NHLBI SESAME (SEptal Scoring Along Midline Endocardium) Early Feasibility Study
Phase: NA
Conditions: Hypertrophic Cardiomyopathy, Left Ventricular Septal Hypertrophy, Mitral Valve Disease, Aortic Valve Stenosis
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
NHLBI SESAME (SEptal Scoring Along Midline Endocardium) Early Feasibility 
Study 
NCT number: 
 
NCT06269640 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
February 14, 2025 
 

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Abbreviated Title: SESAME IDE Protocol
NIH IRB #: 001640
FDA IDE Application#: G220158
Version Date: Amendment B 2025-02-14
Title: NHLBI SESAME (SEptal Scoring Along Midline Endocardium) Early Feasibility Study
Investigational Device(s):
AstatoXS-20 and AstatoXS-40 guidewires
ConfianzaPro-12 guidewire
IDE Number:
 G220158
Sponsor:
Office of Clinical Director, National Heart Lung and Blood 
Institute, National Institutes of Health, USA
Sponsor Representative &
NHLBI Principal Investigator
Robert J. Lederman, MD
Cardiovascular Branch, Division of Intramural Research, 
National Heart Lung and Blood Institute, 
National Institutes of Health,
Building 10, Rm 2c713 MSC 1538, 9000 Rockville Pike
Bethesda, MD 20892-1538
Phone: +1-301-402-6769
E-mail: lederman@nih.gov
Data Coordinating Center:
National Heart Lung and Blood Institute Division of 
Intramural Research
Data and Safety Monitoring 
Board (DSMB)
National Heart Lung and Blood Institute

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1
TABLE OF CONTENTS 
1
TABLE OF CONTENTS ...........................................................................................................2
2
STATEMENT OF COMPLIANCE .............................................................................................5
3
PROTOCOL SUMMARY.........................................................................................................6
3.1
Synopsis ....................................................................................................................6
3.2
Schema ...................................................................................................................11
3.3
Schedule of Activities (SOA)....................................................................................12
4
INTRODUCTION .................................................................................................................13
4.1
Public précis (for clinicaltrials.gov) .........................................................................13
4.2
Study Rationale.......................................................................................................14
5
BACKGROUND....................................................................................................................15
5.1
Left ventricular outflow tract (LVOT) obstruction ..................................................15
5.2
Preclinical SESAME to relieve LVOT obstruction.....................................................16
5.3
Potential applications of SESAME, and phenotypic classifications of candidates ..17
5.4
Clinical SESAME using off-label devices..................................................................19
5.5
Risk/Benefit Assessment.........................................................................................22
6
OBJECTIVES AND ENDPOINTS............................................................................................27
6.1
Objective.................................................................................................................27
6.2
Hypotheses .............................................................................................................27
6.3
Primary Feasibility Endpoint...................................................................................27
6.4
Primary Safety Endpoint.........................................................................................27
6.5
Secondary endpoint................................................................................................27
6.6
Exploratory Endpoints ............................................................................................28
6.7
Rationale for Endpoints ..........................................................................................28
7
STUDY DESIGN ...................................................................................................................28
7.1
Constant values ......................................................................................................28
7.2
Overall Design.........................................................................................................29
7.3
Scientific Rationale for Study Design ......................................................................29
7.4
Regulatory Rationale for Initiating the Study .........................................................29
8
STUDY POPULATION..........................................................................................................29
8.1
Inclusion Criteria.....................................................................................................29
8.2
Willing to return for all scheduled follow-up activities, and eligible or able to 
undergo required protocol and testingExclusion Criteria.....................................................30
8.3
Rationale for selection criteria................................................................................30
8.4
Inclusion of Vulnerable Participants.......................................................................31
8.5
Lifestyle Considerations..........................................................................................32
8.6
Screen Failures........................................................................................................32
8.7
Strategies for Recruitment and Retention..............................................................32
9
TEST ARTICLES AND INDICATIONS FOR USE ......................................................................33
9.1
Asahi-Intecc Astato XS 20, 510(k) K103057, and Astato XS 40, 510(k) K153443....33
9.2
Asahi-Intecc Confianza Pro 12, 510(k) K171933 .....................................................33
10 STUDY INTERVENTION.......................................................................................................34

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10.1
Study Intervention Description...............................................................................34
10.2
Preparation/Handling/Storage/Accountability.......................................................37
10.3
Measures to Minimize Bias: Randomization and Blinding......................................37
10.4
Study Intervention Compliance ..............................................................................37
10.5
Concomitant Therapy .............................................................................................37
11 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..........................................................................................37
11.1
Discontinuation of Study Intervention ...................................................................37
11.2
Aborted or abandoned SESAME .............................................................................37
11.3
Subject Discontinuation/Withdrawal from the Study ............................................38
11.4
Loss to Follow-up....................................................................................................38
12 STUDY ASSESSMENTS AND PROCEDURES .........................................................................38
12.1
Screening Procedures .............................................................................................38
12.2
Efficacy Assessments ..............................................................................................39
12.3
Safety and Other Assessments ...............................................................................40
12.4
Assessment of neurovascular events (stroke and TIA)...........................................40
12.5
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS................................................40
12.6
Unanticipated Problems .........................................................................................44
12.7
Protocol Deviations and Non-Compliance..............................................................44
13 STATISTICAL CONSIDERATIONS .........................................................................................45
13.1
Statistical Hypothesis..............................................................................................45
13.2
Sample Size Determination.....................................................................................45
13.3
Populations for Analyses ........................................................................................45
13.4
Statistical Analyses..................................................................................................45
13.5
Stopping Rule Guidance for Data and Safety Monitoring Board (DSMB) ...............45
14 STUDY GOVERNANCE AND OTHER OPERATIONAL CONSIDERATIONS...............................46
14.1
Sponsor Representative..........................................................................................46
14.2
Site Selection and Training .....................................................................................47
14.3
Study Central Clinical Eligibility Committee............................................................48
14.4
Core Laboratories ...................................................................................................48
14.5
Clinical Events Adjudication Committee (CEAC) .....................................................48
14.6
Data and Safety Monitoring Board (DSMB)............................................................48
14.7
Publications Committee..........................................................................................49
14.8
Publication and Data Sharing Policy .......................................................................49
14.9
Intellectual Property...............................................................................................50
14.10
Informed Consent Process......................................................................................50
14.11
Unscheduled Study Discontinuation and Closure...................................................52
14.12
Confidentiality and Privacy.....................................................................................52
14.13
Future use of Stored Specimens and Data..............................................................53
14.14
Clinical Monitoring..................................................................................................53
14.15
Quality Assurance and Quality Control...................................................................55
14.16
Data Handling and Record Keeping ........................................................................55
14.17
Study Records Retention ........................................................................................57

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14.18
Collaborative Agreements ......................................................................................57
14.19
Conflict of Interest Policy........................................................................................57
15 ABBREVIATIONS.................................................................................................................58
16 REVISIONS..........................................................................................................................60
17 REFERENCES.......................................................................................................................61
18 Appendix A: Tables of Reporting Obligations ....................................................................67
19 Appendix B. Risk Analysis ..................................................................................................69

