NHLBI DIR LAMPOON Study: Intentional Laceration of the Anterior Mitral Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Implantation
Phase: NA
Conditions: Mitral Valve Failure
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
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Protocol Title:  
NHLBI DIR LAMPOON Study: Intentional laceration of the anterior mitral leaflet to prevent left ventricular 
outflow tract obstruction during transcatheter mitral valve implantation  
Version History 
2016-11-07 
IDE Submission 
 
2016-11-14  
NHLBI Branch Review 
 
2016-12-02 
FDA IDE Submission 
 
2016-12-09 
NHLBI Scientific Review 
 
2016-12-27 
NHLBI IRB  
Response to Stipulations for NHLBI Scientific Review 
 2017-03-31 
Amendment A 
Stopping rules, removed consent waiver for retrospective 
review 
2017-04-26 
Response 
Stipulations for Amendment A 
2017-08-17 
Amendment B 
Additional adverse device effect definitions.  Additional 
sites 
2017-10-13 
Amendment C 
Updated selection criteria. Additional sites, new AADE 
2018-01-17 
Amendment D 
Update sites; consent amendment DSMB 
2018-09-05 
Amendment E 
Add Core Lab; Section 9.1 Data Transfer to Collaborators; 
Reclassify additional secondary endpoints as exploratory 
2019-10-17 
Amendment F 
Administrative amendment. Study staff changes only. No 
changes to protocol or consent. 
2019-11-21 
CR approval 
2019 Continuing Review 
2020-04-21 
Amendment G 
Update to adverse event reporting requirements as per NIH 
Policy 801.  
2020-08-24 
Amendment H 
Administrative amendment. NIH study staff change only. 
No changes to protocol or consent.  
 
Investigational Device Exemption 
G160239 issued 2016-12-08 
Sponsor-Investigator: 
Robert J. Lederman, MD, Senior Investigator, NHLBI Division of Intramural Research 

 
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Key Roles 
Role 
Individual 
Affiliation 
FWA If applicable 
 
 
 
 
 
 
Principal Investigator 
(NIH) 
Robert J. Lederman, MD 
NHLBI DIR 
00005897 
 
 
 
 
 
National Co-Principal In-
vestigators 
Adam B. Greenbaum, MD 
Vasilis C. Babaliaros, MD 
Emory University Hospital 
Emory University Hospital 
 
 
 
 
 
Study Manager 
Annette M. Stine, RN 
NHLBI DIR 
 
 
 
Associate Investigators 
(NIH) 
Jaffar M. Khan, BM BCh 
 
NHLBI DIR 
 
Echocardiography core 
lab 
Dee Dee Wang, MD  
Henry Ford Hospital 
 
CT core lab 1 
Dee Dee Wang, MD  
Henry Ford Hospital 
 
CT core lab 2 
Marcus Y. Chen, MD  
NHLBI DIR 
 
Monitoring service 
 
NHLBI Contractors 
 
Independent Clinical 
Events Adjudication 
Committee 
 
Medstar Research Institute Inc. 
 
Data Safety Monitoring 
Board 
Jamieson M. Bourque, 
MD, MHS  
NHLBI  
University of Virginia 
 

 
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IDE Study Sponsor 
Robert J. Lederman, MD, 
on behalf of NHLBI  
NHLBI DIR 
 
Data Coordinating Cen-
ter 
Robert J. Lederman, MD 
NHLBI DIR 
00005897 
Study Statistician 
Xin Tian, PhD 
NHLBI Office of Biostatistics Research 
 
Site 1 PI 
 
Marvin Eng, MD 
Henry Ford Hospital, Detroit, MI 
00005846 
Site 2 PI 
Vasilis C. Babaliaros, MD 
Emory University Hospital, Atlanta, GA 
00005792 
Site 3 PI 
Nilesh J. Goswami, MD 
 
St. John’s Hospital (enrollment), Spring-
field, IL; Prairie Education & Research Co-
operative  
 
00003647 
 
 
Site 4 PI 
Mark Reisman, MD 
James McCabe, MD 
Danny Dvir, MD 
 
University of Washington 
Division of Cardiology 
Seattle, WA 98195 
00006878 
WIRB IRB 
Site 5 PI 
 
Toby Rogers, MD  
Medstar Washington Hospital Center,  
Cardiovascular Research Program 
Washington, D.C. 20010 
00000504 
Site 6 PI 
Jason Foerst, MD 
Carilion Medical Center 
Roanoke, VA 24014 
WIRB IRB 
Site 7 PI 
Shawn Yazdani, MD 
Inova Fairfax Hospital 
Fairfax, VA 
00000573 
 
 
 
 
 
 
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 

 
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Henry Ford Hospital 
FWA#: 00005846 
 
Marvin Eng, MD 
Henry Ford Hospital, Cardiac Cath Lab K-2 
2799 West Grand Blvd, Detroit, MI. 48202 
Phone:  (313) 916-2008 
Email: meng1@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  
St. John’s Hospital (patient enrollment) 
Prairie Education & Research Cooperative 
FWA#: 00003647 
 
Nilesh J. Goswami, MD 
Prairie Education & Research Cooperative 
317 North 5th St. 
Springfield, IL   62701 
Phone: 217-788-0706 
Fax: 217-522-1206 
Email: Ngoswami@prairieheart.com 
University of Washington 
WIRB IRB 
FWA#: 00006878 
 
Mark Reisman, MD, FACC 
Clinical Professor of Medicine 
Section Head, Interventional Cardiology 
Director, Cardiovascular Emerging Therapies 
Auth Endowed Chair in Cardiovascular Innovation 
University of Washington Medical Center 
1959 NE Pacific St. Box 356171 
Seattle, WA 98195 
Email: reismanm@uw.edu 
Office: 206-598-5599 
Fax: 206-598-8269  
 Cell: 425-372-8906 
James McCabe, MD 
Division of Cardiology 
1959 NE Pacific St. Box 356422 
Seattle, VA 98195 
Phone: 206-598-6646 
Fax: 206-616-4847 
Email: jmmccabe@u.washington.edu 
Danny Dvir, MD 
Division of Cardiology 
1959 NE Pacific St. Box 356422 
Seattle, WA 98195 
Phone: 206-543-5898 
Fax: 206-616-4847 
Email: ddvir@cardiology.washington.edu  

 
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Medstar Washington Hospital Center  
FWA#: 00000504 
 
Toby Rogers, MD 
Medstar Washington Hospital Center  
110 Irving Street, NW  
Suite 4B-1  
Washington, DC 20010  
Phone: 202-877-5975  
Fax: 202-877-2715  
E-mail:  toby.rogers@gmail.com 
Carilion Medical Center 
FWA#: 00000392 
 
Jason Foerst, MD 
Director of the Adult Structural Heart and Valve Fel-
lowship Program 
Carilion Clinic Roanoke, VA 
2001 Crystal Spring Ave, Suite 203 
Roanoke, VA 24014 
Phone: 540-632-9220 
Fax: 540-266-6198 
Email: jrfoerst@carilionclinic.org 
 
Inova Fairfax Hospital 
FWA#: 00000573 
 
Shahram Yazdani, MD 
Inova Medical Group - Cardiology 
8100 Ashton Ave 
Manassas, VA 20109 
phone: (703) 335-8750 
 E-mail: Shahram.Yazdani@inova.org 
* No subject enrollment 
Estimated Duration of Study: 
[6 years] 
 
Estimated Completion Date of Study: 
December 31, 2023 
Subjects of study and sites: 
 
 
DISCLOSURES 
The non-NIH investigators have the following conflicts of interest: 
ABG serves as a proctor for Edwards Lifesciences and St Jude Medical.  
VCB is a consultant for Edwards Lifesciences and for Abbott Vascular, and his employer has research con-
tracts from Edwards Lifesciences, Abbott Vascular, Medtronic, St Jude Medical, and Boston Scientific. 
MEG serves as a proctor for, and receives research support from, Edwards Lifesciences. 
Subjects 
Sex 
Age range 
Sites 
60 screened 
30 enrolled 
Men & Women  
шϮϭǇĞĂƌƐ 
Up to 8 

 
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ABBREVIATIONS 
CT 
Computed tomography 
LAMPOON 
Intentional laceration of the anterior mitral valve leaflet to prevent LVOT obstruction 
during TMVR 
LVOT(O) 
Left ventricular outflow tract (obstruction) 
MVARC 
Mitral valve academic research consortium (criteria) 
MR 
Mitral valve regurgitation 
MS 
Mitral valve stenosis 
TAVR 
Transcatheter aortic valve implantation 
TEE 
Transesophageal echocardiography 
THV 
Transcatheter heart valve 
TMVR 
Transcatheter mitral valve implantation 
 
PRÉCIS 
Transcatheter mitral valve replacement (TMVR) is an option to treat mitral valve failure when no surgical 
options exist.  In as many as half of patients, TMVR can cause life-threatening blockage of the left ventri-
cle by displacing the existing mitral valve leaflet. For these patient’s the only options appear to avoid 
TMVR or in some to cause a focused heart attack and to wait 6 weeks.  The investigators have developed 
and tested a technique to tear the existing mitral valve leaflet and enable TMVR in patients who have no 
other options. The procedure is called intentional laceration of the anterior mitral leaflet to prevent left 
ventricular outflow tract obstruction (LAMPOON).  Although there are no dedicated TMVR devices com-
mercially available, there has been short-term success with implanted transcatheter aortic valve devices 
in the mitral position for TMVR. 
The purpose of this study is to perform LAMPOON and TMVR in patients who have no good options to 
treat their mitral valve failure, using heart valve devices designed to implant in the aortic valve position.  

