred to collaborators at Edwards Lifesciences. 
9.0 BIOSTATISTICAL AND ANALYTICAL CONSIDERATIONS 
9.1 Sample Size 
The sample size is not statistically derived.   
This is an early feasibility study of a device not previously used in humans. An arbitrary initial sample size 
of 15 is proposed in coordination with the FDA Centers for Devices and Radiologic Health. 
Up to 30 subjects will be consented until 15 subjects undergo attempted transcaval closure using the test 
article.   
9.2 Study Analysis and Endpoints 
We will adhere to a subset of consensus guidelines for the analysis and reporting of transcatheter aortic 
valve implantation procedures (VARC-2) 11, focusing on vascular access, and modified where necessary to 
adapt to transcaval access 12. This excludes TAVR-only complications.  Bleeding will be classified according 
to MVARC-2, which adds specificity to VARC-2 bleeding classification. 
Clinical events are classified by the local site Principal Investigator and confirmed by the NHLBI Principal 
Investigator.   Key clinical events are independently adjudicated (see section 9.2.6). The results of the 
study will be released within 12 months of study completion. 
The study will be analyzed using descriptive statistics.  Afterwards, we will survey for parameters associ-
ated with an increased risk of major adverse events. 

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Analyses will be performed using principles both of (1) intention-to-treat, defined as attempting or initiat-
ing transcaval crossing procedures (introducing a transcaval crossing guide catheter into the body to at-
tempt traversal), and (2) as-treated, defined as completing transcaval closure attempts.  We expect these 
to be the same. 
There are no prespecified acceptance criteria for failure rate. 
9.2.1 
Primary endpoint 
The primary endpoint is Technical success. This endpoint is measured at exit from the catheterization la-
boratory.  All of the following must be present: 
- 
Alive 
- 
Successful delivery of the TCD, and retrieval of the TCD delivery system 
- 
Deployment and correct positioning of a single intended TCD.  Repositioning and recapture of the 
device, if needed, is not classified as failure. 
- 
No additional unplanned or emergency surgery or re-intervention related to the TCD or delivery 
system  
- 
Adjunctive balloon aortic tamponade is permissible and consistent with technical success  
9.2.2 
Secondary endpoint: Closure success 
This secondary endpoint is a composite of the primary endpoint and hemostasis of the transcaval aortic 
access site. This endpoint is measured at exit from the catheterization laboratory.  All of the following 
must be present: 
- 
Alive 
- 
Successful delivery of the TCD, and retrieval of the TCD delivery system 
- 
Deployment and correct positioning of a single intended TCD.  Repositioning and recapture of the 
device, if needed, is not classified as failure. 
- 
No additional unplanned or emergency surgery or re-intervention related to the TCD or delivery 
system. Adjunctive balloon aortic tamponade is permissible and consistent with technical success  
- 
Complete occlusion of the aortocaval fistula on the completion aortogram. 
  
9.2.3 
Secondary endpoint: Device Success 
A key performance endpoint is Device success.  This endpoint is measured at 30 days and 12-months.  All 
of the following must be present 
- 
Alive 
- 
Original intended TCD in place 
- 
No additional surgical or interventional procedures related to access or the device after exit from 
the cath lab 
- 
Intended performance of the TCD, including all of  

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o Structural Performance: No migration, embolization, detachment, fracture, hemolysis, or 
endarteritis related to the TCD 
o Hemodynamic performance: No abdominal aortic obstruction caused by the TCD implant 
o Absence of para-device complications (large retroperitoneal hematoma, pseudoaneu-
rysm, distal thromboembolism, or pulmonary thromboembolism) 
9.2.4 
Secondary endpoint: Procedural Success 
The primary safety endpoint is Procedural success.  This endpoint is measured at 30 days. All of the fol-
lowing must be present 
- 
Device success 
- 
No device-related Serious Adverse Events, defined as VARC-2 life-threatening bleeding, major vas-
cular or cardiac complications related to the TCD requiring unplanned reintervention or surgery 
(such as covered stent implantation at the transcaval access site). 
9.2.5 
Additional Secondary Endpoints 
Additional secondary endpoints include  
- 
Procedure success classifying covered stent implantation as a normal provisional part of the pro-
cedure. 
- 
Covered stent implantation at the TCD implantation site 
- 
Acute aorto-caval fistula score at procedure completion 12: 0=occlusion, 1=patent fistula, 2=cruci-
form fistula pattern, 3=extravasation. 
- 
Modified VARC-2 vascular complications 12 at 30 days 
- 
VARC-2 bleeding complications 12 at 30 days 
- 
Major adverse cardiovascular events (MACE), defined as VARC-2 Early Safety composite: No mor-
tality, stroke, life-threatening bleeding, AKI stage 2+, major vascular complication, valve-related 
complication 
- 
Closure success at 30 days and 12 months. 
- 
Mortality, all-cause, cardiovascular vs non-cardiovascular, peri- vs non-periprocedural, related to 
TCD or not) 
- 
Aorto-caval fistula patency at each timepoint, assessed combining completion angiography and 
arterial-phase follow-up CT. 
- 
AKIN acute kidney injury 
- 
Freedom from infection related to the TCD at each time point 
- 
Thrombocytopenia < 50,000 attributable to residual aorto-caval fistula or the TCD 
- 
Hemolysis attributable to residual aorto-caval fistula or the TCD 
- 
CT analysis: Device position; Device integrity; Aortocaval fistula patency; Aortocaval tract pseudo-
aneurysm; Aortic pseudoaneurysm; Retroperitoneal hematoma grade (stranding {=absent and not 

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evidence of overt bleeding;} small; moderate; larger); Intracaval mass or thrombus; Aortic dissec-
tion and inferred relatedness to TCD (adjacent to access port) or procedure (remote to access 
port) 
- 
Outcomes of subjects greater than 65 years (i.e. eligible for Medicare based on age), to determine 
generalizability to the Medicare population0F1  
9.2.6 
Independent Clinical Events Adjudication 
An independent Clinical Events Adjudication Committee will review all of the following that occur in the 
first year.  The CEAC adjudication will be performed after 30-day and after 12-month data are collected. 
The CEAC will rely on independently-monitored data collected in the electronic case report forms, with 
additional source document review upon request. The adjudicated endpoints will include: 
- 
Deaths 
- 
Primary endpoint (technical success) and key secondary endpoints (device success, procedure 
success) 
- 
Modified VARC-2 vascular complications 
- 
VARC-2 bleeding complications 
- 
Major adverse cardiovascular events (MACE), defined as VARC-2 Early Safety composite: No mor-
tality, stroke, life-threatening bleeding, AKI stage 2+, major vascular complication, valve-related 
complication 
The CEAC will classify relatedness of the above events to the TCD device. 
9.3 Core Laboratory 
The NHLBI CT core laboratory will analyze follow-up CT scans in comparison with baseline.  Analysis 
will include 
• 
TCD position 
• 
TCD integrity 
• 
Aortocaval fistula patency 
• 
Aortocaval tract pseudoaneurysm 
• 
Aortic pseudoaneurysm 
• 
Retroperitoneal hematoma grade (stranding {=absent and not evidence of overt bleeding}; 
small; moderate; large) 
• 
Intracaval mass or thrombus 
• 
Aortic dissection and inferred relatedness to TCD (adjacent to access port) or procedure (re-
mote to access port) 
 