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2
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation 
Good Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

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3
PROTOCOL SUMMARY
3.1
Synopsis 
Title
NHLBI SESAME (SEptal Scoring Along Midline Endocardium) Early Feasibility 
Study 
Background / 
Précis
Cardiac interventricular septal reduction therapies — to relieve left ventricular 
outflow tract obstruction from transcatheter valve replacement or 
hypertrophic cardiomyopathy — have inherent limitations including 
dependence on coronary anatomy, high pacemaker implantation rate, and 
surgical morbidity. We developed a novel transcatheter ventricular myotomy 
called SEptal Scoring Along the Midline Endocardium (SESAME) that relies on 
intramyocardial guidewire navigation and transcatheter electrosurgery. 
SESAME has been performed on a small number of patients using off label 
devices. 
This study systematically characterizes the safety and early feasibility of 
SESAME at 2 enrolling site. SESAME is performed as septal reduction therapy 
in a heterogeneous group of subjects, including symptomatic hypertrophic 
cardiomyopathy and resting or provoked left ventricular outflow obstruction 
(LVOTO); and severe symptomatic mitral and/or aortic valve disease at high 
risk of standard heart surgical therapy and requiring later transcatheter heart 
valve implantation combined with manifest or potential LVOTO.
A key goal of this study is to attempt to capture generalizable knowledge from 
as many patients as possible, and to add a limited number of research 
procedures to characterize the safety and provisional effectiveness of SESAME. 
Absent realistic non-clinical models of HCM or LVH combined with aortomitral 
disease, we believe little more information can be gleaned without clinical 
investigation.
This protocol was revised to add a second enrolling medical center, and to 
focus inclusion criteria on research participants with hypertrophic 
cardiomyopathy (HCM). This protocol was further revised after the first 
subject died as a result of excessively-deep SESAME laceration. The required 
septal thickness for eligibility was increased from ≥12mm to ≥16mm.
Risk 
classification
Significant risk device protocol requiring Investigational Device Exemption 
(IDE) 
Device 
classification
Class II

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Test articles
Asahi-Intecc Astato XS 20, 510(k) K103057 & Astato XS 40, 510(k) K153443, 
Asahi-Intecc Confianza Pro 12, 510(k) K171933
Design 
overview
Prospective, 2-enrolling site, single arm, open-label, early feasibility study of 
the SESAME procedure
Study phase
Early feasibility study
Sponsor / 
Representative
NHLBI Office of the Clinical Director (NHLBI/OCD) /
Robert J. Lederman, MD, NHLBI/DIR/CB/LCI
Study Manager Annette M. Stine, RN
Objective
The objective of this protocol is to test the safety and effectiveness of the 
SESAME septal debulking in patients with left ventricular outflow tract 
obstruction. 
Hypotheses
We hypothesize that the interventricular septum can be engaged, traversed, 
and lacerated with SESAME to increase the predicted neo-LVOT. We also 
hypothesize that intracameral gradients can be relieved by SESAME.
Number of 
subjects
15 subjects enrolled at up to 2 investigational site in the US.
Up to 30 subjects may be screened for participation.
Sample Size 
Justification
The sample size is arbitrary. 

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Inclusion 
Criteria
•
Adults age ≥ 21 years
•
Requires debulking of left ventricular septum for hypertrophic 
cardiomyopathy 
•
Septal diastolic thickness of obstructive “hump” on CT: 
o
Total ≥16 mm, and 
o
Predicted residual septal thickness ≥ 8 mm, and
o
Predicted laceration depth ≥ 6 mm
•
Severely symptomatic, any of
o
NYHA Class III or greater
o
Canadian Angina Class CCS III or greater
•
Explicitly chooses investigational SESAME over conventional treatment 
approaches including (1) cardiac myosin inhibitor therapy, if eligible; (2) 
transcoronary alcohol septal ablation, if eligible; or (3) surgical left 
ventricular myotomy and/or myectomy, if eligible
•
Concurrence of the multidisciplinary institutional heart team that the 
candidate is at high risk for surgical myectomy
•
Concurrence of the study Central Clinical Eligibility Committee
•
Willing to return for all scheduled follow-up activities, and eligible or able 
to undergo required protocol and testing
Exclusion 
Criteria
•
Does not consent to participate, or unable to consent to participate
•
Requires antegrade SESAME access (because of mechanical aortic valve)
•
Prior completed transcoronary alcohol septal ablation, or prior surgical 
myectomy
•
Pregnant
•
Hemodynamic instability or emergency procedure
•
eGFR < 30 mL/min/1.73m2 
•
Survival despite successful procedure expected < 12months 
Primary 
Feasibility 
Endpoint
The primary feasibility endpoint is Technical success (measured at exit from 
the catheterization laboratory). All of the following must be present:
•
Alive
•
Procedure success including
o
Successful myocardial entry, navigation, and snaring of guidewire 
traversal system; and 
o
Successful laceration of septal myocardium

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Primary Safety 
Endpoint
The primary safety endpoint at 30 days, is freedom from all of the following:
•
All-cause mortality
•
All stroke (disabling and non-disabling)
•
Major cardiac structural complication requiring intervention (such as 
iatrogenic ventricular septal defect, iatrogenic aortic valve regurgitation, 
iatrogenic mitral regurgitation, or pericardial tamponade) related to 
SESAME
Secondary 
endpoint
The secondary endpoint is complete heart block requiring permanent 
pacemaker implantation, assessed at discharge.
Exploratory 
endpoints
•
Gradient reduction among subjects with hypertrophic cardiomyopathy, 
residual gradient ≤ 30mmHg at procedure conclusion and after 30 days 
•
30d VARC-3 complications of SESAME including access, bleeding, vascular, 
stroke, myocardial infarction
•
Symptom and functional status assessed at baseline, 30d, and 12 mo 
assessed by KCCQ-23 OS and CS, NYHA and CCS classifications, and 6 
minute walking test
•
Change in laceration dimensions and, when applicable, neo-LVOT and skirt 
neo-LVOT assessed by CT between baseline and 30 days
•
Undergoes attempted septal reduction therapy ablation after SESAME 
during the study period
•
Freedom from new permanent ventricular pacemaker implantation
•
New electrocardiographic conduction defects before discharge
•
Freedom from ventricular septal defect
•
Freedom from pericardial effusion
•
Freedom from stroke assessed at discharge

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Study 
Overview
NHLBI Data Coordinating Center
Central IRB 
Selected site operators have experience with transcatheter electrosurgery, 
especially LAMPOON, BASILICA, or SESAME
Subjects are identified by site investigators
CT, CMR, Echo, and procedure fluoroscopy are analyzed by core laboratory
Subject eligibility is proposed by institutional multidisciplinary heart team, and 
is confirmed by study Central Clinical Eligibility committee
Subjects are enrolled prospectively
Primary analysis based on 30 day outcomes.
Other datapoints undergo 100% source-data verification
Subjects go “off-study” after 12 months visit
Study Duration 30 months for enrollment + follow-up
Sites
Data Coordinating Center: 
NHLBI, including core laboratories.
Enrolling site(s):
1. Emory University Hospital, Atlanta, GA
2. St Francis Hospital, Roslyn, NY
All enrolling sites will perform same research activities.
Enrollment
Subjects are not enrolled until after they (1) are invited to participate by the 
study Central Clinical Eligibility Committee; (2) thereafter consent to 
participate 
Duration of 
Participation 
for Subjects
12 months