 
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Table of Contents 
1.0 
Protocol Summary ............................................................................................................................. 8 
2.0 
OBJECTIVE ....................................................................................................................................... 11 
3.0 
BACKGROUND ................................................................................................................................. 11 
4.0 
CLINICAL AND SCIENTIFIC JUSTIFICATION ....................................................................................... 12 
5.0 
TREATMENT OPTIONS ..................................................................................................................... 12 
6.0 
STUDY DESIGN ................................................................................................................................. 13 
6.1 
Schematic of Study Design ............................................................................................. 13 
6.2 
Overview of Study Design .............................................................................................. 13 
6.3 
LAMPOON TMVR Procedure .......................................................................................... 13 
6.4 
Time and Events Schedule ............................................................................................. 15 
6.5 
Visit Schedule ................................................................................................................. 16 
7.0 
ELIGIBILITY ASSESSMENT................................................................................................................. 19 
7.1 
Inclusion Criteria ............................................................................................................ 19 
7.2 
Exclusion criteria ............................................................................................................ 19 
7.3 
Rationale for selection criteria ....................................................................................... 20 
8.0 
Strategies for Recruitment .............................................................................................................. 20 
9.0 
SAMPLE COLLECTION, STORAGE AND TRACKING PLAN .................................................................. 20 
9.1 
Data transfer to collaborators ........................................................................................ 21 
9.1 
Core Laboratories ........................................................................................................... 21 
10.0 
BIOSTATISTICAL AND ANALYTICAL CONSIDERATIONS .................................................................... 21 
10.1 
Sample Size .................................................................................................................... 21 
10.2 
Study Analysis ................................................................................................................ 22 
10.3 
Stopping Rules and Data Safety Monitoring .................................................................. 24 
10.4 
Off study criteria ............................................................................................................ 26 
11.0 
ADVERSE EVENT REPORTING .......................................................................................................... 27 
11.1 
Definitions ...................................................................................................................... 27 
11.2 
Adverse event management: ......................................................................................... 29 
12.0 
HUMAN SUBJECT PROTECTION ....................................................................................................... 31 
12.1 
Rationale for Subject Selection ...................................................................................... 31 
12.2 
Risks and Discomforts .................................................................................................... 31 
13.0 
TEST ARTICLES and INDICATIONS FOR USE ..................................................................................... 33 
13.1 
Edwards SAPIEN 3 transcatheter heart valve, PMA P140031 ........................................ 33 
13.2 
Asahi-Intecc Astato XS 20, 510(k) K103057 ................................................................... 33 
14.0 
INVESTIGATOR ADMINISTRATIVE REQUIREMENTS......................................................................... 34 
14.1 
Good Clinical Practice..................................................................................................... 34 
14.2 
IRB Submissions ............................................................................................................. 34 
14.3 
Subject Information and Informed Consent .................................................................. 34 
14.4 
Subject Confidentiality ................................................................................................... 34 
14.5 
Protocol Compliance ...................................................................................................... 34 
14.6 
Direct Access to Source Data ......................................................................................... 35 
14.7 
Case Report Form Completion ....................................................................................... 35 
14.8 
Record Retention ........................................................................................................... 35 
14.9 
Publication and Presentation of Study Findings and Use of Information ...................... 35 
15.0 
SPONSOR REGULATORY REQUIREMENTS ....................................................................................... 36 
15.1 
Role of Sponsor .............................................................................................................. 36 
15.2 
General Duties................................................................................................................ 36 

 
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15.3 
Monitoring ..................................................................................................................... 36 
15.4 
Site Selection and Training ............................................................................................. 36 
REFERENCES ................................................................................................................................................... 38 
APPENDIX A: Risk Analysis ............................................................................................................................. 40 
Appendix B: Kansas City Cardiomyopathy Questionnaire ............................................................................. 43 
 
1.0 Protocol Summary 
Title: 
NHLBI LAMPOON Study: Intentional laceration of the anterior mitral leaflet 
to prevent left ventricular outflow tract obstruction during transcatheter mi-
tral valve implantation 
Précis: 
Transcatheter mitral valve replacement (TMVR) can cause life-threatening 
complications such as left ventricular outflow tract obstruction and 
transcatheter heart valve dysfunction, in cases of extreme septal displace-
ment of the anterior mitral valve leaflet (AML). 
LAMPOON is a new catheter technique to split the AML and prevent iatro-
genic left ventricular outflow tract obstruction immediately before TMVR.  It 
mimics surgical chord-sparing AML resection. It has been used successfully 
in a small number of patients 
Hypothesis: 
LAMPOON enables transcatheter mitral valve implantation (TMVR) without 
life-threatening left ventricular outflow obstruction or transcatheter heart 
valve dysfunction 
Objectives: 
 
Technical success (defined below) of LAMPOON-TMVR 
Safety (Freedom from MACE to hospital discharge and 30days) of LAM-
POON-TMVR 
Safety Endpoints 
Survival to discharge 
Survival to 30days 
Freedom from MACE (according to MVARC) 
Feasibility Endpoints 
Procedure technical success (TMVR with successful LAMPOON, without re-
quiring bailout cardiac surgery or bailout septal reduction) 
Stratified analysis based on predicted LVOT obstruction or predicted THV 
dysfunction (“hanging leaflet”) 
Population: 
Patients with native mitral valve failure (regurgitation or stenosis) after sur-
gical mitral annuloplasty or from native mitral annular calcification, requir-
ing transcatheter mitral valve replacement because of prohibitive risk of mi-
tral valve surgery 

 
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Inclusion Criteria 
Undergoing TMVR for valve-in-ring, valve-in-band, or valve-in MAC: 
ĚƵůƚƐĂŐĞшϮϭǇĞĂƌƐ 
Severe symptomatic native mitral valve failure after mitral annuloplasty re-
pair or related to mitral annular calcification. 
Transcatheter mitral valve replacement (TMVR) is felt indicated by the multi-
disciplinary institutional heart team, including at least one cardiovascular 
surgeon who has examined the patient 
High or prohibitive risk of LVOT obstruction (predicted neo-LVOT less than 
200 mm2)) or transcatheter heart valve dysfunction from long/redundant an-
terior mitral valve leaflet, as determined by the multidisciplinary institu-
tional heart team. 
Anatomic eligibility for LAMPOON based on core lab assessment of the base-
line CT and echocardiogram. 
Concordance of the study selection team 
Exclusion Criteria 
Subjects unable to consent to participate, unless the subject has a legally au-
thorized representative  
Subjects unwilling to participate or unwilling to return for study follow-up 
activities.  
Predicted neo-LVOT created by the Sapien 3 skirt, after LAMPOON, less than 
150 mm2 
TAVR within 6 weeks 
Intended concurrent structural heart procedure, such as aortic or tricuspid 
valve implantation 
Pregnancy or intent to become pregnant prior to completion of all protocol 
follow-up procedures 
Phase: 
Phase IIa 

 
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Study Procedure 
NHLBI Data Coordinating Center 
NHLBI + Local Institutional Review Boards 
Sites are trained by national PIs and NHLBI investigators 
Subjects are identified by site investigators 
CT and echo are analyzed by core laboratories 
Subject eligibility is confirmed by local multidisciplinary heart team including 
cardiac surgery, and is confirmed by study eligibility committee 
Subjects are enrolled prospectively 
Baseline and follow-up echocardiography are analyzed at Henry Ford Hospi-
tal core laboratory, and baseline and follow-up CT are analyzed at the NHLBI 
core laboratory; hemodynamics, fluoroscopy are analyzed at NHLBI 
Primary analysis based on 30-day outcomes; Secondary analysis includes 12-
month outcomes 
Sample Size 
30 subjects at up to 8 sites 
Risk-benefit determina-
tion 
These subjects have no therapeutic alternatives and have the potential to 
benefit from this procedure 
Number of Sites enrolling 
participants: 
8 
Study Duration: 
Six years  
Participant Duration: 
Five years 
 
 

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2.0 OBJECTIVE 
The objective of this protocol is further to characterize the feasibility and safety of intentional laceration 
of the anterior mitral leaflet to prevent left ventricular outflow tract obstruction (LAMPOON), in patients 
who require transcatheter mitral valve replacement (TMVR) for native mitral valve failure, but who are at 
risk of left ventricular outflow tract (LVOT) obstruction.  
In this protocol, we use a transcatheter heart valve (THV), marketed for implantation in the aortic or pul-
monic positions, off-label.  The THV device is the Sapien 3 marketed by Edwards Lifesciences. 
It is important to discriminate the principal research objective, which is evaluation of the LAMPOON tech-
nique, from the off-label use of the significant risk medical device, the Edwards Sapien 3 THV, which is 
used in the clinical TMVR procedure. 
3.0 BACKGROUND 
The anterior mitral valve leaflet (AML) is a mobile structure that 
physically separates inflow and outflow zones of the left ventricle 
1.  Preserving the anterior mitral leaflet during surgical mitral 
valve replacement can cause LVOT obstruction, either when the 
prosthesis struts protrude into the LVOT or when a long redun-
dant anterior leaflet prolapses into the LVOT 2, 3.   In a similar 
manner, implantation of a transcatheter heart valve (THV) inside 
the native or repaired mitral valve enforces an “open position” of 
the anterior mitral valve leaflet that may encroach on the left 
ventricular outflow tract 4-7.  This septal displacement of the AML 
is exaggerated when the aortic and mitral annular planes are 
acutely angulated rather than parallel, when the interventricular 
septum bulges towards the LVOT, when the AML is elongated, 
and when the implant extends or flares into the left ventricle.  In 
this setting TMVR may cause life-threatening LVOT obstruction 
[Figure].  Moreover, after TMVR an excessively long AML may 
prolapse anteriorly into a narrowed LVOT as in hypertrophic car-
diomyopathy, or it can prolapse posteriorly and interfere with bi-
oprosthetic heart valve opening or closing by mechanical or Ber-
noulli effects after surgical 3 or transcatheter mitral replacement 
8.  Longer AMLs are more susceptible to these effects9. Although 
few data are available to guide decision-making, half of TMVR 
candidates having an intact AML in an ongoing clinical investiga-
tion [Mayra Guerrero personal communication, NCT02370511], 
are excluded because of the perceived risk of life-threatening 
LVOT obstruction.   
One approach to prevent or treat TMVR-related LVOT obstruction is pre-emptive transcoronary alcohol 
septal ablation 10, 11, which sacrifices myocardium, risks conduction system injury and pacemaker-depend-
ence in patients with cardiomyopathy, which is unsuitable in patients with thin interventricular septa, and 
which delays TMVR by 4-6 weeks to allow remodeling in highly symptomatic patients.  Another option is 
surgical anterior mitral leaflet resection combined with TMVR during thoracotomy and cardiopulmonary 
bypass 12-14, with attendant risk and comorbidity.   
 