9.4 Data Safety Monitoring 
A Data Safety and Monitoring Board (DSMB) appointed by the NHLBI Division of Intramural Research will 
monitor the safety of subjects in the study as described in the investigational plan. All members of the 
                                                          
1 Guidance for the Public, Industry, and CMS Staff Coverage with Evidence Development Document Issued on No-
vember 20, 2014, https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-de-
tails.aspx?MCDId=27 

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DSMB are unaffiliated to the study. The NHLBI DSMB will review the protocol progress report at six month 
intervals. The DSMB may recommend early termination of the study for considerations of safety and effi-
cacy. Unanticipated Adverse Device Effects (UADEs) will be submitted to the DSMB following the same 
timelines as the IRB (See section 10.2.4). 
In the case of death or serious UADE, if the sponsor and the principal investigator determine that the 
event presents an unreasonable risk to the participating subjects, the clinical trial will be terminated 
within 5 working days after making that determination and not later than 15 working days after the spon-
sor first receives notice of the effect. [21 CFR 812.46]. All clinical sites will be notified of this action. 
Each institutional IRB will review all Serious Adverse Events, Unanticipated Adverse Device Effects, and 
Unanticipated Problems, and may choose to suspend or terminate the protocol based on those findings. 
We believe this will protect subject safety.   
9.4.1 
Stopping Rules 
The study will be monitored to ensure that the mortality within 30-days after the procedure does not sub-
stantially exceed an anticipated rate. We anticipate the rate of 30-day mortality is 10% or less and deter-
mine the stopping rule by a Bayesian approach 13. The stopping boundary is reached if the posterior prob-
ability that the 30-day mortality rate exceeds 10% is at least 90%.  We take our prior distribution to be a 
beta distribution so that our prior clinical opinion is worth 20% of the weight we will place on the new data. 
This gives the prior parameters a = 0.3, b =2.7. Hence when we make decisions about stopping the study, 
the data from the study will dominate over the prior opinion.  
The following table summarizes the threshold numbers for the stop rule boundary, which would lead to a 
recommendation to stop the study due to the excess 30-day mortality. 
Number of subjects 
Stop if the number of deaths 
within 30 days reaches 
2-5 
2 
6-11 
3 
12-15 
4 
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, 
we generated a study with 15 independent Bernoulli trials, each with a true certain 30-day mortality, and 
compared these outcomes with the above stopping boundary to determine whether the study was stopped.  
We repeated the simulation 100,000 times and computed the proportion of stopped studies using the 
above stopping rule.  The following table summarizes the performance of this stopping rule: 
True 30-day mortality rate 
2.5% 
5% 
10% 
15% 
20% 
25% 
30% 
35% 
Proportion of Stopped Studies (%) 
0.7 
3.1 
13.8 
30.4 
48.6 
65.5 
78.6 
88 
Average number of subjects (n) 
14.9 
14.7 
13.8 
12.5 
11 
9.5 
8.1 
6.9 
Average number of 30-day mortality (n) 
0.4 
0.7 
1.4 
1.9 
2.2 
2.4 
2.4 
2.4 
These simulation results suggest that our stopping rule has a low probability of stopping a study when the 
true 30-day mortality rate is 10% or less, and the probability of stopping a study is high when the true 30-
day mortality rate exceeds 10%.  There, we believe that our stopping rule for 30-day mortality has satis-
factory statistical properties. 

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9.5 Off study criteria 
• 
Completion of the 12-month follow-up 
• 
The subject voluntarily withdraws 
• 
Significant subject non-compliance with follow-up visits, despite repeated investigator effort to 
assure compliance, including baseline counseling and consent, telephone encouragement, and 
registered letter reminders if necessary. Such non-compliance will be documented and monitored 
independently. 
• 
Death 
10.0 
ADVERSE EVENT REPORTING 
10.1 
Definitions 
Adverse events: Any untoward medical occurrence in a human subject, including any abnormal sign (e.g., 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the sub-
ject’s participation in the research, whether or not considered related to the subject’s participation in the 
research. 
 
This will include: 
• 
Expected events related to the subject’s disease process during active enrollment in the research 
protocol and do not directly result from use of the investigational device or study. 
• 
Procedural events directly related to the cardiac catheterization procedure and recovery from the 
procedure and do not directly result from use of the investigational device. 
Serious Adverse Event (SAE):  A serious adverse event that results in any of the following and NOT directly 
related to the device.  This includes any event that 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurs); 
• 
results in in-patient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant incapacity; 
• 
results in a congenital anomaly/birth defect (not relevant to this study) ;  
• 
that may not result in death, be life-threatening, or require hospitalization may be considered se-
rious when, based upon appropriate medical judgment, they may jeopardize the patient (“im-
portant medical event); or 
• 
based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition. 
Adverse Device Effect (ADE): Any untoward or unintended response to a medical device.  This definition 
includes any event resulting from insufficiencies or inadequacies in the instructions for use or the deploy-
ment of the device or any event that is a result of user error. 
During this clinical investigation, an event should be considered related to the TCD when it is the result of: 