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3.2
Schema
Septal reduction 
therapy indicated
Screening
Central 
eligibility review
Informed Consent & 
Baseline assessment
Pre-discharge safety 
assessment
SESAME Procedure
30-day assessment
Hypertrophic cardiomyopathy (HCM) 
group 
Transcatheter Heart Valve (THV) groups:
With- and Without-
intracameral gradients
THV implanted as practice of medicine or 
as part of other investigation?
30-day assessment
30-day post-THV assessment, 
chart review
Yes
No
6-month assessment
12-month assessment and 
termination visit

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3.3
Schedule of Activities (SOA)
Screening (± 6 mo)
Baseline (± 6 wk)
Day 0 (procedure)
Pre-discharge
30 d (-7+14d) FU
TMVR data, if applicable 
(post-TMVR d30)
6 mo (± 4 wk)
12 mo (± 4 wk) FU 
Research informed consent:
X
Local multidisciplinary heart team eligibility determination 
X
Central Clinical Eligibility Committee concurrence
X
Clinical in-person assessment including vital signs, NYHA & CCS 
classification
X
X
X
X
X
Stroke assessment: mRS and NIHSS
X
X
X
6 minute walk test
X
X
X
X
Kansas City Cardiomyopathy Questionnaire (KCCQ-23)
X
X
X
X
Blood test for pregnancy (hCG) for CT or MR if premenopausal woman
X
X
Blood tests: CBC, Platelet, Chemistry Panel, 
X
X
X
Blood test: BNP/Pro-BNP
X
X
X
Blood test: Troponin I 24-48 hours post-procedure
X
X
Blood test and buccal mucosal swab: optional commercial genetic testing 
panel for HCM and phenocopies
§
Cardiac CT gated dynamic, with contrast 
Screening or baseline*, **
§
X
X
Cardiac MR including function, volume, relaxometry, (Gadolinium 
contrast if not contraindicated)
§
X
§
SESAME index procedure including hemodynamic catheterization
X
Optional follow-up hemodynamic cath
§
Procedural echocardiography (transthoracic, transesophageal, and/or 
intracardiac)
X
Transthoracic echocardiogram, including exercise
Screening or baseline*, **
X
X
X
X
ECG
X
X
X
X
X
Exercise VO2 exam
X
X
Pacemaker interrogation (when applicable)
X
X
X
Adverse event assessment
X
X
X
X
X
X
Unscheduled clinically-driven cardiac imaging exams are analyzed by the core laboratories.
* Standard of care tests will be used to determine eligibility if obtained within 6 months. 
**Screening CT, CMR, and echocardiography may be used for baseline exams if obtained for 
standard medical care, otherwise research exams will be obtained. “Out-of-window” baseline 
imaging exams may be employed if deemed acceptable by study eligibility committee.
§ Optional exams. 
Optional CT scan before discharge as clinically-indicated and as determined by the treating 
physicians. If obtained, it will be analyzed for research.

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3.3.1
Blood tests
All of the blood tests specified here are mandatory for routine medical care before, during, and after 
transcatheter SESAME procedure. The results are recorded as research values and in surveillance for 
adverse events. No other blood tests are reported as adverse events. 
The specific blood tests are enumerated below, and reported as study adverse events only if they 
change from baseline > 10% AND out-of-range.
Test
Detail
Inpatient 
value to 
record
Timepoints to 
collect
Blood count: white blood cell count Nonspecific marker of inflammation and infection.
Highest
Baseline through 
30d
Chemistry: Creatinine 
Marker of renal excretion. eGFR 
Highest
Baseline through 
30d
Chemistry: Estimated glomerular 
filtration rate (eGFR)
Calculated from age, sex, race, and creatinine
Lowest
Baseline through 
30d
The following blood tests will be acquired and will not be reported as adverse events, because they are 
expected to be abnormal in every patient/subject.
Chemistry: Cardiac troponin
Marker of cardiomyocyte injury, institution-
specific subtype (Troponin-I or Troponin-T).
Highest
Baseline & 24-48 
hrs postprocedure. 
Chemistry: NT-Pro-Brain natriuretic 
peptide (NT-Pro-BNP) or Brain 
natriuretic peptide (BNP)
Marker of volume overload. Sites must use 
identical BNP/NT-Pro-BNP assay for each subject 
throughout the first 12 months of the study
Lowest
Baseline, 30d, 12 
mo 
Blood count: hemoglobin
Marker of anemia and hemodilution.
Lowest
Baseline through 
30d
Blood count: hematocrit
Marker of anemia and hemodilution.
Lowest
Baseline through 
30d
Blood count: platelet
Nonspecific marker of coagulation and of 
inflammation.
Lowest
Baseline through 
30d
Genetic test: HCM phenocopies
Inherited cause of primary cardiac hypertrophy if 
identifiable
All
Baseline
Commercial genetic testing for HCM phenocopies is optional pending CMS or insurance 
coverage of the genetic test, typically under CMS CTP program coverage (see section 8.7.1 
"Costs").
4
INTRODUCTION
4.1
Public précis (for clinicaltrials.gov)
This is an early study of a new catheter-based minimally invasive  procedure called SESAME to 
slice thick heart muscle as described below.
Excessively-thick heart muscle can cause serious heart disease, especially heart failure with 
preserved ejection fraction, which causes shortness of breath and heart failure symptoms such 

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as edema (swelling) and pulmonary congestion (lung water). Specific circumstances of 
excessively-thick heart muscle can block outflow of blood from the main heart pumping 
chamber (left ventricle).
We have developed a new catheter technique called SESAME (SEptal Scoring Along Midline 
Endocardium) to slice the excessively-thick heart muscle causing such problems. SESAME can 
be used in patients who have symptoms related to excessively-thick heart muscle in a part of 
the heart that restricts blood ejection from the heart; the problem is called “left ventricular 
outflow tract obstruction (LVOTO).”
One group of patients who might benefit from SESAME suffer from a common inherited heart 
muscle disease called “hypertrophic cardiomyopathy (HCM).” Patients with HCM and symptoms 
from LVOTO can be treated with medications, open heart surgery, or catheter-based 
destruction of heart muscle in “alcohol septal ablation.” If these treatments fail or are not 
suitable, then SESAME may be an option, because it resembles surgery treatment without open 
heart surgery.
This is an early feasibility study of SESAME in some of the first patients in the world to undergo 
the procedure, to understand how well it works and whether it is safe.
4.2
Study Rationale
Cardiac interventricular septal reduction therapies — to relieve left ventricular outflow tract 
obstruction from transcatheter valve replacement or hypertrophic cardiomyopathy — have 
inherent limitations including dependence on coronary anatomy, high pacemaker implantation 
rate, and surgical morbidity. We developed a novel transcatheter ventricular myotomy called 
SEptal Scoring Along the Midline Endocardium (SESAME) that relies on intramyocardial 
guidewire navigation and transcatheter electrosurgery. SESAME has been performed on a small 
number of patients using off label devices. 
This study systematically characterizes the safety and early feasibility of SESAME at 2 enrolling 
site. SESAME is performed as septal reduction therapy in a heterogeneous group of subjects, 
including symptomatic hypertrophic cardiomyopathy and resting or provoked left ventricular 
outflow obstruction (LVOTO); and severe symptomatic mitral and/or aortic valve disease at high 
risk of standard heart surgical therapy and requiring later transcatheter heart valve 
implantation combined with manifest or potential LVOTO.
A key goal of this study is to attempt to capture generalizable knowledge from as many patients 
as possible, and to add a limited number of research procedures to characterize the safety and 
provisional effectiveness of SESAME. Absent realistic non-clinical models of HCM or LVH 
combined with aortomitral disease, we believe little more information can be gleaned without 
clinical investigation.
This protocol was revised to add a second enrolling medical center, and to focus inclusion 
criteria on research participants with hypertrophic cardiomyopathy (HCM). This protocol was 
further revised after the first subject died as a result of excessively-deep SESAME laceration. 
The required septal thickness for eligibility was increased from ≥12mm to ≥16mm.