Figure 1.   

 
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4.0 CLINICAL AND SCIENTIFIC JUSTIFICATION 
As an alternative, we have developed a simple transcatheter adjunct to TMVR, and described its preclini-
cal use 15.  This technique resembles Tirone David’s surgical anterior resection with chordal sparing 16 
which has become widely adopted as a method of surgical mitral valve replacement. We create a longitu-
dinal split of the middle scallop (A2) of the AML, immediately before TMVR.  As a result, chordal attach-
ments displace the split AML away from the LVOT after the cylindrical THV is implanted, and blood flows 
unobstructed across the THV stent struts [Figure 1]. 
We recently reported the initial human experience with this intentional Laceration of the Anterior Mitral 
leaflet to Prevent left ventricular Outflow tract Obstruction (LAMPOON) procedure 17.  Five patients with 
prohibitive risk of LVOT obstruction or transcatheter heart valve (THV) dysfunction from TMVR success-
fully underwent LAMPOON, with longitudinal splitting of the A2 scallop of the AML, prior to valve implan-
tation. Multiplane CT modelling predicted hemodynamic collapse assuming an intact AML.  However, criti-
cal LVOT gradients were not seen following LAMPOON and TMVR. Doppler blood flow was seen across 
THV struts that encroached the LVOT, because the AML was split. Transcatheter heart valve function was 
unimpeded. We concluded that this novel catheter technique, which resembles surgical chord-sparing 
AML resection, may enable TMVR in patients with prohibitive risk of LVOT obstruction or THV dysfunction.  
Recently there have been reports of late transcatheter heart valve thrombotic dysfunction18.  This war-
rants further investigation using follow-up imaging. 
Since preparation of the clinical manuscript, there have been four patients who underwent clinical non-
research TMVR with LAMPOON at Emory and Henry Ford Hospital, respectively.  Three of four were tech-
nically successful, and two of four were clinically successful. One patient underwent concurrent transca-
rotid TAVR and LAMPOON TMVR, and unfortunately suffered dislocation of the TMVR device, causing fa-
tal mitral regurgitation and heart failure, before it could be flared on the ventricular aspect by post-dilata-
tion after delivery.  This classifies as technically unsuccessful because the TMVR device was not correctly 
positioned. One patient with extreme comorbidity underwent technically successful LAMPOON TMVR but 
suffered a cardiac arrest overnight afterwards.  This additional clinical experience teaches that LAMPOON 
TMVR should not be combined with other intended valve procedures such as TAVR during the same pro-
cedure, and that technically successful LAMPOON TMVR may nevertheless prove fatal in patients with ex-
treme comorbidity.  
5.0 TREATMENT OPTIONS 
Candidates for TMVR with LAMPOON have no good alternative treatment options.  They are not eligible 
for definitive treatment using surgical mitral valve repair or replacement.  They are not eligible for TMVR 
using off-label THV devices because of the risk of LVOT obstruction.  They are not deemed suitable for an 
alternative investigational preemptive treatment through transcoronary alcohol septal ablation/infarc-
tion/debulking because of anatomic limitations and/or the attendant hazard and myocardial injury and 
requisite 4-6 weeks delay in highly symptomatic patients.  

 
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6.0 STUDY DESIGN 
6.1 Schematic of Study Design 
Native mitral valve 
failure from MAC or 
after surgical 
annuloplasty
Ineligible for TMVR 
because of risk of LVOT 
obstruction or THV 
dysfunction
Central eligibility review 
(PI and Sponsor)
Informed Consent 
and Baseline 
assessment
Pre-
discharge 
CT and echo
30 day 
follow-up 
with echo
TMVR with 
LAMPOON
6 month 
follow-up
12-month 
follow-up and 
echo
2 year,
3 year, and 
4 year follow-
up contact not 
visit
5 year follow-
up contact not 
visit, and study 
conclusion.
 
6.2 Overview of Study Design 
This is a prospective, open-label, single-arm, multi-center, investigator-initiated, independently-adjudi-
cated trial of LAMPOON immediately before transcatheter antegrade transseptal TMVR in subjects other-
wise ineligible for TMVR. 
Candidates will be identified by the participating structural heart disease programs.  In evaluation of mi-
tral valve disease, candidates will undergo clinical evaluation including transesophageal imaging and con-
trast-enhanced gated cardiac CT.  Eligibility will be reviewed and proposed by the local multidisciplinary 
heart teams.  Candidates will then undergo central eligibility review by the sponsor and designated inves-
tigators.  If deemed eligible, candidates will be offered participation in the study.  
Once enrolled, subjects will undergo baseline assessment, which includes quality of life questionnaires, 
walking tests, frailty assessments, and blood tests. 
Subjects will be admitted to the hospital and undergo TMVR with LAMPOON.  They will undergo endpoint 
assessment before discharge, after 30 days, 6 months, and then 12 months. 
6.3 LAMPOON TMVR Procedure 
The TMVR procedure is planned from a contrast-enhanced CT of the heart to select a suitable transcathe-
ter heart valve size, predict suitability of the mitral annular landing zone, and predict post-TMVR LVOT ob-
struction related to TMVR encroachment and long or redundant anterior mitral valve leaflets.  The LAM-
POON procedure uses the same clinical CT exam to choose a crossing point for the anterior mitral valve 
leaflet and to select appropriate fluoroscopic projection angles and radiographic landmarks.    

 
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The procedure is performed under general anesthesia or under moderate sedation at the discretion of the 
institutional heart team.   The LAMPOON procedure has three steps: (1) leaflet traversal with a guidewire, 
followed by (2) leaflet laceration, immediately followed by (3) TMVR.  These are all guided by fluoroscopy 
combined with TEE or intracardiac echocardiography. 
First catheter access is obtained typically via three transfemoral arterial (two for LAMPOON and one for 
LV hemodynamics and angiography) and two transfemoral venous introducers sheaths (one for TMVR and 
another for temporary transvenous pacing).  After anticoagulation with heparin or equivalent to achieve 
an activated clotting time > 300s, transvenous atrial transseptal puncture is performed under echocardio-
graphic guidance.  Atrial septostomy is performed, and a percutaneous transapical rail is established at 
operator discretion as needed.   
Hemodynamic and echocardiography measurements are recorded at baseline including gradients across 
the mitral and aortic valves and LVOT, and severity of valvular regurgitation. 
Two retrograde catheters are positioned, using a guidewire rail with the antegrade transseptal catheter as 
needed, in the LVOT and LA respectively.  Catheter and echocardiographic maneuvers are performed at 
operator discretion to assure traversal of the major orifice of the mitral valve.  Typically, these maneuvers 
include advancement of a large-volume inflated balloon tip catheter from the LA to the LVOT under angio-
graphic and echocardiographic guidance to assure no entrapment. Next a snare catheter is positioned in 
the mitral inflow via the LA catheter.  An insulated transcatheter electrosurgery catheter system (typically 
a rigid 0.014” guidewire inside a polymer jacket wire convertor) is positioned against the anterior mitral 
leaflet target at the A2 scallop, using fluoroscopic and echocardiographic guidance.  Nonionic conductive 
flush (dextrose 5%) can be administered as needed via the guiding catheters to reduce guidewire char and 
thromboembolism. 
Traversal is accomplished by transcatheter electrosurgery by connecting the back end of the 0.014” guide-
wire to an electrosurgery pencil during short bursts of “pure, cutting” radiofrequency energy at approxi-
mately 50W.  The guidewire is repositioned as needed until it crosses the mitral leaflet and is snare-re-
trieved. 
Next the polymer jacket wire convertor is withdrawn, and the traversal wire is modified at the bedside by 
the operator by (1) denuding a non-circumferential segment ~2mm in length, 90o arc and (2) kinking the 
denuded segment to enforce its position at the inner curvature of the intended guidewire lacerating sur-
face.  Next the polymer jacket radiopaque marker tip is locked adjacent to the kinked denuded shaft seg-
ment.  Next the ensnared guidewire is externalized to position the lacerating surface across the base of 
the leaflet. 
Next, at operator discretion, the transcatheter heart valve may be positioned in the left atrium or across 
the mitral valve before or after the laceration step.  If before, the operator assures no entrapment of the 
TMVR system with the laceration system of catheters. 
Laceration is performed by positioning the laceration surface along the intended leaflet base and applying 
tension on both free ends of the guidewire, while simultaneously apply electrosurgery energy in short 
bursts, until the laceration is complete and the guidewire is free. 
Hemodynamics are recorded quickly after laceration before TMVR.  Then TMVR is performed using estab-
lished techniques14 typically during rapid ventricular pacing.  The THV device is used outside the manufac-
turer instructions for use, in that it is implanted in the mitral position. The device size and inflation vol-
umes are selected and applied at the discretion of the operator.  A balloon flaring maneuver is encour-
aged to reduce the likelihood of THV embolization into the left atrium. 