IDE Transcaval Closure Device 
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• 
Delivery and implantation of the TCD 
• 
Retrieval of the TCD delivery system 
• 
Adjunctive balloon aortic tamponade if performed 
An event will be considered NOT related to the TCD when it is the result of:  
• 
A pre-existing medical condition 
• 
Clearly attributable to TAVR or to transcaval aortic access before undertaking transcaval site clo-
sure (example: paravalvular leak or transcaval guidewire crossing) 
Anticipated Adverse Device Effects (ADEs): An ADE is an adverse event with a reasonable possibility that 
the device or procedure caused or contributed to the event. The following ADEs are considered antici-
pated based on previous human experience: 
• 
Transcaval closure device (TCD) failure, including failure to deliver, failure to deploy, failure to po-
sition or align correctly, failure to achieve hemostasis, and catastrophic mechanical failure requir-
ing transcatheter or surgical retrieval, device fracture, device embolization 
• 
Death 
• 
Persistent aorto-caval fistula  
• 
Intolerable acute left-to-right cardiovascular shunt across the aorto-caval access port causing my-
ocardial dysfunction 
• 
Bleeding causing decreased hemoglobin and anemia and possible blood transfusion. Hemoglobin 
is also known to decline after conventional transfemoral TAVR. 
• 
Shock requiring intravenous fluid resuscitation, vasoactive medications, or mechanical circulatory 
support. 
• 
Hypotension or hypertension requiring pharmacologic intervention.  These are also commonly 
also observed after conventional transfemoral TAVR. 
• 
Retroperitoneal or perivascular hematoma  
• 
Aortic injury such as aortic dissection or pseudoaneurysm or perforation 
• 
Vascular access site complications including femoral artery and vein hematoma, pseudoaneurysm, 
and arteriovenous fistula. These are also commonly also observed after conventional transfemo-
ral TAVR. 
• 
Thrombocytopenia (<50,000/mm2) as a consequence of residual aorto-caval fistula. Platelet 
counts are known to decline after standard transfemoral TAVR.  
• 
Hemolysis (decreased hemoglobin and decreased haptoglobin, increased LDH, positive schizo-
cytes on blood smear) attributable to residual aorto-caval fistula or the TCD. 
• 
Venous thrombosis or thromboembolism, including pulmonary thromboembolism, related to the 
femoral or caval access site or device 
• 
Atheroembolism or thromboembolism related to catheter and device manipulations in the de-
scending aorta 
• 
Infection/inflammation of the caval-aortic access site related to the TCD , or endocarditis or 
endarteritis or sepsis 
• 
Elevated white blood count, inflammation, infection, and/or fever post procedure involving the 
TCD or other body system infections such as urinary or pulmonary. 
• 
Acute kidney injury (reduced urinary output, elevated creatinine, decreased eGFR), whether tran-
sient or permanent, that may be caused by iodinated radiocontrast and/or by acute hypovolemia 
from the TCD, from the conventional TAVR procedure, and/or from the follow-up CT scan. 

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• 
Volume overload, congestive heart failure, pleural effusion, or dyspnea from procedure-related 
volume perturbations causing respiratory failure or prolonged mechanical ventilation 
• 
Respiratory failure requiring oxygen or mechanical support or mechanical ventilation 
• 
Pain including back pain and access site and generalized 
• 
Cardiac arrhythmia, including atrial fibrillation, supraventricular tachycardia, ventricular tachycar-
dia, ventricular fibrillation, advanced atrioventricular conduction block.  These are known to ac-
company conventional transfemoral TAVR. 
• 
Allergic or toxic reactions to medicine, anesthesia, contrast dye, or materials in the catheters. 
• 
Hypersensitivity or anaphylactoid reaction to the delivery system or TCD or its components 
Serious Adverse Device Effect (SADE): An adverse effect that may have been or is attributed to the use of 
the device and produce an injury or illness that is life-threatening, results in permanent impairment or 
damage to the body, or requires medical or surgical intervention to prevent permanent harm to the body.  
Unanticipated Adverse Device Effect (UADE): 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 ap-
plication (including a supplementary plan or application), or any other unanticipated serious problem as-
sociated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
Unanticipated Problem (Up): An unanticipated problem is any incident, experience, or outcome that 
meets ALL of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency in relation to: 
a. the research risks that are described in the IRB-approved research protocol and informed consent docu-
ment, Investigator’s Brochure or other study documents, and  
b. the characteristics of the subject population being studied, and  
• 
Related or possibly related to participation in the research, and  
• 
Places subjects or others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized.  
Protocol Deviation: A protocol deviation is any change, divergence, or departure from the study design or 
procedures of an IRB-approved research protocol. 
Non-Compliance: Non-compliance is defined as failure to comply with applicable NIH Human Research Pro-
tections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of hu-
man research subjects. Non-compliance may be further characterized as: 
1. Serious non-compliance: Non-compliance that: 
a. Increases risks, or causes harm, to participants. 
b. Decreases potential benefits to participants. 
c. Compromises the integrity of the NIH HRPP. 
d. Invalidates the study data. 
2. Continuing non-compliance: Non-compliance that is recurring. 
3. Minor (non-serious) non-compliance: Non-compliance that is neither serious nor continuing. 

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10.2 
Adverse event management: 
The following adverse event management guidelines are intended to ensure the safety of each subject 
while on the study.  Adverse events and adverse device effects will be attributed to study procedure and 
graded by severity according to the following tables: 
10.2.1 Grading of adverse events and adverse device effects 
Category 
Description 
Mild 
Awareness of symptom. Not expected to have a clinically significant effect on 
the subject’s condition. Not surpassing the expected standard medical inter-
vention. 
Moderate 
Condition creates a level of discomfort that interferes with the subject’s usual 
activity or affects clinical status. May require medical intervention.  
Severe 
Incapacitating and significantly affects the subject’s clinical status. Likely re-
quires medical intervention and prolonged hospitalization.  
 
10.2.2 Attribution of adverse events to the research protocol 
The relatedness of adverse events will be classified as: 
Classification 
Description 
Definite 
The event is clearly related to the research protocol. 
Probable 
The event is likely related to the research protocol. The event has a reasona-
ble temporal relationship to the research device or research procedure and 
alternative causes, such as underlying disease, concomitant medications, or 
concomitant treatment-can be excluded. 
Possible 
The event may be related to the research protocol. The event has a reasona-
ble temporal relationship to the research device or research procedure, and 
attribution of the event to the device or procedure cannot be excluded. How-
ever, alternative causes—such as underlying disease, concomitant medica-
tions, or concomitant treatments—are presumably responsible. 
Unlikely 
It is doubtful the event is related to the research protocol. The event can rea-
sonably be explained by other factures, including underlying disease, concom-
itant medications, or concomitant treatments.  
Unrelated 
The event is clearly not related to the research protocol. There either is no 
temporal association with the research device or procedure, or the event is 
readily explained by other factures, including underlying disease, concomitant 
medications, or concomitant treatments.  
 

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10.2.3 Adverse Event Reporting 
Adverse event recording will start on Day (0) of the Transcaval TAVR procedure and will continue through 
the 12 month Follow Up. New events or conditions present at baseline that increase in severity will be 
recorded and evaluated and reported on the case report form. Once the subject has completed the 30 
day follow up, only serious adverse events (SAE), serious adverse device effects (SADE), unanticipated de-
vice effects (UADE) and unanticipated problems (UP) will be reported to the Sponsor.  It is the responsibil-
ity of the site investigator to report adverse events and adverse device effects to their respective IRBs or 
other regulatory bodies according to their reporting requirements. Monitoring visits will be conducted by 
the Sponsor to review source documentation, and accuracy and completion of the adverse event case re-
port forms. 
10.2.4 Adverse event reporting timeframes: 
Serious Adverse Events (SAEs) 
• 
All serious adverse events will be reported to the Sponsor immediately but not later than five 
(5) working days from the event. The respective institutional IRB should be notified according 
to their requirements.  
• 
The serious adverse event will be evaluated by the sponsor. If determined to be an unantici-
pated adverse device effect that increases the risk to the participating subjects, the sponsor 
will terminate the investigation within 5 days after making the determination, and not later 
than 15 working days after the sponsor was first notified of the event. [21 CFR 812.46] 
Unanticipated Adverse Device Effects (UADE) 
• 
Must be reported to the Sponsor and the institutional IRB immediately but no later than 10 
working days after the investigator learns of the event. [21 CFR 812.150] 
• 
Unanticipated Adverse Device Effects should be reported via telephone as well as on the ad-
verse event section of the case report form.  
• 
If the event is determined by the Sponsor to be a UADE, the Sponsor will report the event to 
all investigators to enable reporting to their respective IRB/regulatory bodies. The Sponsor 
will provide this notification to participating sites and to the FDA within 10 working days after 
they first receive notice of the effect.  [21 CFR 812.150] 
• 
All Unanticipated Adverse Device Effects will be reported by the Sponsor to the NHLBI IRB im-
mediately upon notification but no later than 10 working days.  
Deaths 
• 
The investigator will notify the Sponsor immediately but within 3 working days of notification 
of a subject’s death, whether the death is device related or clinical condition. Institutional 
IRB’s will be notified according to the specific institutional regulatory requirements for report-
ing a death.  
• 
The Sponsor will notify the NHLBI IRB of a subject’s death within 7 days.  
• 
A subject’s death will be recorded on the Case Report Form.  