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5
BACKGROUND 
5.1
Left ventricular outflow tract (LVOT) obstruction 
LVOT obstruction is present in 75% of patients with hypertrophic cardiomyopathy (HCM)[1]. 
Obstruction is due to hypertrophy of the interventricular septum and symptoms are 
exacerbated by abnormalities in the mitral valve apparatus (long anterior leaflet, anterior 
dislocation of the papillary muscle) causing a Bernoulli effect and systolic anterior motion 
(SAM) of the anterior mitral leaflet. Symptoms may improve with negative-inotropic 
pharmacologic therapy (beta-adrenergic blockers and new myosin inhibitors). Surgical septal 
myectomy and percutaneous trans-coronary alcohol septal ablation (TCASA) are invasive septal 
reduction treatment options that relieve LVOT obstruction in symptomatic patients with HCM 
despite guideline directed medical therapy[2]. 
There are limitations to these septal reduction and 
leaflet modification therapies, including surgical 
morbidity, anatomic feasibility, technical complexity, 
conduction system injury and inadequate LVOT 
enlargement.  Maron and colleagues graphically 
depicted the incidence of LVOT obstruction after 
conventional therapy (Figure 1).
Although no longer directly relevant to this study, LVOT obstruction also complicates 
transcatheter mitral valve replacement (TMVR)[3], and is a leading cause of ineligibility for 
TMVR[4]. Pre-emptive trans-coronary alcohol septal ablation (TCASA) and laceration of the 
anterior mitral leaflet to prevent outflow obstruction (LAMPOON) are two widely-employed 
techniques to prevent LVOT obstruction from TMVR[5-8]. Even despite LAMPOON, TMVR in 
patients with small cardiac chambers may still result in functionally significant, if non-lethal, 
narrow LVOT. Septal debulking combined with LAMPOON may further reduce residual LVOT 
Figure 1. Incidence of residual LVOT 
obstruction after treatment. From Maron, 
Circulation, 2021;143:1181.

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obstruction at rest or during exercise. Surprisingly, a significant poorly-defined proportion of 
patients undergoing planned septal reduction therapy in anticipation of TMVR derive 
symptomatic benefit sufficient to delay or defer the planned TMVR[8, 9]. The mechanism of this 
benefit is not understood, and may reflect alterations in diastolic compliance of the 
hypertrophied ventricles from septal reduction, or even placebo effect. Deferral of TMVR may 
be desirable in the treatment of mitral valve stenosis associated with mitral annular 
calcification (MAC), wherein residual TMVR-transmitral gradient limits the functional benefit of 
therapy. In combination these clinical 
considerations warrant collection of additional 
data.
5.2
Preclinical SESAME to relieve LVOT 
obstruction
An early surgical technique to treat LVOT 
obstruction in hypertrophic cardiomyopathy was 
a simple ventricular myotomy without 
myectomy[10]. An incision is made across the 
hypertrophied bar of septal muscle in line with 
the left-right coronary cusp commissure. The cut 
muscle splays apart, reducing septal 
encroachment into the LVOT without removal of 
muscle tissue, relieving LVOT obstruction. A 
longitudinal series of 36 patients demonstrated 
symptomatic benefit maintained at 4-year mean 
follow-up[11]. In 21 patients with hemodynamic 
assessment available, the LVOT pressure 
gradient was abolished in 71% and reduced to 
below 20mmHg in 24% with this surgical 
technique[11]. Surgical myotomy and myectomy 
have evolved into standard therapy[12-14] 
incorporated into treatment guidelines for 
appropriately-selected symptomatic patients[2].
Combining techniques developed in our 
laboratory for transcatheter electrosurgery [15] 
and intramyocardial guidewire navigation[16], 
we developed a new transcatheter procedure 
for septal reduction therapy, mimicking surgical 
ventricular myotomy, called SEptal Scoring 
Along the Midline Endocardium (SESAME)[17, 
18]. 
Figure 2. SESAME Schematic. A. A guiding catheter directs a 
coronary guidewire and microcatheter into the base of the 
hypertrophied interventricular septum. The broken gray 
arrow depicts the intended guidewire trajectory. The red 
arrow depicts blood flow through a narrowed LVOT. B. The 
guidewire completes the intramyocardial trajectory, with 
microcatheter support, and re-enters the left ventricle cavity 
into a a snare. C. A modified “flying V” lacerating surface is 
created and traction applied to the guidewires and catheters 
during electrification to create the SESAME laceration. D. 
Following transcatheter SESAME, the muscle splays 
creating extra space in the LVOT, with increased area for 
blood flow, depicted by the red arrow. E. The left ventricle 
and aorta are  displayed opened at the left-noncoronary 
cusp commissure, depicting the SESAME laceration in 