 
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2020-08-24 
Completion hemodynamics and echocardiography are recorded.   Adjunctive transcatheter procedures, 
including to close paravalvular leaks and to close iatrogenic atrial septal defects, are performed at opera-
tor discretion and details are recorded. Finally, percutaneous femoral artery and vein vascular hemostasis 
is obtained and the subject convalesces in the appropriate inpatient recovery unit. 
Before discharge, follow-up transthoracic echocardiography is recorded.   A single contrast-enhanced CT 
of the heart is obtained before discharge if renal function allows, otherwise it is deferred as long as 30-
days. Blood tests are recorded for research only as obtained for medical care. 
After discharge, subjects are recommended to undergo at least 3 months of warfarin anticoagulation with 
a target INR of 2-3, along with aspirin 81mg indefinitely.  These recommendations are superseded by indi-
cations for long-term anticoagulation (such as atrial fibrillation), or P2Y12 inhibitors. 
6.4 Time and Events Schedule 
 
Screening 
Baseline 
Day 0 
Inpatient 
30 d (±14d) FU 
6 mo (± 30 Days) 
12 mo (± 4 wk) 
(range) FU
2 yrs (± 1 mo) (range) 
FU
3 yrs (± 1 mo) 
4 yrs (± 1 mo) 
5 yrs (± 1 mo) 
Baseline informed consent: 
 
X 
 
 
 
 
 
 
 
 
 
Multidisciplinary heart team eligibility deter-
mination 
 
X 
 
 
 
 
 
 
 
 
 
Baseline clinical assessment 
 
X 
 
 
 
 
 
 
 
 
 
6 minute walk test 
 
X 
 
 
X 
 
X 
 
 
 
 
Kansas City Cardiomyopathy Questionnaire 
(KCCQ) 
 
X 
 
 
X 
 
X 
 
 
 
 
NYHA Classification 
 
X 
 
 
X 
X 
X 
 
 
 
 
Frailty tests: Katz ADL, 5MW, Albumin 
 
X 
 
 
 
 
 
 
 
 
 
Blood tests: CBC, Platelet, Haptoglobin, Liver 
panel, Chemistry Panel, Albumin, LDH, 
BNP/Pro-BNP (as clarified below) 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Vital signs and in-person visit 
 
X 
 
 
X 
X 
X 
 
 
 
 
Cardiac CT contrast-enhanced gated dy-
namic 
Screening or 
baseline 
Screening or 
baseline 
 
Inpatient 
or 30D 
Inpatient 
or 30D 
 
 
 
 
 
 
Transesophageal echocardiogram 
Screening or 
baseline 
Screening or 
baseline 
X 
 
 
 
 
 
 
 
 
TMVR with LAMPOON 
 
 
X 
 
 
 
 
 
 
 
 
Surface echocardiogram 
Screening or 
baseline 
Screening or 
baseline 
 
X 
X 
X 
X 
 
 
 
 
ECG 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Adverse event assessment 
 
 
 
X 
X 
X 
X 
 
 
 
 
Vital status and clinical echo or report 
 
 
 
 
 
 
 
X 
X 
X 
X 
Subjects would receive continuing care from their primary physicians with consultant input as requested 
from the structural heart disease program. 
For subjects who die, necropsy evaluation is requested to examine the heart at NIH. 

 
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Page 16 of 43 
2020-08-24 
6.4.1 
Applicability to CMS Coverage Evaluation Determination 
Requirements for a Coverage Evaluation Determination (CED) by Centers for Medicare and Medicaid Ser-
vices (CMS) are reviewed here.  (1) The principal purpose of the study is to test whether LAMPOON TMVR 
meaningfully improves health outcomes of affected beneficiaries.  (2) Scientific evidence supports the 
study rationale. (3) The study does not unjustifiably duplicate existing knowledge. (4) The study design is 
methodologically appropriate and sufficiently powered to answer the research question.  Even though the 
sample size is not statistically driven, the experience is expected to set the standard for TMVR using com-
mercially available valves.  (5) The study sponsor is capable of completing the study.  (6) The study com-
plies with applicable Federal Law and obtains meaningful informed consent regarding risks and the data 
disposition.  (7) The study is conducted ethically.  (8) There is a written study protocol that adheres to 
CMS standards. (9) The study does not test exclusively toxicity nor natural history, although the studied 
condition is lethal. (10) The study will be registered in clinicaltrials.gov.  (11) The study indicates results 
will be released within 12 months of completing enrollment, irrespective of outcome. (12) The study pro-
tocol explicitly discusses beneficiary subpopulations affected by TMVR LAMPOON, especially medically 
underrepresented groups, with a recruitment and retention plan. 
6.5 Visit Schedule 
All activities except TMVR/LAMPOON, Consent, KCCQ, and Adverse event assessment are performed for 
standard clinical care. 
Timing 
Event 
Screening (any time) 
Medical, Surgical and Interventional Assessment, determination and docu-
mentation that the subject has no other options for MVR 
Screening (any time) 
Cardiac CT contrast enhanced, gated dynamic 
Screening (any time) 
Transesophageal echocardiogram 
Screening (any time) 
Multidisciplinary heart team eligibility determination and documentation 
Baseline (within 30 days of 
procedure) 
Research Informed Consent to include documented Inclusion and Exclusion 
criteria 
Baseline (within 30 days of 
procedure) 
Clinical Assessment to include: 
x 
Vital signs 
x 
Baseline symptoms 
x 
Medication Assessment 
x 
NYHA Classification 
x 
Other co-morbidities that could preclude the subject living the re-
quired 6 months post procedure 
x 
ECG 
x 
Surface echocardiogram-transthoracic  

 
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Page 17 of 43 
2020-08-24 
Baseline (within 30 days of 
procedure) 
Clinical Blood tests: 
x 
CBC 
x 
Platelets 
x 
Haptoglobin 
x 
Liver Function panel 
x 
Chemistry panel 
x 
Troponin 
x 
Albumin 
x 
LDH 
x 
BNP/Pro-BNP 
x 
Pregnancy test if applicable 
Baseline (within 30 days of 
procedure) 
6-minute walk 
Baseline (within 30 days of 
procedure) 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Baseline (within 30 days of 
procedure) 
Frailty Tests: Katz ADL, 5-meter walk, Albumin 
Day 0 
TMVR with Lampoon procedure  
Within 48 hours of Lampoon 
TMVR 
Blood work to include: 
x 
Troponin 
Pre-discharge  
Clinical Evaluation to include:  
x 
Cardiac CT scan contrast enhance, gated dynamic- if not clinically 
suitable then re-schedule for 30 Day follow up visit 
x 
Surface echocardiogram 
x 
ECG 
x 
Medication Assessment 
x 
Adverse Event Assessment 

 
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2020-08-24 
30-day (±14 days) 
Clinic/office visit to update subject’s vital status to include: 
x 
Vital signs 
x 
ECG 
x 
Medication Assessment 
x 
NYHA Classification 
x 
Surface Echocardiogram 
x 
Cardiac CT scan contrast enhance, gated dynamic- if not conducted 
pre-discharge for clinical reasons 
x 
6-minute walk 
x 
Kansas City Cardiomyopathy Questionnaire 
x 
Blood work to include: 
CBC with platelets 
Haptoglobin 
Chemistry Panel 
PT INR 
BNP/Pro-BNP 
x 
Adverse Event Assessment 
6-month (±30 days) 
Clinic/office visit to update subject’s vital status to include: 
x 
Vital signs 
x 
NYHA Classification 
x 
ECG 
x 
Medication Assessment 
x 
Surface Echocardiogram 
x 
Blood work to include: 
CBC with platelets 
Haptoglobin  
PT INR 
BNP/Pro-BNP 
Chemistry Panel 
x 
Adverse Event Assessment 

 
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Page 19 of 43 
2020-08-24 
12 month (±30 days) 
Clinic/office visit to update subject’s vital status to include: 
x 
Vital signs 
x 
ECG 
x 
Medication Assessment 
x 
NYHA Classification 
x 
Surface Echocardiogram 
x 
6-minute walk 
x 
Kansas City Cardiomyopathy Questionnaire 
x 
Blood work to include: 
CBC with platelets 
Haptoglobin  
Chemistry Panel 
PT INR 
BNP/Pro-BNP 
x 
Adverse Event Assessment 
Annually years 2-5 ( r 30  
days) 
x 
Telephone call or local physician contact to assess vital status 
x 
Collect results or images of clinical echocardiogram 
 