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10.3 
Scheduled reporting to FDA 
Given that this is a first-in-human study, FDA requests reporting of 30 day outcomes via IDE progress re-
port after every 5 subjects for the first 15. 
These reports may contain data that have not yet undergone independent data monitoring.  These re-
ports will not have undergone independent adjudication, which is performed after completion of the 
study. 
11.0 
HUMAN SUBJECTS PROTECTION 
11.1 
Rationale for Subject Selection 
11.1.1 Study population: 
Subjects are selected for being adults undergoing transcatheter aortic valve replacement (TAVR) who are 
not eligible for conventional transfemoral artery access, and who are anatomically suitable for transcaval 
access based on analysis of a baseline CT.  
No patient will be excluded from participation based on gender, race or ethnicity.   
11.2 
Risks and Discomforts 
There are no approved commercial devices indicated to close transcaval access ports. 
A formal risk analysis is provided in APPENDIX A. 
The risks of transcaval access for transcatheter aortic valve replacement are elaborated on the section de-
scribing Adverse Device Effects (ADE) on page 19.  
The most common access-agnostic complications of conventional TAVR are listed here  myocardial perfo-
ration and pericardial tamponade, aortic annular disruption, acute coronary artery occlusion and myocar-
dial ischemia or infarction, paravalvular aortic regurgitation, stroke, pacemaker-induced myocardial dys-
function, conduction abnormalities requiring temporary or permanent pacemaker therapy, cardiac ar-
rhythmias, cardiogenic shock, respiratory failure, renal injury or failure, THV failure requiring emergency 
cardiac surgery or emergency mechanical circulatory assistance, radiation injury including intractable skin 
injury, hypertension or hypotension. 
11.2.1  Risks Related to Radiation 
In this research protocol, subjects will be exposed to radiation from 2 follow-up CT scans and from fluor-
oscopy related to deployment of the TCD.  It is estimated that the amount of research radiation that a 
subject will be exposed to during participation in this research protocol will be approximately 3-4 REM 
from the CT scans and 0.03 Gy from approximately 3-5 minutes of fluoroscopy during deployment of the 
TCD.  We believe this amount to be reasonable in this setting, given the seriousness of their cardiovascu-
lar disease and risks of non-transfemoral artery access for TAVR. We estimate the benefit to the research 
subjects for these procedures to outweigh the risks. Each participating site will obtain approval by an In-
stitutional Radiation Safety Office to confirm with local requirements.  
11.2.2 Personal Identifiable Information 
Clinical data from subjects participating in this trial will retain personally identifiable information. This in-
cludes CT scans, echocardiograms, and medical records. 

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Abstracted data will be coded and de-identified for transmission to participating subcontracting investiga-
tors, such as core imaging laboratories, clinical events adjudication committee, and statistician. 
DICOM data will be stored in a secured NIH research PACS system for analysis, including personally identi-
fiable information.  
12.0 
TEST ARTICLES and INDICATIONS FOR USE 
The Transmural Systems Transcaval Closure Device (TCD) is a percutaneous, catheter-based system de-
signed to close an opening in the abdominal aorta created by a large-caliber vascular introducer sheath 
and is fully retrievable using its delivery system.  The TCD consists of two main elements: (1) a delivery 
system and (2) the closure implant.   
The transcaval closure implant is designed to close an opening in the abdominal aorta created when using 
a large-caliber vascular introducer sheath advanced from the nearby inferior vena cava (IVC) during a 
transcaval catheter-based procedure.  The closure device body is constructed from a nitinol wire which 
creates a mesh frame consisting of a Intravascular Disk (Distal Disk), Neck region and an EXTRAVASCULAR 
Disk (Proximal Disk).  The nitinol wire provides visibility during the implant procedure using fluoroscopy.   
When implanted, the Intravascular Disk is placed within the lumen of the aorta and the Extravascular  Disk 
is placed on the exterior (adventitia) of the aorta. An inner spring coil, attached at each end of the nitinol 
mesh frame, provides a mechanical compressive force that brings the center of the  intravascular and ex-
travascular disks together across the adventitia and aortic lumen when deployed.  A cranial paddle made 
from Nitinol wire is attached to the inner surface of the intravascular disk and covered with the knitted 
polyester fabric.  The cranial paddle acts as an extension of the intravascular disk and is designed to re-
duce the likelihood of a pull-through. 
High density, woven polyester fabric is incorporated inside of both the Intravascular and Extravascular 
Disks, which creates a sealing hemostatic patch on either side of the opening in the aortic vessel.  A knit-
ted polyester fabric is shaped and secured to the outside of the closure device, covering the neck and a 
woven polyester fabric is secured to the insides of the Intravascular and Extravascular Disks. These polyes-
ter fabrics are designed to aid with hemostasis by sealing around the opening in the aorta as the neck 
area expands during deployment. 
The transcaval delivery system consists of three separate components, used as a system, to load, deliver 
and release the closure device: The Outer Delivery Catheter, a Delivery shaft and an inner Extension Rod.  
The components of the delivery system are designed to provide the flexibility necessary to be advanced 
through the vasculature but the stability required to position and deploy the TCD.   
12.1 
Indications for use 
Transcaval Closure Device (TCD) is intended for the closure of percutaneous aortic vascular access for pa-
tients who have undergone diagnostic or interventional transcaval catheterization procedures using intro-
ducer sheaths up to 26Fr as long as the expanded outer diameter (OD) does not exceed 8.9mm .   
This study will evaluate subjects undergoing transcaval TAVR procedures. 
13.0 
INVESTIGATOR ADMINISTRATIVE REQUIREMENTS 
13.1 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) E6 
(Guideline for Good Clinical Practice), the ethical principles that have their origin in Title 21 of the Code of 