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We developed SESAME in naïve swine and in a porcine model of mild (minimal) left ventricular 
hypertrophy[17]. SESAME myotomy was achieved in all animals, including septal entry, 
intramyocardial navigation, septal exit, and laceration along the intended trajectory. The 
myocardial laceration was splayed immediately (median 11.2mm) and at follow-up (median 
14.8mm). One animal developed a conduction abnormality (left axis deviation on ECG, 
representing injury of a branch of the left bundle) but no higher conduction block was seen in 
any animal. Two naïve pigs with thin baseline septa, developed ventricular septal defects due to 
excessively deep lacerations, that were an expected complication in this exploratory preclinical 
technique development protocol. Coronary angiography and CMR perfusion imaging revealed 
no abnormalities. Cardiac function by chamber volumes, aortic flow and strain analysis was 
preserved. No acute myocardial oedema was evident on CMR T1 mapping. The preclinical 
experience demonstrated feasibility of SESAME and highlighted the importance of careful 
trajectory planning, and avoidance of excessively thin septa, to prevent iatrogenic ventricular 
septal defect which also complicates standard septal reduction therapy.
5.3
Potential applications of SESAME, and phenotypic classifications of candidates
Transcatheter myotomy can splay the interventricular septum and either relieve manifest 
intraventricular pressure gradients, or it can create space to allow valve implantation that might 
otherwise obstruct left ventricular outflow. Accordingly there are several potential clinical 
applications.
SESAME can relieve basal or mid-chamber outflow obstruction complicating primary 
hypertrophic cardiomyopathy, an inherited phenotype common to numerous genotypes. In 
practice, hypertrophic cardiomyopathy is diagnosed on clinical and not genetic criteria. 
Hypertrophic cardiomyopathy is often associated with functional mitral valve regurgitation, 
related to Bernoulli-force-induced systolic anterior motion of the mitral valve towards the 
septum. Hypertrophic cardiomyopathy is also often associated with primary mitral valve 
regurgitation related to architectural chordal or papillary abnormalities.
Severe secondary left ventricular hypertrophy, presumably related to systemic hypertension 
and other forms of excessive afterload, is common and often accompanies degenerative aortic 
and mitral valve disease. It is possibly that some patients exhibiting these features may have 
underlying primary hypertrophic cardiomyopathy, but we classify them as “secondary” left 
ventricular hypertrophy. These patients may have not heretofore undergone systematic genetic 
screening for HCM phenocopies.
Infrequently, septal left ventricular hypertrophy that accompanies aortic valve stenosis is so 
severe that sudden unloading of the left ventricular by aortic valve replacement causes acute 
life-threatening dynamic left ventricular outflow tract obstruction, sometimes described as 
“suicide left ventricle.” Such patients benefit from prophylactic or emergency bailout septal 
reduction therapy[19-22].
Severe left ventricular hypertrophy is associated with mitral annular calcification, a 
degenerative phenomenon associated with mitral valve failure, both stenotic, regurgitant, or 
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causally, to tissue stress imparted by the underlying ventricular hypertrophy[23-27]. Affected 
patients are typically older, women, and have moderate or severe pulmonary artery 
hypertension; collectively these indicate high risk of surgical morbidity and mortality. 
Moreover, at least half of patients with symptomatic mitral valve disease related to mitral 
annular calcification, have insufficiently large left ventricular cavities to accommodate 
transcatheter mitral valves[28].  And of these, approximately half also have manifest (resting or 
provoked) intraventricular pressure gradients. Treatment of primarily-regurgitant mitral valve 
failure may better relieve symptoms than treatment of primarily-stenotic mitral valve failure 
attending mitral annular calcification, in part because of residual prosthetic transmitral 
gradients.  
Still others with left ventricular hypertrophy and mitral annular calcification develop serious or 
life-threatening left ventricular outflow tract obstruction immediately following mitral valve 
implantation, either predictably or as a result of a technical complication, and require urgent or 
emergency septal reduction therapy. 
The many permutations of left ventricular hypertrophy, mitral annular calcification and forms 
of mitral valve failure, and intracameral geometry or obstruction, make clinical evaluation of 
Ventricle
Valve
Intracameral gradient 
present
At-risk for 
intracameral gradient
Primary 
LVH (HCM)
Mitral leaflets intact 
despite functional (e.g. 
SAM) MR
Present
—
Secondary 
LVH
Aortic stenosis
LVOTO present, risking 
“suicide left ventricle”
—
Prosthetic mitral valve
After TMVR or SMVR
—
MAC with MR
Present at baseline
Small neo-LVOT
MAC with MS or 
mixed MS/MR
Present at baseline
Small neo-LVOT
Native mitral failure 
without MAC, or after
mitral ring annuloplasty
—
Small neo-LVOT
Table 1. Proposed phenotype scheme
Gradient
HCM
No Gradient

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septal reduction therapy complex. We propose a working following phenotypic classification 
scheme for SESAME transcatheter myotomy candidates, below and in Table 1:
1: Hypertrophic cardiomyopathy with intracameral gradient (LVOTO), described as 
“HCM” and depicted in green.
2: Secondary left ventricular hypertrophy (LVH) with aortic or mitral valve disease and 
resting or provocable intracameral gradient, described as “Gradient group” and 
depicted in orange.
3: Secondary left ventricular hypertrophy (LVH) with aortic or mitral valve disease AND 
no intracameral gradient, but at risk for LVOT obstruction as a predicted complication of 
mitral valve replacement because of small neo-LVOT, described as “No gradient group” 
and depicted in light blue.
This three-category phenotypic classification may be crude and imprecise, especially because of 
our failure to distinguish primary from secondary LVH. Nevertheless we find it useful to try to 
dissect the value of SESAME on diverse clinical scenarios.
5.4
 Clinical SESAME using off-label devices
Greenbaum and colleagues at Emory University recently reported the first case of SESAME 
using off-label devices[18], with one-year of clinical and CT-follow-up, in an elderly patient with 
concomitant obstructive HCM and symptomatic mitral stenosis associated with mitral annular 
calcification. Her neo-LVOT was prohibitively small. Her LVOT area increased, and her resting 
and provoked LVOT gradients fell immediately after SESAME and were nearly absent one 
month later. She then underwent TMVR without LVOT obstruction. Analogous to surgical 
ventriculo-myotomy, she exhibited no evolution of SESAME myotomy splay dimensions or 
septal thinning over one year of follow-up.
During the period January 1 2021 to November 23 2022, the team at Emory University 
undertook 37 attempted SESAME procedures as  the practice of medicine. In addition, we are 
aware of at least 7 additional attempts at two other medical centers that are not further 
described here. The Emory data below derive from retrospective chart abstraction and did not 
undergo source-data verification. We apply our three-category phenotypic classification 
described earlier, despite potential imprecision.
Of the 37 patients, 86% were women, and median age was 75 (72, 81) years. Twenty-eight 
(78%) underwent SESAME with the intent to perform TMVR afterwards. The remainder had 
HCM or required TAVR. Half of those intending TMVR had baseline LVOT gradients (≥30mm Hg 
at rest of ≥50mm provoked). All but one had high or prohibitive operative risk; median STS 
predicted risk of mortality from mitral surgery was 9% (5, 14); 26 had severe mitral annular 
calcification; and 32 had severe pulmonary artery hypertension.
Six of 37 would have been excluded from this proposed protocol: two because of cardiogenic 
shock at baseline, one who underwent SESAME as emergency bailout during Tendyne TMVR 