7.0 ELIGIBILITY ASSESSMENT 
7.1 Inclusion Criteria  
• 
ĚƵůƚƐĂŐĞшϮϭǇĞĂƌƐ 
• 
Severe symptomatic native mitral valve failure after mitral annuloplasty repair or related to mitral 
annular calcification. 
• 
Unacceptably high or prohibitive risk for surgical mitral valve replacement and indicated for 
transcatheter mitral valve replacement (TMVR) as determined by the multidisciplinary institu-
tional heart team, including at least one cardiovascular surgeon who has examined the patient 
• 
High or prohibitive risk of LVOT obstruction (predicted neo-LVOT less than 200 mm2) or transcath-
eter heart valve dysfunction from long/redundant anterior mitral valve leaflet, as determined by 
the multidisciplinary institutional heart team.   
• 
Anatomic eligibility for LAMPOON based on core lab assessment of the baseline CT and echocardi-
ogram. 
• 
Concordance of the study selection team 
7.2 Exclusion criteria 
• 
Subjects unable to consent to participate, unless the subject has a legally authorized representa-
tive  
• 
Subjects unwilling to participate or unwilling to return for study follow-up activities.  
• 
Predicted neo-LVOT created by the Sapien 3 skirt, after LAMPOON, less than 150 mm2 

 
IDE LAMPOON 
Page 20 of 43 
2020-08-24 
• 
TAVR within 6 weeks 
• 
Intended concurrent structural heart procedure, such as aortic or tricuspid valve implantation 
• 
Pregnancy or intent to become pregnant prior to completion of all protocol follow-up procedures 
7.3 Rationale for selection criteria 
The selection criteria allow enrollment of the intended population with little anticipated selection bias. 
Instead of functional or geometric selection criteria, the study will enroll all subjects deemed otherwise 
suitable for TMVR yet at risk of the problem to be addressed by LAMPOON, the investigational procedure. 
Planned concurrent valve procedures such as TAVR are disallowed based on a recent fatal adverse event 
described in section 4.0. 
In Amendment C, an additional exclusion criterion was added. This considers whether the fabric-covered 
“skirt” of the Sapien 3 transcatheter heart valve might obstruct the left ventricular outflow tract despite 
successful LAMPOON.  Candidates who might continue to have an obstructive “skirt neo-LVOT” are ex-
cluded.  This amendment also formalizes a threshold neo-LVOT for selection. 
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.  Specifically, the 
results are expected to be generalizable to Medicare and Medicaid beneficiaries because of age and dis-
ease-related disability. 
8.0 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. 
One site investigator, Dr Mayra Guerrero, is the Principal Investigator of the MITRAL study (NCT02370511) 
of TMVR which specifically excludes subjects suitable for this study.  She estimates as many as half of her 
study candidates fail screening because of predicted LVOT obstruction [Mayra Guerrero, MD, Personal 
Communication, October [2016].  Dr Guerrero will recommend referring physicians refer to sites partici-
pating in this study. 
During the early clinical development of the LAMPOON procedure, 9 clinical patients were treated in ap-
proximately 5 months at two centers, which suggest the recruitment objectives will be met. 
 
9.0 SAMPLE COLLECTION, STORAGE AND TRACKING PLAN 
Imaging data (from angiography, CT, and echocardiography) constitute the only specimens to be col-
lected.  CT examinations performed for clinical evaluation prior to signing informed consent may be used 
as the baseline scan. 

 
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Page 21 of 43 
2020-08-24 
CT and Echocardiography data will be analyzed at the Henry Ford Hospital Core Laboratory as well as to 
the NHLBI for concurrent analysis.    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 
SFTP or https://secureemail.nih.gov).  
Imaging data are stored according to local institutional standards. 
Copies of imaging studies are transmitted to a central facility (NHLBI) using secure HIPAA compliant meth-
ods 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. 
9.1 Data transfer to collaborators 
De-identified and de-linked data and images will be posted at the NHLBI Cardiovascular Intervention 
Structural Heart Image Data Repository (https://ledermanlab.nhlbi.nih.gov/repository/index.htm or 
equivalent). They are provided for the purpose of medical education and research.  They are de-identified 
and de-linked, so that patients can not readily be identified, and are therefore not considered human re-
search subjects research data under US 45CFR§46.102(f). 
De-identified and de-linked images will also be transferred to collaborating investigators at academic and 
industry sites. They are provided for the purpose of medical education and research.  They are de-identi-
fied and de-linked, so that patients can not readily be identified, and are therefore not considered human 
research subjects research data under US 45CFR§46.102(f). 
These recipients include all enrolling site investigators and: 
Ajit Yogonathan, PhD 
Georgia Institute of Technology 
Atlanta, Georgia, USA 
Martijn Chatrou, PhD 
3mensio Pie Medical Esaote 
Bilthoven, Netherlands 
Nasser Rafiee 
Transmural Systems 
Andover, MA, USA 
Bill Havel, PhD 
Cook Medical 
West Lafayette, IN, USA 
Kanishka Ratnayaka, MD 
UCSD Rady Childrens Hospital 
San Diego, CA 
9.2 Core Laboratories 
Core laboratories are employed for centralized and systematic analysis of key imaging data, including 
echocardiography and CT. 
Amendment E adds a core laboratory #2 for analysis of CT. Measurements from core laboratory #1 are 
superseded by core lab #2. 
10.0 
BIOSTATISTICAL AND ANALYTICAL CONSIDERATIONS 
10.1 
Sample Size 
The sample size is not statistically derived.  This is a safety and feasibility study that enables patient access 
to off-label use of a medical device, when these patients have no other good medical options to treat 

 
IDE LAMPOON 
Page 22 of 43 
2020-08-24 
symptomatic mitral valve failure. An arbitrary initial sample size of 30 is proposed, and will be increased if 
needed, until a commercial solution is found for medical care.  
Up to 60 subjects will be consented until 30 subjects undergo attempted LAMPOON TMVR in this proto-
col.   
We will adhere to the extent possible to consensus guidelines that have been established for the analysis 
and reporting of transcatheter mitral valve repair investigational procedures.19, 20 
10.2 
Study Analysis 
Clinical events are classified by the local site Principal Investigator and confirmed by the Principal Investi-
gator.   The results of the study will be released within 12 months of study completion. 
Analyses will be stratified according to the setting for TMVR, whether valve-in-ring, valve-in-band, or 
valve-in-MAC. 
The study will be analyzed using descriptive statistics, including a case-by-case narrative summary of ma-
jor adverse events.  Afterwards, we will survey for parameters associated with an increased risk of major 
adverse events. 
Primary and secondary endpoints will also be analyzed separately among patients with- and without- mi-
tral annular calcification as the primary indication for TMVR. 
10.2.1 
Primary endpoint 
The primary endpoint is Technical success ACCEPTABLE (measured at exit from the catheterization labor-
atory)19.  All of the following must be present: 
- 
Successful LAMPOON traversal and laceration; and 
- 
Peak LVOT gradient < 50 mm Hg; and 
- 
Absence of procedural mortality; and 
- 
Successful access, delivery, and retrieval of the LAMPOON device system; and 
- 
Successful deployment and correct positioning of the first intended device; and 
- 
Freedom from emergency surgery or reintervention related to the device or access procedure. 
The first two factors are modifications of the MVARC (mitral valve academic research consortium) consen-
sus endpoint19, specific for LAMPOON procedure. 
10.2.2 
Co-Primary endpoint 
Based on feedback from the FDA, the co-primary endpoint is Technical Success OPTIMAL (measured at 
exit from the catheterization laboratory).  This differs from “Technical Success ACCEPTABLE” only in the 
magnitude of the peak LVOT gradient.   
All of the following must be present: 
- 
Successful LAMPOON traversal and laceration; and 
- 
Peak LVOT gradient < 30 mm Hg; and 
- 
Absence of procedural mortality; and 
- 
Successful access, delivery, and retrieval of the LAMPOON device system; and 

 
IDE LAMPOON 
Page 23 of 43 
2020-08-24 
- 
Successful deployment and correct positioning of the first intended device; and 
- 
Freedom from emergency surgery or reintervention related to the device or access procedure. 
10.2.3 
 Exploratory Endpoints 
- 
LVOT obstruction measured as a pressure gradient on catheterization and echocardiography 
- 
Incidence of LVOT obstruction > 20 mm Hg before discharge and at 30 days, including as an alternative 
LVOT gradient threshold to the primary endpoint 
- 
Predicted neo-LVOT area based on THV frame had LAMPOON not been performed 
- 
MVARC 30-day Device Success 
- 
MVARC 30-day Procedure Success 
- 
MVARC 1-year Patient Success 
- 
Mortality, all-cause, cardiovascular vs non-cardiovascular, peri- vs non-periprocedural, LAMPOON and 
TMVR relatedness) 
- 
Neurological events as reported by the site clinicians only 
- 
Pre-discharge stroke, alone, and in combination with the primary endpoint 
- 
Myocardial infarction 
- 
Access and vascular complications 
- 
MVARC bleeding complications 
- 
AKIN acute kidney injury 
- 
Arrhythmia and conduction disturbances 
- 
Freedom from infection related to the TMVR at each time point 
- 
Freedom from hemolytic anemia related to TMVR/LAMPOON 
- 
Device related technical failure: Device Failure, Paravalvular Leak, Pericardial effusion, Conversion to open 
surgery, Device mal-positioning or migration or detachment, Device fracture, Unintended damage to native 
mitral valve apparatus 
- 
Aortic valve regurgitation change 
- 
Device thrombosis 
- 
Outcomes of subjects greater than 65 years (i.e. eligible for Medicare based on age), to determine generali-
zability to the Medicare population1  
10.2.4 
Rationale for primary endpoint 
The main clinical objective of LAMPOON is to allow TMVR without causing death from acute severe LVOT 
obstruction, which often is greater than 100 mm Hg.  This is in contrast to MVR or TMVR in patients who 
are not believed to be at risk of life threatening LVOT obstruction.   
 