IDE Transcaval Closure Device 
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2018-02-12 
Federal Regulations, Parts 50 (Protection of Human Subjects), and 56 (Institutional Review Boards), and 
other appropriate regulatory requirement(s). The Investigator will be thoroughly familiar with the trans-
caval technique as described in the protocol and the Investigational plan. Essential clinical documents will 
be maintained to demonstrate the validity of the study and the integrity of the data collected. Regulatory 
files should be established at the beginning of the study, maintained for the duration of the study and re-
tained according to the appropriate regulations. 
13.2 
IRB Submissions 
The IRB/IEC and other appropriate institutional regulatory bodies will review all appropriate study docu-
mentation in order to safeguard the rights, safety, and well-being of the subjects. The study will only be 
conducted at sites where IRB/IEC and other appropriate institutional regulatory body approval have been 
obtained. The protocol, informed consent, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/IEC and other appropriate institutional regulatory bodies by 
the Investigator. 
13.3 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the subject or 
his/her legal representative prior to study participation. The method of obtaining and documenting the 
informed consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory 
requirement(s). 
Subjects who are unable to provide consent may be enrolled, if allowed by participating IRBs.  Consent for 
these subjects must be obtained from a legally authorized representative. The process for obtaining this 
consent must conform to local human subjects protection policies and to state laws. 
13.4 
Study Eligibility Committee 
Clinical data for all research candidates are confirmed by the study eligibility committee before enroll-
ment. 
The study eligibility committee consists of the NHLBI investigators, the local site principal investigators, 
and the NHLBI Core Lab.  A quorum of the committee requires a local site investigator where the candi-
date is not to be enrolled, as well as at least two NHLBI investigators and the NHLBI Core Lab. This also 
assures that at least one member of the Study Eligibility Committee is not an inventor of the TCD and does 
not have an actual or perceived financial conflict of interest. 
The considerations and determination of the Study Eligibility Committee will be recorded. 
13.5 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by the Sponsor, and 
given approval/favorable opinion by the IRB/IEC and other appropriate institutional regulatory bodies. 
Modifications to the protocol should not be made without agreement of both the Investigator and the 
Sponsor. Changes to the protocol will require written IRB/IEC and other appropriate institutional regula-
tory body approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory authority 
(ies) permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval /favorable opinion of the IRB/IEC and other appropriate institutional regulatory bodies. 

IDE Transcaval Closure Device 
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2018-02-12 
The Sponsor will submit all protocol modifications to the regulatory authority(ies) in accordance with the 
governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to subjects, 
the Investigator will contact the Sponsor, if circumstances permit, to discuss the planned course of action. 
Any departures from the protocol must be fully documented in the CRF and source documentation. 
13.6 
Investigational Device Accountability 
Access to investigational devices shall be controlled and the investigational devices shall be used only in the 
clinical investigation and according to the investigational plan.  The Sponsor shall keep records to document 
the physical location of all investigational devices from shipment of investigational devices to the investiga-
tion sites until return or disposal.  The Principal Investigator or an authorized designee shall keep records 
documenting the receipt, use, return and disposal of the investigational devices, which shall include  
• 
The date of receipt, 
• 
Identification of each investigational device (serial number or unique code), 
• 
The expiry date, if applicable, 
• 
The date or dates of use, 
• 
Subject identification, 
• 
Date on which the investigational device was returned/explanted from subject, if applicable, and 
• 
The date of return of unused, expired or malfunctioning investigational devices, if applicable. 
The investigational devices will include the following labeling “CAUTION: Investigational Device. Limited by 
United States law to investigational use.” 
13.7 
Data monitoring plan 
13.7.1 Direct Access to Source Data 
Monitoring and auditing procedures developed by the Sponsor will be followed, in order to comply with 
GCP guidelines. 
Regulatory authorities, the IRB/IEC and other appropriate institutional regulatory bodies, and/or the 
Sponsor may request access to all source documents, CRFs, and other study documentation for on-site 
audit or inspection. Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. 
13.7.2 
Subject Confidentiality 
In order to maintain subject privacy, all CRFs, accountability records, study reports, and communications 
will identify the subject by initials and the assigned subject number. The Investigator will grant research 
data monitor(s) and auditor(s) from the Sponsor or its designee and regulatory authority (ies) access to 
the subject’s original medical records for verification of data gathered on the CRFs and to audit the data 
collection process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 

IDE Transcaval Closure Device 
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2018-02-12 
13.7.3 Case Report Form Completion 
CRFs will be completed for each study subject. It is the Principal Investigator’s responsibility to ensure the 
accuracy, completeness, and timeliness of the data reported in the subject’s CRF. Source documentation 
supporting the CRF data should indicate the subject’s participation in the study and should document the 
dates and details of study procedures, AEs, and subject status. 
The Principal Investigator or designated representative, should complete the CRF as soon as possible after 
information is collected, preferably on the same day that a study subject is seen for an examination, treat-
ment, or any other study procedure but no more than 5 days post procedure. An explanation should be 
given for all missing data. 
The Principal Investigator must sign and date the Investigator’s Statement at the end of the CRF to en-
dorse the recorded data. 
Data recordation will not necessarily be 21CFR11 compliant (which describes data management quality 
practices for electronic data recordation when collecting research data for regulatory filings towards com-
mercialization).  If not, data recordation will use paper documents. 
Datasets will be locked for analysis after appropriate monitoring against source documentation, and locked 
scanned or electronic copies sequestered that correspond to the primary publication and the report(s) of 
findings to FDA.     
13.7.4 Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory require-
ment(s). Records will be retained for at least 2 years following marketing application approval or 2 years 
after formal discontinuation of the clinical development of the investigational product or according to ap-
plicable regulatory requirement(s). If the Investigator withdraws from the responsibility of keeping the 
study records, custody must be transferred to a person willing to accept the responsibility. The Sponsor 
must be notified in writing if a custodial change occurs. 
The Sponsor and Transmural Systems, LLC, have full rights over any invention, discovery, or innovation, 
patentable or not, that may occur in performing the study. 
13.8 
Publication and Presentation of Study Findings and Use of Information 
It is anticipated that the results of this study will be presented at scientific meetings and/or published in a 
peer reviewed scientific or medical journal. A Publications Committee comprised of Investigators partici-
pating in the study and the Sponsor, as appropriate, will be formed to oversee the publication and presen-
tation of the study results, which will reflect the experience of all participating clinical sites. No publica-
tion or disclosure of study results will be permitted except under the terms and conditions of a separate 
written agreement between Sponsor and the investigator and/or the investigator's institution. 
14.0 
SPONSOR REGULATORY REQUIREMENTS 
14.1 
Role of Sponsor 
As the study sponsor of this clinical study, Dr. Robert Lederman has the overall responsibility for the con-
duct of the study, including assurance that the study meets the regulatory requirements of the appropri-
ate regulatory bodies.  