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implantation for shock, one with HCM and systemic-level pulmonary artery hypertension at 
baseline, and two with end-stage renal disease on hemodialysis.
Nine underwent concomitant procedures during the same procedure as SESAME, including 7 
TAVR, 1 TEER, and 1 Tendyne TMVR (creating the requirement for rescue SESAME). 
The SESAME procedure was technically successful in all (defined as in this protocol as surviving 
the cath lab procedure with successful myocardial traversal and SESAME laceration).
Four (11%) had serious complications. One patient had a free wall perforation successfully 
managed conservatively. It was attributed to a “steam pop” caused by excessively prolonged 
radiofrequency energy application in an otherwise intended laceration trajectory. Three 
patients had new ventricular septal defects (VSD), including the one with the free wall 
perforation. All were small and did not require treatment. Two underwent one-time pericardial 
drainage, including the patient with the free-wall perforation; the etiology of the other is 
unknown but likely related to trans-septal intracardiac echocardiography probe. One 
underwent uneventful defibrillation for iatrogenic ventricular fibrillation induced by septal 
guidewire navigation. None had iatrogenic aortic or mitral valve injury. All survived to 
discharge.
Intracameral gradients were measured in all 37 before and after SESAME:
HCM 
Gradient Group
NoGradient Group
Phenotype
baseline, N = 5 post, N = 5 baseline, N = 17 post, N = 17 baseline, N = 15 post, N = 13
proc.lvot.peak.peak (mmHg)
62 (50, 82)
26 (18, 31)
43 (32, 81)
22 (12, 46) 10 (3, 18)
4 (3, 12)
proc.lvot.peak.peak.pvc (mmHg) 136 (106, 172) 104 (84, 122) 105 (66, 154)
53 (19, 92) 18 (6, 34)
10 (7, 32)
Data are median (1st quartile, 3rd quartile). 
Thirty four of 37 (91%) survived to discharge. Of the three inpatient deaths, two had 
cardiogenic shock at baseline; a third with severe MAC/MS/MR, aortic stenosis, failed prior 
alcohol septal ablation, and dementia suffered pulmonary edema during convalescence and 
transitioned to hospice at family request.
One patient had a stroke recognized in retrospect after discharge. One underwent permanent 
pacemaker implantation (and recovered normal atrioventricular conduction afterwards). Six 
had VARC3 major bleeding, two had VARC3 major vascular complications.
Cumulative post-discharge adverse events are reported here. During follow-up a median of 44 
(38, 117) days, there were 7 cumulative deaths (19%), 2 cumulative strokes (6%, one ischemic 

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and one hemorrhagic), and 1 permanent pacemaker. Twelve (32%) were readmitted to a 
hospital (8 non-cardiac, 4 non-cardiac).
On preliminary evaluation of baseline- and follow-up CT, among all patients, and ascribing 
baseline values to missing values, SESAME effectively enlarged LVOT as assessed by neo-LVOT 
and skirt-neo-LVOT:
HCM Group
Gradient Group
NoGradient Group
Phenotype
baseline, N = 5
post, N = 5 baseline, N = 17
post, N = 17
baseline, N = 15
post, N = 13
ct.neo.lvot (mm2)
—
—
4 (0, 27)
107 (65, 320)
35 (7, 107)
171 (105, 208)
ct.skirt.neo.lvot (mm2)
—
—
197 (154, 254)
236 (195, 311)
207 (174, 251)
248 (210, 300)
Data are median (1st quartile, 3rd quartile). 
We assessed the evolution of the thinnest portion of the lacerated septum in 29 patients 
available for at least two CT examinations after discharge.  There were no new ventricular 
septal defects or perforations after discharge. The table below summarizes the findings:
Characteristic
HCM, N = 3
Gradient Group, N = 13
NoGradient Group, N = 13
min.discharge.sysstole
8.9 (7.9, 10.9)
4.8 (2.2, 6.2)
6.6 (5.1, 9.2)
min.latest.sysstole
11.7 (10.2, 11.9)
6.5 (2.5, 9.0)
6.6 (3.6, 9.3)
delta.systole
1.90 (0.55, 2.35)
0.30 (0.00, 2.20)
0.00 (-1.77, 1.22)
min.discharge.diastole
7.4 (7.1, 8.7)
3.9 (3.2, 6.3)
6.0 (4.4, 7.4)
min.latest.diastole
6.0 (5.7, 8.6)
6.1 (1.9, 7.0)
5.6 (4.0, 7.5)
delta.diastole
-0.80 (-1.45, 0.20)
0.00 (-0.40, 2.30)
0.00 (-1.10, 0.73)
days.after.discharge
30 (30, 34)
42 (33, 242)
42 (35, 49)
Data are median (1st quartile, 3rd quartile). 
During follow-up, of 28 subjects who underwent SESAME with an intent to undergo TMVR:
-
6 underwent TMVR
-
10 reported sufficient symptomatic improvement that TMVR was deferred (of these 
9/10 had baseline significant MS or MS/MR) 
-
1 did not have sufficient enlargement of the neoLVOT allowing TMVR, which was 
therefore deferred
-
3 deferred TMVR because of frailty (n=2) or ultimately proved ineligible for large-
annulus investigational TMVR (n=1) 
-
2 died without TMVR
-
6 await disposition regarding TMVR at the time of this preliminary report
The off-label Emory experience, including 76 total patients, was recently reported[29] and 
extended the observations described above.

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5.4.1
Summary of off-label clinical experience
In summary, during initial human application of SESAME for diverse indications, technical 
success was high (100%), and death (8%) and non-fatal serious complications (11%) were 
common. There appeared to be no SESAME-related complications after hospital discharge, 
analogous to the experience after surgical myotomy/myectomy. A large proportion of patients 
who underwent SESAME intending to enable TMVR either await disposition or were able to 
defer TMVR. These observations warrant further systematic investigation.
The off-label clinical experience informed selection criteria for the proposed protocol, which 
excludes patients with baseline hemodynamic instability. 
5.5
Risk/Benefit Assessment
A formal risk assessment is included in Section 19.
5.5.1
Known Potential Risks (Anticipated Adverse Device Effects)
Complications of SESAME
-
Ventricular septal defect from excessively deep cut
-
Free wall ventricular perforation from excessively deep cut
-
Pericardial effusion or tamponade, possibly requiring catheter-based or surgical 
drainage or repair
-
Insufficiently deep cut causing procedural failure, and possibly requiring an alternative 
approach such as alcohol septal ablation, radiofrequency ablation, surgical ablation, or 
perhaps a second attempt at SESAME.
-
Cardiac arrhythmia including atrial fibrillation, atrial flutter, ventricular tachycardia, 
ventricular fibrillation including cardiac arrest
-
Conduction system defect which may require a temporary or permanent pacemaker
-
Mitral valve injury, possibly requiring transcatheter or surgical repair
-
Injury to the aortic valve causing aortic regurgitation, possibly causing hypotension or 
cardiogenic shock
-
Coronary-cameral fistula, coronary artery spasm, or other coronary artery injury 
requiring treatment
-
Thrombus formation in the laceration pocket
-
Embolization of air, thrombus/clot, heart tissue, or atheroma, to coronary, cerebral, 
visceral, pulmonary or systemic circulation possibly causing symptomatic 
ischemia/infarction
-
Heart enlargement (“remodeling”) over time, including causing heart failure
-
Stroke or transient ischemic attack or paralysis
-
Permanent disability
-
Death