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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Page 24 of 43 
2020-08-24 
There are few data to guide clinical estimations of acceptable thresholds for iatrogenic LVOT obstruction.  
As for other elements of this protocol, we sought and found guidance in hypertrophic cardiomyopathy, 
which is a better-characterized but related phenotype of non-valvular LVOT obstruction. 
Based on these data we estimate that residual iatrogenic LVOT obstruction less than 50mm is tolerable, 
because by consensus21, 22 it appears not sufficiently severe to warrant surgical intervention in HCM.  
Moreover,  a systematic review by Maron 23 distinguished obstructive from non-obstructive HCM at a 
ƚŚƌĞƐŚŽůĚŽĨшϱϬŵŵ,Ő͘/ŶĂĚĚŝƚŝŽŶ͕ƚŚĞƌĞŝƐĞǀŝĚĞŶĐĞƚŚĂƚƉĞĂŬ-instantaneous echocardiographic as-
sessment of LVOT gradient appears to correspond to an equivalent catheter peak-to-peak measurement 
of LVOT gradient, in contrast to valvular aortic stenosis where the echocardiographic measurement corre-
sponds to a lower catheter peak-to-peak LVOT gradient24. 
The primary endpoint is designed around the MVARC guidelines19, to allow comparison with other mitral 
valve implantation trials, although tailored for the unique features of LAMPOON TMVR.  We believe these 
data and guidelines justify a residual LVOT threshold of up to 50 mm Hg as a component of the study pri-
mary endpoint.    
However, we concur with the FDA reviewer that the gradient in 0 is not optimal, especially in a patient 
with cardiomyopathy treated for pure mitral valve regurgitation.  Therefore, we introduced a co-primary 
endpoint in 10.2.2 with a lower allowed peak LVOT gradient. 
 
10.2.5 
Independent Clinical Events Adjudication 
An independent Clinical Events Adjudication Committee will review all of the following that occur in the 
first year: 
- 
Deaths 
- 
Primary endpoints 
- 
Valve embolization events 
- 
Site-reported strokes 
The CEAC will classify relatedness of the above events to the LAMPOON procedure. 
10.3 
Stopping Rules and 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 
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 efficacy. Unanticipated Adverse Device Effects (UADEs) will be submitted to the DSMB following the 
same timelines as the IRB (See section 9.2.4). 
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.   

 
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Page 25 of 43 
2020-08-24 
Stopping rules were changed in Amendment A to be more statistically robust, to accommodate two strata 
of patients, and to focus on 30-day survival.  There are two clearly different strata of subjects to be en-
rolled in this study.  For TMVR in the setting of prior annuloplasty (aka “valve-in-ring” or “valve-in-band”), 
the risk of valve migration and of severe paravalvular leak, attendant mortality, are much lower.  For 
TMVR in the setting of mitral annular calcification (aka “valve-in-MAC”), patients are older and have more 
comorbidity, and the procedures are much more technically complex.  Accordingly, valve-in-MAC TMVR 
has higher mortality.  The reported 30-day mortality of valve-in-MAC in the global registry of 64 patients 
was 30%14.     
We propose two different stopping rules, one for valve-in-ring and valve-in-band, and another for valve-
in-MAC.  While rules are provided for up to 30 subjects in each stratum, the total treated within both 
strata combined will not exceed 30. 
10.3.1 Stopping Rules for valve-in-ring and for valve-in-band stratum 
The study will be monitored to ensure that the mortality with 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 25. 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 study 
data, which gives the prior parameters a = 0.6, b =5.4. 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 in the stratum 
Stop if the number of deaths within 30 days reaches 
2-4 
2 
5-10 
3 
11-17 
4 
18-24 
5 
25-30 
6 
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, 
we generated a study with 30 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 
5% 
10% 
15% 
20% 
25% 
30% 
35% 
40% 
Proportion of Stopped Studies 
2.9% 
16.9% 
42.1% 
68.7% 
86.0% 
94.9% 
98.6% 
99.7% 
Average number of subjects 
29.4 
27 
22.8 
17.9 
13.8 
10.6 
8.2 
6.6 
Average number of 30-day mortality 
1.5 
2.7 
3.4 
3.6 
3.4 
3.2 
2.9 
2.7 
These simulation results suggest that our stopping rule has a low probability 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 Bayesian stopping rule for 30-day mortality 
has satisfactory statistical properties. 

 
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Page 26 of 43 
2020-08-24 
10.3.2 Stopping Rules for valve-in-MAC stratum 
The study will be monitored to ensure that the mortality with 30-days after the procedure does not sub-
stantially exceed an anticipated rate. We anticipate the rate of 30-day mortality is 30% or less and deter-
mine the stopping rule by a Bayesian approach 25. The stopping boundary is reached if the posterior prob-
ability that the 30-day mortality rate exceeds 30% 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 = 1.8, b =4.2. 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 in the “valve-in-
MAC” stratum 
Stop if the number of deaths within 30 days reaches 
3 
3 
4-6 
4 
7-8 
5 
9-11 
6 
12-14 
7 
15-16 
8 
17-19 
9 
20-22 
10 
23-25 
11 
26-27 
12 
28-30 
13 
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, 
we generated a study with 30 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 
20% 
25% 
30% 
35% 
40% 
45% 
50% 
55% 
Proportion of Stopped Studies (%) 
3.9 
10.2 
21.8 
38.9 
58.5 
76.6 
89.1 
95.9 
Average number of subjects 
29.2 
28.1 
26.1 
23.3 
20 
16.4 
13.2 
10.5 
Average number of 30-day mortality 
5.8 
7 
7.8 
8.2 
8 
7.4 
6.6 
5.8 
These simulation results suggest that our stopping rule has a low probability stopping a study when the 
true 30-day mortality rate is 30% or less, and the probability of stopping a study is high when the true 30-
day mortality rate exceeds 30%.  There, we believe that our Bayesian stopping rule for 30-day mortality 
has satisfactory statistical properties. 
10.4 
Off study criteria 
• 
Completion of the 5-year follow-up 
• 
The subject voluntarily withdraws 
• 
Significant subject non-compliance with follow-up visits 
• 
Death 

 
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2020-08-24 
11.0 
ADVERSE EVENT REPORTING 
11.1 
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) ; 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 device when it is the result 
of: 
• 
 LAMPOON procedure 
• 
Edwards Sapien 3 transcatheter heart valve or accessories 
• 
Asahi-Intecc Astato XS 20 guidewire 
An event will be considered NOT related to the LAMPOON procedure when it is the result of:  
• 
A pre-existing medical condition 
• 
Clearly attributable to TMVR but not LAMPOON part of procedure (example: commissural para-
valvular leak) 
Anticipated Adverse Device Effects (AADEs): An AADE is an adverse event with a reasonable possibility that 
the device or procedure caused or contributed to the event. The following AADEs are considered antici-
pated based on previous human experience: 
• 
LAMPOON device failure including failure to traverse, to lacerate, or to position catheters or 
guidewires 
• 
Valve malposition, reposition, dislocation, migration, or embolization or deployment in unin-
tended location 
• 
Interatrial shunt 

 
IDE LAMPOON 
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2020-08-24 
• 
LVOT gradient 
• 
Aortic valve injury 
• 
Paravalvular leak 
• 
Atrial-ventricular conduction defects to include bundle branch block and complete heart block 
requiring placement of a temporary or permanent pacemaker 
• 
Cardiac arrhythmia including ventricular tachycardia and atrial fibrillation  
• 
Transient myocardial dysfunction attributed to rapid ventricular pacing required for mitral valve 
implantation, including brady-asystole or pulseless electrical activity, or requiring cardiopulmo-
nary resuscitation 
• 
Angina and myocardial ischemia 
• 
Coronary artery obstruction or injury that may require intervention 
• 
Myocardial infarction 
• 
Congestive heart failure or BNP elevation 
• 
Cardiogenic shock that may require intervention 
• 
Infective endocarditis 
• 
Left ventricular or left atrial perforation 
• 
Pericardial effusion or tamponade 
• 
Hypertension 
• 
Hypotension requiring vasopressor support or mechanical circulatory support 
• 
Stroke or TIA or seizure 
• 
Hemolysis which requires transfusions and which requires confirmatory dramatic schizocytes and 
haptoglobin decline 
• 
Low platelets or thrombocytopenia or increased or reduced leukocytes 
• 
Mechanical injury to the myocardium, access vasculature, cardiac valves that may require inter-
vention or that may elevate Troponin 
• 
Bleeding causing anemia and blood transfusions 
• 
Mitral valve thrombosis 
• 
Embolization of air, calcific valve material, atheroma, or thrombus to coronaries, brain, limbs, or 
viscera causing myocardial infarction, stroke, or limb ischemia 
• 
Retroperitoneal bleed or hematoma or access site injury 
• 
Contrast-induced nephropathy requiring temporary or permanent hemodialysis or medical treat-
ment 
• 
Volume overload, pleural effusion, or dyspnea from procedure-related volume perturbations  
• 
Respiratory failure requiring oxygen or mechanical support or mechanical ventilation 
• 
Infection including access site or urinary or pulmonary or including sepsis 
• 
Pain including back pain and access site and generalized 
• 
Cardiac arrest 
• 
Death 
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)). 

 
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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. 
11.2 
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: 
11.2.1 
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.  
 
11.2.2 
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 

 
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2020-08-24 
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.  
 