IDE Transcaval Closure Device 
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2018-02-12 
14.2 
General Duties 
The Sponsor's general duties consist of submitting the appropriate regulatory applications, selecting in-
vestigators, obtaining their signed agreement, providing them with the information necessary to conduct 
the study, ensuring proper clinical site monitoring, and ensuring study subject informed consent is ob-
tained.   
14.3 
Research Monitoring Plan 
An independent research monitor will be designated by the Sponsor.  Monitoring will be done by personal 
visits and will include on-site review of the informed consent documents and case report forms for com-
pleteness and clarity, cross-checking with source documents, and clarification of administrative matters 
will be performed. The review of medical records will be performed in a manner to ensure that subject 
confidentiality is maintained. The site monitor will ensure that the investigation is conducted according to 
protocol design and regulatory requirements by frequent communications (letter, e-mail, telephone, and 
fax). 
Data from all treated subjects will be monitored (100% subject monitoring). 
14.4 
Site Selection and Training 
The sponsor or its designee (national co-principal investigator) will ensure appropriate training in the 
technique of caval-aortic access and operation of the TCD system prior to treatment with the TCD at any 
participating institution. 
14.4.1 Site selection: 
Site selection will be based on  
• 
Physician expression of interest and need to apply this treatment approach to patients at the site. 
• 
Physician prior experience with at least 10 successful transcaval access and closure procedures, to 
assure operator competence 
• 
Site prior participation in IDE protocols evaluating a treatment of structural heart disease 
• 
Site ability to obtain CT examinations that are satisfactory for consideration of transcaval 
access. 
• 
Site investigators willing and able to comply with the requirements of this protocol. 
14.4.2 Site training: 
Site training will consist of 
• 
Principal investigator and/or sponsor didactic training about the technique, preclinical, and clinical 
experience to date. 
• 
Proper use of the TCD System and protocol requirements.   
• 
Site Initiation Visits (SIV) will be conducted by the designated monitoring contractor and will be 
attended by research coordinators, research assistants and other staff participating in this re-
search study. The SIV will typically be conducted prior to enrollment of the first subject.   

IDE Transcaval Closure Device 
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REFERENCES 
1. 
Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana 
GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, 
Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S and Investigators PT. Transcatheter aortic-valve 
implantation for aortic stenosis in patients who cannot undergo surgery. The New England journal of 
medicine. 2010;363:1597-607. 
2. 
Popma JJ, Adams DH, Reardon MJ, Yakubov SJ, Kleiman NS, Heimansohn D, Hermiller J, Jr., 
Hughes GC, Harrison JK, Coselli J, Diez J, Kafi A, Schreiber T, Gleason TG, Conte J, Buchbinder M, Deeb 
GM, Carabello B, Serruys PW, Chenoweth S, Oh JK and CoreValve United States Clinical I. Transcatheter 
aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at 
extreme risk for surgery. J Am Coll Cardiol. 2014;63:1972-81. 
3. 
Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana 
GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, Pichard AD, 
Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D, Pocock SJ and Investigators PT. 
Transcatheter versus surgical aortic-valve replacement in high-risk patients. The New England journal of 
medicine. 2011;364:2187-98. 
4. 
Adams DH, Popma JJ, Reardon MJ, Yakubov SJ, Coselli JS, Deeb GM, Gleason TG, Buchbinder 
M, Hermiller J, Jr., Kleiman NS, Chetcuti S, Heiser J, Merhi W, Zorn G, Tadros P, Robinson N, Petrossian 
G, Hughes GC, Harrison JK, Conte J, Maini B, Mumtaz M, Chenoweth S, Oh JK and Investigators USCC. 
Transcatheter aortic-valve replacement with a self-expanding prosthesis. The New England journal of 
medicine. 2014;370:1790-8. 
5. 
Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, Thourani VH, Tuzcu EM, 
Miller DC, Herrmann HC, Doshi D, Cohen DJ, Pichard AD, Kapadia S, Dewey T, Babaliaros V, Szeto WY, 
Williams MR, Kereiakes D, Zajarias A, Greason KL, Whisenant BK, Hodson RW, Moses JW, Trento A, 
Brown DL, Fearon WF, Pibarot P, Hahn RT, Jaber WA, Anderson WN, Alu MC, Webb JG and Investigators 
P. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. The New England 
journal of medicine. 2016;374:1609-20. 
6. 
Halabi M, Ratnayaka K, Faranesh AZ, Chen MY, Schenke WH and Lederman RJ. Aortic access 
from the vena cava for large caliber transcatheter cardiovascular interventions: pre-clinical validation. J Am 
Coll Cardiol. 2013;61:1745-6. 
7. 
Greenbaum AB, O'Neill WW, Paone G, Guerrero ME, Wyman JF, Cooper RL and Lederman RJ. 
Caval-aortic access to allow transcatheter aortic valve replacement in otherwise ineligible patients: initial 
human experience. J Am Coll Cardiol. 2014;63:2795-804. 
8. 
Lederman RJ, Babaliaros VC and Greenbaum AB. How to perform transcaval access and closure 
for transcatheter aortic valve implantation. Catheter Cardiovasc Interv. 2015;86:1242-54. 
9. 
Lederman RJ, Greenbaum AB, Rogers T, Khan JM, Fusari M and Chen MY. Anatomic Suitability 
for Transcaval Access Based on Computed Tomography. JACC Cardiovasc Interv. 2017;10:1-10. 
10. 
Marchand A, Galen RS and Van Lente F. The predictive value of serum haptoglobin in hemolytic 
disease. JAMA : the journal of the American Medical Association. 1980;243:1909-11. 
11. 
Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, 
Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, 
Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW and Leon MB. Updated standardized 
endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 
consensus document. J Am Coll Cardiol. 2012;60:1438-54. 
12. 
Greenbaum AB, Babaliaros VC, Chen MY, Stine AM, Rogers T, O'Neill WW, Paone G, Thourani 
VH, Muhammad KI, Leonardi RA, Ramee S, Troendle JF and Lederman RJ. Transcaval Access and 

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Closure for Transcatheter Aortic Valve Replacement: A Prospective Investigation. J Am Coll Cardiol. 
2017;69:511-521. 
13. 
Geller NL, Follman D, Leifer ES and Carter SL. Design of Early Trials in Stem Cell Transplantation: 
A Hybrid Frequentist-Bayesian Approach In: N. L. Geller, ed. Advances in Clinical Trial Biostatistics: 
Chapman & Hall / CRC Press 2003. 