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Complications of diagnostic and interventional catheterization
-
Complications of percutaneous venous and/or arterial access including bleeding, 
retroperitoneal hematoma, local hematoma, perforation, fistula, pseudoaneurysm, 
compartment syndrome, peripheral nerve injury, chronic pain, infection, among other 
things
-
Hypotension or shock or cardiopulmonary arrest including requiring cardiopulmonary 
resuscitation, chest compressions, cardioversion/defibrillation, vasoactive medications, 
and/or mechanical circulatory support and/or extracorporeal membrane oxygenation
-
Myocardial ischemia or infarction (acute coronary syndrome or heart attack)
-
Cardiac perforation from the catheterization tools, including the guiding catheters, 
electrified and non-electrified guidewires, snares, and intracardiac echocardiography 
catheters 
-
Mechanical failure of catheter tools including breakage and unintended retention of 
catheter or guidewire fragments
-
Thromboembolism including venous thrombosis 
-
Other blood vessel perforation or injury, including requiring catheter or surgical 
treatment
-
Acute kidney injury related to SESAME procedure or CT requiring temporary or 
permanent hemodialysis or other medical treatment
-
Congestive heart failure, elevated natriuretic peptides, or cardiogenic shock that may 
require intervention
-
Volume overload, pleural effusion, pulmonary edema, dyspnea, edema, pericardial 
effusion, or other congestion from procedure-related volume perturbations or other 
heart failure
-
Respiratory failure requiring oxygen therapy, mechanical support or mechanical 
ventilation
-
Infection including device infection, endocarditis, infection of a blood vessel
-
Infection or sepsis including access sites, lung, urinary tract, or other system
-
Abnormal blood tests including serum chemistry tests (creatinine, troponin), electrolyte 
imbalance, and including hematology tests (hemoglobin, hematocrit, platelets, white 
blood cells)
-
Hemorrhage requiring transfusion or intervention
-
Pain including chest pain, angina, back pain, access site pain, neuropathy, and 
generalized pain
-
Pericardial effusion or tamponade requiring percutaneous or surgical treatment
-
Pneumothorax, hydrothorax, and hemothorax
-
Syncope, pre-syncope, seizure, delirium, or other loss of consciousness
-
Other venous thrombosis or thromboembolism including deep vein thrombosis, and 
pulmonary thromboembolism
-
Radiation injury including intractable skin injury
-
High blood pressure
Allergic or inflammatory reactions to

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-
anesthesia,
-
contrast media
5.5.2
Risks related to Radiation
In this research protocol, subjects will be exposed to fluoroscopy to guide SESAME. It is 
estimated (conservatively) that the amount of research radiation that a subject will be exposed 
to during participation in this research protocol will be approximately 3.6 rem from 
approximately 30 minutes of fluoroscopy during performance of SESAME, and 0.79 rem (each 
of two CT exams), and 5 minutes of fluoroscopy during follow-up catheterization. The total 
amount of radiation exposure from these procedures is equal to approximately 6.0 rem. This is 
equivalent to 20 years’ worth of background terrestrial radiation exposure estimated at 0.3 rem 
per year.
We believe the total fluoroscopy exposure to be justifiable in this setting, given the seriousness 
of their cardiovascular disease. We estimate the benefit to the research subjects for these 
procedures to outweigh the risks.
5.5.3
Risks of Other Study Tests and Procedures
Electrocardiogram: 
Skin irritations can occur where the adhesives attach. 
Echocardiogram: 
Some people feel discomfort during the echo with pressure from the echo probe. Some people 
feel tired from optional exercise.
Blood collection and Intravenous catheter: 
Minor complications including bleeding, pain, and hematoma formation at the site of blood 
draws, vasovagal reactions or infections may rarely occur.
Six-minute walk test: 
Fatigue, chest pain, rapid heart rate, and shortness of breath may occur. 
Exercise VO2 test:
A mask placed over the face while you walk on a treadmill or peddle a bicycle. Some people feel 
claustrophobic from the mask. Some people feel tired from the exercise.
CT Scan:
Oral and/or intravenous contrast agents will be used and are usually well tolerated. However, 
some subjects will experience allergic reactions to intravenous contrast. Some patients who 
receive contrast agents may experience a temporary reduction in kidney function lasting up to 

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2 weeks following infusion. In rare instances, permanent renal damage can result from the use 
of the IV contrasting agent.
MRI
Magnetic fields in MRI scanners can cause dangerous interactions in patients with metallic 
foreign bodies: projectile effect, twisting, burning, artifacts, and device malfunction 
(interference with a pacemaker). Therefore, all patients need to thoroughly be screened 
individually for foreign bodies before undergoing an MRI scan. 
The noise from the scanner may damage hearing, hearing protection must be used. 
Risks from Gadolinium Based Contrast Agents (GBCA)
Gadolinium is a relatively very safe contrast; however, it rarely might cause allergic reactions in 
patients. Patients with impaired kidney function need to be evaluated carefully before injection 
of gadolinium for MRI procedure.
5.5.4
Risks to privacy: Personal Identifiable Information
Clinical data from subjects participating in this trial will retain personally identifiable 
information. This includes CT scans, X-ray fluoroscopy acquisitions, echocardiograms, and 
medical records.
Abstracted data will be coded (personally identifiable information removed but linking codes 
retained) and for transmission to participating investigators, clinical events adjudication 
committee, statistician.
DICOM data will be stored in a secured NIH research PACS system for analysis, including 
personally identifiable information.
5.5.5
Known Potential Benefits
5.5.5.1
Direct benefits
SESAME is intended to treat three related clinical problems described in Table 1 and listed 
below:
1: Hypertrophic cardiomyopathy with intracameral gradient (LVOTO), described as 
“HCM” and depicted in green.
2: Secondary left ventricular hypertrophy (LVH) with aortic or mitral valve disease and 
resting or provocable intracameral gradient, described as “Gradient group” and 
depicted in orange.
3: Secondary left ventricular hypertrophy (LVH) with aortic or mitral valve disease AND 
no intracameral gradient, but at risk for LVOT obstruction as a predicted complication of 
mitral valve replacement because of small neo-LVOT, described as “No gradient group” 
and depicted in light blue.

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As such, SESAME may avert complications of standard treatments or techniques to prevent left 
ventricular outflow obstruction:
-
SESAME is expected to reduce the frequency of failure known to complicate transcoronary 
alcohol septal ablation, which relies on anatomic coincidence of septal perforator coronary 
arteries and the obstructing ventricular septal tissue. SESAME may also avert other known 
complications of transcoronary alcohol septal ablation, including complete heart block 
requiring permanent pacemaker implantation, and including potentially-catastrophic non-
target coronary injury from alcohol spillage.
-
SESAME is expected to avert the known morbidity and complications of surgical ventricular 
myectomy related to cardiac surgery and cardiopulmonary bypass. 
5.5.5.2
Indirect benefits
There is an indirect benefit of this protocol to society, through generalizability of findings to 
future patients.
5.5.6
Alternatives to research participation
Recently updated AHA/ACC guidelines on the management of hypertrophic cardiomyopathy 
confer a “Class I” indication, to patients with persistent LVOTO symptoms despite standard 
pharmacologic therapy, for septal reduction therapy or myosin inhibitors[30].
Surgical myotomy and/or myectomy is an alternative to SESAME.
Transcoronary alcohol septal ablation is an alternative to SESAME. Especially among patients 
requiring TMVR, transcoronary septal ablation is associated with a high incidence of complete 
heart block requiring permanent pacing therapy with attendant myocardial dyssynchrony, and 
with a high incidence of inadequate septal reduction related to coronary-artery-septal 
geographic mismatch[8]. Candidates for this study may already have undergone attempts at 
transcoronary alcohol septal ablation. 
SESAME can be performed as “practice of medicine” outside of this research protocol.
Another alternative is pharmacologic management, which applies mostly to left ventricular 
outflow obstruction caused by hypertrophic cardiomyopathy. Pharmacologic options include 
monotherapy or combined therapy with agents including Class Ia sodium-blockers such as 
disopyramide, beta-adrenergic blockers, non-dihydropyridine calcium-channel blockers such as 
verapamil, and myosin inhibitors such as mavacamten.
Another alternative is conservative management, which typically combines pharmacologic 
management with deferral of surgical or transcatheter heart valve therapy and possibly of 
other therapies.
5.5.7
Investigator assessment of Potential Risks and Benefits
This is an early feasibility evaluation. The risks described above have been characterized and 
accumulated  for this completely new strategy through the early clinical application of SESAME 