11.2.3 
Adverse Event Reporting 
Adverse event recording will start on Day (0) of the LAMPOON TMVR 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. 
11.2.4 
Adverse event reporting timeframes: 
Serious Adverse Events (SAEs) 
• 
All serious adverse events will be reported to the Sponsor immediately but not later than 3 
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] 

 
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• 
All Unanticipated Adverse Device Effects will be reported by the Sponsor to the NIH IRB per 
NIH Policy 801 “Reporting Research Events”.  
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 NIH IRB of a subject’s death, if applicable, per NIH Policy 801 “Re-
porting Research Events”.  
• 
A subject’s death will be recorded on the Case Report Form.  
12.0 
HUMAN SUBJECT PROTECTION 
12.1 
Rationale for Subject Selection 
12.1.1 
Study population: 
Subjects are selected for being adults who are determined otherwise likely to benefit from transcatheter 
mitral valve replacement yet are expected to suffer TMVR-related left ventricular outflow tract (LVOT) ob-
struction. The determination will be made by the local institutional multidisciplinary heart team.   No pa-
tient will be excluded from participation based on gender, race or ethnicity.   
Subjects who are unable to provide consent may be enrolled, if allowed by participating IRBs. 
12.2 
Risks and Discomforts 
There are no approved commercial devices indicated for TMVR. 
A formal risk analysis is provided in APPENDIX A. 
Risks of TMVR will be considered separately from the risks of preparatory LAMPOON before TMVR.  
Known risks of TMVR include 
• 
Death 
• 
Left ventricular outflow tract obstruction 
• 
Toxic reaction to anesthesia, medications, contrast media, or device materials 
• 
Bleeding, hypotension, shock, anemia and complications of their treatment 
• 
Vascular complications including requiring mechanical repair  
• 
Conduction system injury which may require pacemaker therapy 
• 
Embolization of air, calcific valve material, atheroma, or thrombus to coronaries, brain, limbs, 
or viscera causing myocardial infarction, stroke, etc 
• 
Paravalvular leak 
• 
Malposition or embolization of the TMVR device 
• 
Transcatheter heart valve dysfunction, including mechanical, degenerative, or thrombotic 
• 
Myocardial perforation and pericardial tamponade 
• 
Complications of transcatheter or surgical transapical access including hemorrhage, pericar-
dial tamponade, hemothorax 
• 
Cardiac valvular or subvalvular injury causing myocardial dysfunction 
• 
Congestive heart failure, cardiomyopathy, cardiogenic shock, respiratory failure 

 
IDE LAMPOON 
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• 
Renal injury or failure 
• 
TMVR failure requiring emergency cardiac surgery or emergency mechanical circulatory assis-
tance 
• 
Radiation injury including intractable skin injury 
• 
Endocarditis or endarteritis or sepsis 
• 
Hemolysis 
Anticipated risks of preparatory LAMPOON before TMVR include: 
• 
Death 
• 
Avulsion or other injury of the aortomitral curtain, which is expected to lead to death 
• 
Failure of the LAMPOON procedure, leading to LVOT obstruction, the life-threatening compli-
cation the LAMPOON procedure is intended to obviate 
• 
Early or late thrombosis or thromboembolism causing stroke or acute visceral or limb ische-
mia 
• 
Hemorrhage requiring blood transfusion 
• 
Hemorrhagic shock requiring vasopressor support 
• 
Injury to the aortic valve causing aortic valve regurgitation 
• 
Aortic injury such as aortic dissection or pseudoaneurysm 
• 
Hemolytic anemia or thrombocytopenia as a consequence of blood flow across the struts of 
the THV  
• 
Infective endocarditis related to the TMVR of the lacerated mitral valve leaflet 
• 
Nephrotoxic injury due to iodinated radiocontrast used in follow-up CT assessment, including 
causing temporary or permanent hemodialysis 
• 
Embolization of the THV is a theoretical risk of LAMPOON although we do not expect LAM-
POON to contribute to this life-threatening complication. 
The sponsor and investigators recognize these risks are high and reflect the underlying comorbidities yet 
consider procedural hemorrhage overall to be an acceptable compromise to enable treatment of the un-
derlying mitral valve failure in patients otherwise ineligible. 
12.2.1 
Risks Related to Radiation 
In this research protocol, subjects will be exposed to radiation from 2 CT scans.  The CT scans are per-
formed for surveillance of transcatheter heart valve dysfunction.  It is estimated that the amount of re-
search radiation that a subject will be exposed to during participation in this research protocol will be ap-
proximately 3-4 REM from the CT scans, and 72mSv26 from approximately 60-100 minutes of fluoroscopy 
during performance of LAMPOON and TMVR.  This is equivalent to 740 chest X-rays. 
We believe the total fluoroscopy exposure to be justifiable in this setting, given the seriousness of their 
cardiovascular disease and limited options. We estimate the benefit to the research subjects for these 
procedures to outweigh the risks.  
12.2.2 
Data collection from patients who have undergone LAMPOON at participating 
sites before this protocol begins enrollment 
As of the time of submission of this protocol for review, 9 patients are known to have undergone 
standalone antegrade TMVR with LAMPOON.  We wish to aggregate all available follow-up data on these 
patients to the extent possible, including patients who have died during the follow-up period. This num-
ber of patients analyzed retrospectively will not count against (“reduce”) the number of prospectively en-
rolled patients. 

 
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Subjects must have undergone LAMPOON and TMVR before enrollment begins in this protocol, which is 
expected April 2017.  Retrospective findings will be analyzed separately from the subjects in the main 
(prospective) investigational IDE arm. 
12.2.3 
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. 
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.  
13.0 
TEST ARTICLES and INDICATIONS FOR USE 
The study uses two main test articles, a transcatheter heart valve and a guidewire. 
13.1 
Edwards SAPIEN 3 transcatheter heart valve, PMA P140031 
This protocol tests a method (LAMPOON).  It also uses marketed devices off-label.  The indications for use 
of these devices are shown below. 
The Edwards SAPIEN 3 transcatheter heart valve, model 9600TFX, and accessories are indicated for relief 
of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis 
who are judged by a Heart Team, including a cardiac surgeon, to be at intermediate or greater risk for open 
ƐƵƌŐŝĐĂůƚŚĞƌĂƉǇ;ŝ͘Ğ͕͘ƉƌĞĚŝĐƚĞĚƌŝƐŬŽĨƐƵƌŐŝĐĂůŵŽƌƚĂůŝƚǇшϯйĂƚϯϬĚĂǇƐ, based on the Society of Thoracic 
Surgeons (STS) risk score and other clinical co-morbidities unmeasured by the STS risk calculator). 
We do not plan to market these devices.  We plan to employ these devices in a valve position different 
from the intended use, in the mitral valve position whether in the presence of a surgical annuloplasty ring 
or band, or in the presence of native mitral annular calcification.    For this off-label use, the Sapien 3 THV 
is delivered using its intended delivery system, but it is loaded with the orientation reversed for antegrade 
implantation via a transfemoral transseptal catheter route. 
The LAMPOON method is described in the study procedures. 
13.2 
Asahi-Intecc Astato XS 20, 510(k) K103057 
The Astato 0.014” guidewire is used for transcatheter electrosurgery in two steps in this procedure.  First 
it is used for leaflet traversal during electrification.  This procedure is similar to the use of the Astato XS20 
and an amputated Asahi Confienza Pro 12 in the transcaval IDE investigation recently published 27. 
Second, the midshaft is focally denuded and electrified for the leaflet traversal step.  This is described in 
the pre-clinical 15 and early clinical 17 manuscript. 
Neither of these procedures are addressed in the indications for use: 
Asahi-Intec Astato XS 20: This product is intended to facilitate the placement and exchange of diag-
nostic and therapeutic devices during intravascular procedures. This device is intended for peripheral 
vascular use only. 

 
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14.0 
INVESTIGATOR ADMINISTRATIVE REQUIREMENTS 
14.1 
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 the Declaration of Hel-
sinki, Title 21 of the Code of Federal Regulations, Parts 50 (Protection of Human Subjects), and 56 (Institu-
tional Review Boards), and other appropriate regulatory requirement(s). The Investigator will be thor-
oughly familiar with the LAMPOON-TMVR 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 in-
tegrity of the data collected. Regulatory files should be established at the beginning of the study, main-
tained for the duration of the study and retained according to the appropriate regulations. 
14.2 
IRB Submissions 
The study will be conducted in accordance with ethical principles founded in the Declaration of Helsinki. 
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. 
14.3 
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 subject’s protection policies and to state laws. 
14.4 
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 monitor(s) 
and auditor(s) from the Sponsor or its designee and regulatory authority (ies) access to the subject’s origi-
nal 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 per-
mitted by the applicable laws and regulations. 
14.5 
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 

 
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have the approval /favorable opinion of the IRB/IEC and other appropriate institutional regulatory bodies. 
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. 
14.6 
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. 
14.7 
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 screens as soon as possi-
ble after information is collected, preferably on the same day that a study subject is seen for an examina-
tion, treatment, 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. 
14.8 
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 has full rights over any invention, discovery, or innovation, patentable or not, that may occur 
when performing the study. 
14.9 
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 representatives from the Sponsor, as appropriate, will be formed to oversee the 
publication and presentation of the study results, which will reflect the experience of all participating clin-

 
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ical sites. No publication or disclosure of study results will be permitted except under the terms and con-
ditions of a separate written agreement between Sponsor and the investigator and/or the investigator's 
institution. 
15.0 
SPONSOR REGULATORY REQUIREMENTS 
15.1 
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.  
15.2 
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.   
15.3 
Monitoring 
The study will be monitored by the Sponsor designee, an independent contract research organization. 
Monitoring will be done by personal visits and will include on-site review of the informed consent docu-
ments and case report forms for completeness 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 in-
vestigation is conducted according to protocol design and regulatory requirements by frequent communi-
cations (letter, e-mail, telephone, and fax). 
15.4 
Site Selection and Training 
The sponsor or its designee (national co-principal investigator) will ensure appropriate training in the 
technique of caval-aortic access prior to enrollment at any participating institution. 
15.4.1 
Site selection: 
Site selection will be based on  
x 
Physician expression of interest and need to apply this treatment approach to patients at the site. 
x 
Physician prior experience with 10 antegrade transseptal transcatheter mitral valve replacement 
procedures, to assure competence in TMVR procedures 
x 
Physician prior experience performing or proctoring 10 transcaval TAVR procedures to assure 
competence in transcatheter electrosurgery 
x 
Site prior participation in IDE protocols evaluating a treatment of structural heart disease 
x 
Site ability to obtain CT examinations that are satisfactory for consideration of LAMPOON TMVR. 
x 
Site investigators willing and able to comply with the requirements of this protocol. 