KEY LEVEL 
1 
2 
3 
4 
5 
Probability 
Rare 
Uncommon 
Common 
Normal 
Severity 
Easy to correct, no anticipated harm to 
patient 
Difficult to correct, no anticipated harm to 
patient 
Potentially harmful to pa-
tient 
Likely harmful, even with immediate cor-
rection 
Life threaten-
ing 
Risk Score 
1-4 
5-9 
10-20 
>20 
Risk Interpreta-
Negligible 
Tolerable 
Tolerable but undesirable Intolerable 
 
15.0 
Appendix A: Risk Analysis 
Event 
Narrative 
Probability Severity Risk (Probability 
x Severity) 
Available Evidence to Consider Risk 
Conclusion and risk mitigation strategy 
Death 
Death is an expected complica-
tion of complex and high risk 
structural heart interventional 
procedures, especially in those 
with no good conventional op-
tions. 
1 
5 
5 
All testing performed to date in both animal 
and bench studies has demonstrated that the 
device is robust and will perform as expected.  
The TCD was specifically designed to over-
come challenges associated with off-label use 
of commercially-available devices. 
The risk, while appreciable, is graded as tol-
erable in light of the potential benefit.  
Risk will further be mitigated with informed con-
sent. 
Hemorrhage re-
quiring blood 
transfusion 
Hemorrhage is expected after 
transcaval access and closure.  
Bleeding attributed to transcaval 
access is expected to be retro-
peritoneal (see below). 
1 
4 
4 
Animal testing with the TCD demonstrated imme-
diate hemostasis.  The TCD was specifically de-
signed to overcome challenges associated with 
off-label use of commercially-available devices.  
This risk is graded as negligible, and justified 
in light of the potential benefit. 
Risk will be further mitigated by monitoring of 
subjects for signs and symptoms of blood loss to 
allow for early treatment. In addition, the clinical 
protocol will instruct physicians to deploy a cov-
ered stent if required to control bleeding.   
Hemorrhagic 
shock requiring 
intervention 
Persistent bleeding, presumed 
retroperitoneal, may require ad-
ditional management including 
crystalloid, vasopressor, blood 
transfusion, and mechanical in-
tervention. 
1 
5 
5 
Animal testing with the TCD demonstrated imme-
diate hemostasis.  The TCD was specifically de-
signed to overcome challenges associated with 
off-label use of commercially-available devices. 
The risk, while tolerable, is considered justi-
fied in light of the potential benefit. 
Risk will be further mitigated by monitoring of 
subjects for signs and symptoms of blood loss to 
allow for early treatment. In addition, the clinical 
protocol will instruct physicians to deploy a cov-
ered stent if required to control bleeding.   
Persistent 
aorto-caval fis-
tula requiring 
intervention 
Residual aorto-caval fistula is ex-
pected to be universal 
1 
3 
3 
Animal testing with the TCD demonstrated imme-
diate hemostasis.  The TCD was specifically de-
signed to overcome challenges associated with 
off-label use of commercially-available devices. 
Based on clinical features, this aorto-caval shunt 
is hemodynamically insignificant, especially com-
pared with intentional arteriovenous shunts such 
as those implanted to facilitate hemodialysis. 
This risk is graded as negligible, and justified 
in light of the potential benefit. 
Risk will be further mitigated by having the proto-
col include CT examinations at each follow up 
through 1 year to monitor the presence of A/V 
Fistula. 

KEY LEVEL 
1 
2 
3 
4 
5 
Probability 
Rare 
Uncommon 
Common 
Normal 
Severity 
Easy to correct, no anticipated harm to 
patient 
Difficult to correct, no anticipated harm to 
patient 
Potentially harmful to pa-
tient 
Likely harmful, even with immediate cor-
rection 
Life threaten-
ing 
Risk Score 
1-4 
5-9 
10-20 
>20 
Risk Interpreta-
Negligible 
Tolerable 
Tolerable but undesirable Intolerable 
 
Event 
Narrative 
Probability Severity Risk (Probability 
x Severity) 
Available Evidence to Consider Risk 
Conclusion and risk mitigation strategy 
Retroperitoneal 
hemorrhage 
Retroperitoneal bleeding is ex-
pected in all patients undergoing 
transcaval access for TAVR. The 
expected mechanism is that aor-
tic hemorrhage pressurizes the 
retroperitoneal space causing de-
compression of the hemorrhage 
into the hole in the inferior vena 
cava. 
1 
3 
3 
Animal testing with the TCD demonstrated imme-
diate hemostasis.  The TCD was specifically de-
signed to overcome challenges associated with 
off-label use of commercially-available devices. 
The risk is rated as negligible. It is considered 
justified in light of the potential benefit. 
Risk will further be mitigated with informed con-
sent. 
Aortic or other 
vascular injury 
such as aortic dis-
section, pseudo-
aneurysm or per-
foration 
Heavily diseased aortas may be in-
jured during caval-aortic crossing 
or during closure device deploy-
ment 
2 
4 
8 
The TCD Implant and delivery system are de-
signed to overcome challenges associated with 
off-label use of commercially-available devices.   
Iatrogenic aortic pseudoaneurysm is part of the 
spectrum of retroperitoneal hemorrhage, and 
represents a volume of blood in continuity with 
the aorta that is partly or completely surrounded 
by fresh or organized thrombus. We expect the 
pseudoaneurysm and hematoma, both in physi-
cal proximity to the implanted TCD, to resolve in 
follow-up as part of healing. 
The risk is rated as tolerable. It is considered 
justified in light of the potential benefit. 
Risk will be further mitigated by monitoring of 
subjects for signs and symptoms of blood loss to 
allow for early treatment. The clinical protocol 
will instruct physicians to use either balloon aor-
tic tamponade or a covered stent in the case of 
aortic injury. 
The protocol will include CT examinations at each 
follow up through 1 year to monitor vascular in-
jury.  
Thrombocyto-
penia or hemo-
lytic anemia as a 
consequence of 
aorto-caval fis-
tula 
Mechanical injury to blood cells 
may result from residual aorto-
caval shunt after device closure 
of the caval-aortic access site 
1 
3 
3 
Animal testing with the TCD demonstrated imme-
diate hemostasis.  The TCD was specifically de-
signed to overcome challenges associated with 
off-label use of commercially-available devices. 
The risk is rated as negligible. It is considered 
justified in light of the potential benefit. 
Risk will be further mitigated by monitoring of 
subjects for signs and symptoms of blood loss to 
allow for early treatment. The clinical protocol 
will instruct physicians to use either balloon aor-
tic tamponade or a covered stent in the case of 
aortic injury. 
The protocol will include CT examinations at 
each follow up through 1 year to monitor vascu-
lar injury. 

KEY LEVEL 
1 
2 
3 
4 
5 
Probability 
Rare 
Uncommon 
Common 
Normal 
Severity 
Easy to correct, no anticipated harm to 
patient 
Difficult to correct, no anticipated harm to 
patient 
Potentially harmful to pa-
tient 
Likely harmful, even with immediate cor-
rection 
Life threaten-
ing 
Risk Score 
1-4 
5-9 
10-20 
>20 
Risk Interpreta-
Negligible 
Tolerable 
Tolerable but undesirable Intolerable 
 
Event 
Narrative 
Probability Severity Risk (Probability 
x Severity) 
Available Evidence to Consider Risk 
Conclusion and risk mitigation strategy 
Late erosion or 
migration or un-
expected peri-
vascular pathol-
ogy 
There is a theoretical risk of un-
expected late complications of 
caval-aortic access and closure, 
including device erosion, failure, 
migration, or late vascular or 
perivascular remodeling or other 
pathology. 
1 
4 
4 
The adaptive geometry of the Intravascular disk 
and neck along with compression element and 
outer PET fabric is designed to conform to aortic 
pathology and irregular mural rents to achieve 
hemostasis under a range of anatomies.  In addi-
tion, outer PET fabric is designed to allow for tis-
sue ingrowth for long-term hemostasis. 
This risk is graded as negligible and justified in 
light of the potential benefit. 
Risk will be further mitigated by the protocol in-
cluding CT examinations at each follow up 
through 1 year to monitor the presence of ero-
sion 
Nephrotoxic in-
jury due to ad-
ditional io-
dinated radio-
contrast during 
transcaval TAVR 
and associated 
follow-up 
Iodinated radiocontrast is neces-
sary for X-ray procedures includ-
ing TAVR. Aortography is per-
formed as part of transcaval ac-
cess and closure and requires io-
dinated contrast.  This may be 
offset in part or in whole by io-
dinated contrast not adminis-
tered as part of management of 
large-bore arterial access for con-
ventional TAVR 
1 
3 
3 
 
The risk is rated as negligible. It is considered 
justified in light of the potential benefit. 
Risk will further be mitigated with informed con-
sent. 
Infection, early 
or late 
Prosthetic implants risk early or 
late infection 
2 
4 
8 
Sterilization and packaging validation results con-
firm that the product, as packaged, will maintain 
a sterility assurance level (SAL) of 10-6 and that 
the sterile barrier is maintained through transit. 
Antimicrobial prophylaxis is a routine component 
of TAVR performed during the same session as 
the transcaval access and closure. 
This risk is graded as tolerable.  It is considered 
justified in light of the potential benefit. 
Risk will be further mitigated by the IFU includ-
ing a precaution for physicians to evaluate the 
packaging at the time of use and to not use 
product where the sterile barrier may be com-
promised.  In addition, prophylactic antibiotics 
will be prescribed per standard TAVR follow up. 

KEY LEVEL 
1 
2 
3 
4 
5 
Probability 
Rare 
Uncommon 
Common 
Normal 
Severity 
Easy to correct, no anticipated harm to 
patient 
Difficult to correct, no anticipated harm to 
patient 
Potentially harmful to pa-
tient 
Likely harmful, even with immediate cor-
rection 
Life threaten-
ing 
Risk Score 
1-4 
5-9 
10-20 
>20 
Risk Interpreta-
Negligible 
Tolerable 
Tolerable but undesirable Intolerable 
 
Event 
Narrative 
Probability Severity Risk (Probability 
x Severity) 
Available Evidence to Consider Risk 
Conclusion and risk mitigation strategy 
Aortic lumen re-
duction/ occlu-
sion 
During or after placement of the 
TCD implant, the aortic lumen 
could be reduced or occluded 
due to improper placement of 
the implant. 
1 
5 
5 
The TCD implant is designed to be repositionable 
and re-deployable to allow the physician to opti-
mally place the device. 
Animal testing has been performed which 
demonstrates that the TCD can be repositioned 
and re-deployed with no safety concerns. 
The risk is rated as tolerable. It is considered 
justified in light of the potential benefit.   
Risk will be further mitigated by the instructions 
for use and user training providing users infor-
mation on how to recognize improper device ori-
entation under imaging and how to correct the 
orientation.  
The clinical protocol will instruct physicians to 
use either balloon aortic tamponade or a cov-
ered stent to aid with re-opening of the lumen. 
Thromboembo-
lism / Throm-
bosis 
During or after placement of the 
TCD implant, thrombosis of the 
implant could occur due to im-
proper placement of the implant. 
1 
4 
4 
The TCD implant is designed to be repositionable 
and re-deployable to allow the physician to opti-
mally place the device. 
Animal testing has been performed which 
demonstrates that the TCD can be repositioned 
and re-deployed with no safety concerns. 
Animal testing has been performed and no 
thromboembolism/thrombosis observed grossly 
or via histopathology.   
This risk is graded as negligible, and justified in 
light of the potential benefit. 
Risk will be further mitigated by the instructions 
for use and user training providing users infor-
mation on how to recognize improper device ori-
entation under imaging and how to correct the 
orientation. 
Venous throm-
bosis or throm-
boembolism 
Thrombosis may occur related to 
the femoral vein access site, re-
lated to the TCD implant, or caus-
ing thromboembolism from ei-
ther nidus. 
2 
4 
5 
Large-bore femoral vein access is a common step 
in structural heart interventional procedures 
such as Mitraclip and transcatheter mitral valve 
implantation. Catheter related femoral throm-
bosis is treated only if clinically symptomatic and 
manifest.  
TCD thrombogenicity is evaluated pre-clinically. 
TCD is expected to encroach on IVC less than 
comparator Amplatzer devices implanted in the 
transcaval position. 
The risk is rated as tolerable. It is considered jus-
tified in light of the potential benefit. 
Risk will be further mitigated through CT evalua-
tion of the TCD implant site during follow-up, 
and by clinical surveillance for adverse events. 

KEY LEVEL 
1 
2 
3 
4 
5 
Probability 
Rare 
Uncommon 
Common 
Normal 
Severity 
Easy to correct, no anticipated harm to 
patient 
Difficult to correct, no anticipated harm to 
patient 
Potentially harmful to pa-
tient 
Likely harmful, even with immediate cor-
rection 
Life threaten-
ing 
Risk Score 
1-4 
5-9 
10-20 
>20 
Risk Interpreta-
Negligible 
Tolerable 
Tolerable but undesirable Intolerable 
 
Event 
Narrative 
Probability Severity Risk (Probability 
x Severity) 
Available Evidence to Consider Risk 
Conclusion and risk mitigation strategy 
Adverse biologi-
cal reaction 
The materials of the TCD implant 
or delivery system have the po-
tential to illicit a biological re-
sponse due to non-compatibility. 
1 
4 
4 
The materials for the delivery system and the im-
plant were selected based upon known previous 
biocompatibility with blood and tissue. 
A suite of biocompatibility testing has been per-
formed which demonstrates the delivery system 
and the implant are non-toxic and not expected 
to illicit an adverse biological response. 
This risk is graded as negligible, and justified in 
light of the potential benefit. 
Risk will be further mitigated by monitoring of 
subjects for signs and symptoms of allergic reac-
tions.  Labeling will include a contraindication for 
patients allergic to nickel. 
Thermal injury 
The TCD is a permanent implant 
constructed of metal and there-
fore may be susceptible to heat-
ing in a MRI environment 
1 
3 
3 
1.5T and 3.0T testing in a standard MRI demon-
strates that the TCD Implant is MR Conditional. 
This risk is graded as negligible, and justified in 
light of the potential benefit. 
Risk will be further mitigated by the IFU and pa-
tient implant card providing the information to 
support appropriate MRI use.