 
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15.4.2 
Site training: 
Site training will consist of 
x 
Principal investigator and/or sponsor didactic training about the technique, preclinical, and clinical 
experience to date. 
x 
Proctored conduct of LAMPOON TMVR procedures in patients at the local site, at the sole discre-
tion of the Sponsor and/or Principal Investigator.   
x 
Completion of training, and suitability for independent LAMPOON TMVR enrollment, will be certi-
fied by the Principal Investigator and with the concurrence of the Sponsor. 
 
 

 
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He S, Hopmeyer J, Lefebvre XP, Schwammenthal E, Yoganathan AP and Levine RA. Importance 
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Holzhey D, O'Hair D, Dumonteil N, Rodes-Cabau J, Piazza N, Palma JH, DeLago A, Ferrari E, Witkowski 
A, Wendler O, Kornowski R, Martinez-Clark P, Ciaburri D, Shemin R, Alnasser S, McAllister D, Bena M, 
Kerendi F, Pavlides G, Sobrinho JJ, Attizzani GF, George I, Nickenig G, Fassa AA, Cribier A, Bapat V, 
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MY and Lederman RJ. Intentional Laceration of the Anterior Mitral Valve Leaflet to Prevent Left Ventricular 
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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 antici-
pated harm to patient 
Potentially harmful to patient 
Likely harmful, even with im-
mediate correction 
Life threatening 
Risk Score 
1-4 
5-9 
10-20 
>20 
 
Risk Interpretation 
Negligible 
Tolerable  
Tolerable but undesirable 
Intolerable 
 
IDE LAMPOON TMVR 
Page 40 of 43 
2020-08-24 
APPENDIX A: Risk Analysis 
This is a patient-centered risk analysis28 in accordance with 21 CFR 812.25(c).  It considers probable and not possible risk.  This risk analysis applies to candi-
dates for TMVR with LAMPOON, who have a fatal disease with few or no therapeutic options.  
 
Category 
Failure 
Impact 
Severity 
Likelihood 
/ fre-
quency 
Score Available evidence to con-
sider risk 
Mitigation 
LAMPOON 
devices  
Failure to traverse or 
lacerate 
Small to large hole in 
AML exacerbate mitral 
regurgitation; Loss of 
therapeutic option 
4 
2 
8 
Preclinical and early clini-
cal experience 
Abandon procedure with loss of thera-
peutic option; implant nitinol occluder 
  
Char forms on denuded 
shaft of guidewire 
Loss of traversal or lac-
eration during electro-
surgical steps 
2 
3 
6 
Preclinical and early clini-
cal experience 
Minimize electrification time; Consider 
non-ionic insulating (dextrose 5%) flush 
during electrification 
  
Cavitation bubble forms 
during electrification 
Silent gas embolization 
2 
3 
6 
Preclinical and early clini-
cal experience with ICE 
and TEE; EP ablation liter-
ature 
Heparinization, minimum ablation en-
ergy.  Cavitation is common to all left-
sided (EP) RF ablation procedures 
  
Thrombus from electrifi-
cation of guidewire 
Thromboembolism in-
cluding cerebral 
4 
1 
4 
Preclinical and early clini-
cal experience; EP ablation 
literature; Transcaval ex-
perience 
Heparin to ACT>300; Minimize electrifi-
cation; Escalation of power from lower 
to higher energy settings 
LAMPOON 
technique 
Failure to lacerate com-
pletely 
MR exacerbation; Pro-
cedure failure 
5 
2 
10 Preclinical and early clini-
cal experience 
Careful technique 
  
Avulsion of aortomitral 
curtain 
Death 
5 
2 
10 Theoretical 
Careful technique 
  
Insulation failure: Piggy-
back 
Increased laceration 
force required 
3 
3 
9 
Preclinical and early clini-
cal experience 
Careful technique 

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 antici-
pated harm to patient 
Potentially harmful to patient 
Likely harmful, even with im-
mediate correction 
Life threatening 
Risk Score 
1-4 
5-9 
10-20 
>20 
 
Risk Interpretation 
Negligible 
Tolerable  
Tolerable but undesirable 
Intolerable 
 
IDE LAMPOON TMVR 
Page 41 of 43 
2020-08-24 
Category 
Failure 
Impact 
Severity 
Likelihood 
/ fre-
quency 
Score Available evidence to con-
sider risk 
Mitigation 
  
Kink / denudation fail-
ure 
Increased laceration 
force required 
3 
3 
9 
Preclinical and early clini-
cal experience 
Careful technique 
  
Wrong orifice traversal LAMPOON failure 
4 
2 
8 
Preclinical and early clini-
cal experience 
Technique assurance major orifice: 
BWEC & TEE 
  
Longitudinal inadequate 
crossing 
Inadequate LAMPOON 
3 
2 
6 
Theoretical 
TEE positioning close to AML base, ,but 
no QA postprocedure available except 
necropsy 
  
Failure to traverse 
LAMPOON failure 
2 
2 
4 
Theoretical 
Clinical technique: assure proper elec-
trosurgery technique, proper insulating 
catheter 
  
Failure to lacerate at all LAMPOON failure 
2 
2 
4 
Theoretical 
Careful technique 
  
Bystander tissue injury 
such as aortic valve 
Aortic regurgitation, 
thromboembolism 
4 
1 
4 
Theoretical 
Minimize exposed lacerating guidewire 
between two guiding catheters 
  
Avulsion TAVR 
Life-threatening repeat 
TAVR 
4 
1 
4 
Theoretical 
Careful technique; Exclude recent TAVR 
from protocol 
  
Wire or device entan-
glement with TMVR 
Failure, hemo instabil-
ity, recrossing 
2 
1 
2 
Theoretical 
Careful technique to assure no entan-
glement 
  
Guidewire lacerates JL 
catheters 
Bystander tissues are 
not protected from 
guidewire injury 
1 
1 
1 
Early clinical experience 
Careful technique 
  
Hemodynamic instabil-
ity from successful LAM-
POON 
Hypotension, shock 
3 
3 
9 
Preclinical and early clini-
cal experience 
Pre-position THV at operator discretion 
TMVR 
Geographic miss causing 
skirt leak 
LV failure, acute & sub-
acute 
5 
2 
10 Clinical literature 
Careful THV positioning; 

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 antici-
pated harm to patient 
Potentially harmful to patient 
Likely harmful, even with im-
mediate correction 
Life threatening 
Risk Score 
1-4 
5-9 
10-20 
>20 
 
Risk Interpretation 
Negligible 
Tolerable  
Tolerable but undesirable 
Intolerable 
 
IDE LAMPOON TMVR 
Page 42 of 43 
2020-08-24 
Category 
Failure 
Impact 
Severity 
Likelihood 
/ fre-
quency 
Score Available evidence to con-
sider risk 
Mitigation 
  
Paravalvular Leak 
LV failure, acute & sub-
acute 
2 
3 
6 
Clinical literature 
Careful THV sizing; careful THV posi-
tioning with regard to THV skirt and tar-
get tissue; Off-label implantation of ni-
tinol occluder devices to close PVL 
  
THV dysfunction from 
stent deformation 
THV dysfunction 
chronic 
3 
2 
6 
Clinical literature 
None 
  
LVOTO 
LV failure, acute & sub-
acute 
5 
1 
5 
Clinical literature, clinical 
experience 
LAMPOON procedure; Bailout transcor-
onary alcohol septal ablation 
  
Embolization 
Rescue ectopic implan-
tation, LV failure, death 
2 
2 
4 
Clinical literature, clinical 
experience 
Careful THV technique including "flare" 
of LV aspect 
  
Redundant native mitral 
leaflet causing THV dys-
function 
THV dysfunction, acute 
4 
1 
4 
Clinical literature, clinical 
experience 
LAMPOON procedure; Major orifice tra-
versal 
  
THV Thrombosis 
THV dysfunction, stroke 
4 
1 
4 
Clinical literature, clinical 
experience 
Post-procedure anticoagulation as tol-
erated 
Follow-up ATN from contrast CT 
Temporary or perma-
nent hemodialysis 
3 
2 
6 
Clinical literature, clinical 
experience 
Request low-energy and low-contrast 
time-resolved CT to minimize contrast.  
Follow operator discretion about timing 
of contrast exposure 
 
 
 

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 antici-
pated harm to patient 
Potentially harmful to patient 
Likely harmful, even with im-
mediate correction 
Life threatening 
Risk Score 
1-4 
5-9 
10-20 
>20 
 
Risk Interpretation 
Negligible 
Tolerable  
Tolerable but undesirable 
Intolerable 
 
IDE LAMPOON TMVR 
Page 43 of 43 
2020-08-24 
Appendix B: Kansas City Cardiomyopathy Questionnaire