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technique in the care of patients at Emory to date. These risks appear necessary to endure in 
order to undergo SESAME for septal reduction therapy. 
These risks appear appropriate to achieve medically-necessary septal reduction therapy using 
investigational SESAME given the selection criteria. Because of the medical necessity of septal 
reduction therapy, combined with the risk profile of participants meeting the selection criteria, 
and the potential clinical benefit, we believe the risks of undergoing investigational therapy are 
outweighed by the potential clinical benefits.
6
OBJECTIVES AND ENDPOINTS
6.1
Objective
The objective of this protocol is to test the safety and effectiveness of the SESAME septal 
debulking in patients with left ventricular outflow tract obstruction. 
6.2
Hypotheses
We hypothesize that the interventricular septum can be engaged, traversed, and lacerated with 
SESAME to increase the predicted neo-LVOT. We also hypothesize that intracameral gradients 
can be relieved by SESAME.
6.3
Primary Feasibility Endpoint
The primary feasibility endpoint is Technical success (measured at exit from the catheterization 
laboratory). All of the following must be present:
•
Alive
•
Procedure success including
o
Successful myocardial entry, navigation, and snaring of guidewire traversal system; 
and 
o
Successful laceration of septal myocardium
6.4
Primary Safety Endpoint
The primary safety endpoint at 30 days, is freedom from all of the following:
•
All-cause mortality
•
All stroke (disabling and non-disabling)
•
Major cardiac structural complication requiring intervention (such as iatrogenic ventricular 
septal defect, iatrogenic aortic valve regurgitation, iatrogenic mitral regurgitation, or 
pericardial tamponade) related to SESAME
6.5
Secondary endpoint
The secondary endpoint is complete heart block requiring permanent pacemaker implantation, 
assessed at discharge.

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6.6
Exploratory Endpoints
•
Gradient reduction among subjects with hypertrophic cardiomyopathy, residual gradient ≤ 
30mmHg at procedure conclusion and after 30 days 
•
30d VARC-3 complications of SESAME including access, bleeding, vascular, stroke, 
myocardial infarction
•
Symptom and functional status assessed at baseline, 30d, and 12 mo assessed by KCCQ-23 
OS and CS, NYHA and CCS classifications, and 6 minute walking test
•
Change in laceration dimensions and, when applicable, neo-LVOT and skirt neo-LVOT 
assessed by CT between baseline and 30 days
•
Undergoes attempted septal reduction therapy ablation after SESAME during the study 
period
•
Freedom from new permanent ventricular pacemaker implantation
•
New electrocardiographic conduction defects before discharge
•
Freedom from ventricular septal defect
•
Freedom from pericardial effusion
•
Freedom from stroke assessed at discharge
6.7
Rationale for Endpoints
Preliminary experience with clinical SESAME performed in the practice of medicine suggest that 
SESAME-related clinical events and myocardial septal remodeling appear largely complete 
within the first 30 days. We therefore propose to assess primary endpoints in the first 30 days.
The primary feasibility and safety endpoints capture the main intent of the SESAME procedure, 
which is to achieve anatomic lengthwise LVOT laceration (primary feasibility endpoint), without 
major complications (primary feasibility, safety, and exploratory endpoints), and with 
corresponding functional and anatomic benefit (exploratory endpoints).
The primary safety endpoint is assessed at 30d rather than at discharge to capture theoretical 
risk of stroke complicating intentional myocardial tissue injury.
Exploratory functional and anatomic outcomes are characterized at 30 days. MVARC endpoints 
are defined by Stone and colleagues[31].
7
STUDY DESIGN
7.1
Constant values
Number of subjects
15
Number of candidates screened, up to
30
Number of enrolling sites
2
Follow-up duration per subject
12 months
Expected study duration
30 months for enrollment + follow-up
Threshold of intracameral gradient 
considered significant
(30mmHg peak while resting; 50mmHg peak 
when provoked)

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7.2
Overall Design
This is a prospective, open-label, single-arm, 2-enrolling site, independently-adjudicated early 
feasibility investigation of the SESAME (SEptal Scoring Along Midline Endocardium) procedure 
in subjects with manifest or potential left ventricular outflow tract obstruction. 
Subjects are assessed before discharge and after 30 days, before follow-on procedures may be 
performed. Timing and rationale for endpoints are discussed in section 6.7 on page 28. 
Additional assessments are made at additional timepoints during the 12 months of study 
follow-up.
Enrolling site volunteer participation without direct financial support. NHLBI Division of 
Intramural Research is the data coordinating center that will not enroll subjects. Subjects 
undergo the study intervention and all screening and follow-up tests and procedures only at 
enrolling site(s).
7.3
Scientific Rationale for Study Design
The study is open-label and single-arm because it is an early feasibility study. It is premature to 
compare against other treatments. 
7.4
Regulatory Rationale for Initiating the Study
SESAME was first developed and characterized in large-mammal non-clinical experiments. 
Thereafter SESAME was applied to a small number of patients as a practice of medicine. We 
have been unable to collect data adequately to characterize the risks, limitations, and benefits 
of SESAME without a significant-risk medical device study utilizing commercial devices off-label. 
Therefore we seek FDA license and ethics oversight.
8
STUDY POPULATION
8.1
Inclusion Criteria
In order to be eligible to participate in the study, candidates must meet all of the following 
criteria:
•
Adults age ≥ 21 years
•
Requires debulking of left ventricular septum for hypertrophic cardiomyopathy 
•
Septal diastolic thickness of obstructive “hump” on CT: 
o
Total ≥16 mm, and 
o
Predicted residual septal thickness ≥ 8 mm, and
o
Predicted laceration depth ≥ 6 mm
•
Severely symptomatic, any of
o
NYHA Class III or greater
o
Canadian Angina Class CCS III or greater

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•
Explicitly chooses investigational SESAME over conventional treatment approaches 
including (1) cardiac myosin inhibitor therapy, if eligible; (2) transcoronary alcohol septal 
ablation, if eligible; or (3) surgical left ventricular myotomy and/or myectomy, if eligible
•
Concurrence of the multidisciplinary institutional heart team that the candidate is at high 
risk for surgical myectomy
•
Concurrence of the study Central Clinical Eligibility Committee
8.2
Willing to return for all scheduled follow-up activities, and eligible or able to undergo 
required protocol and testingExclusion Criteria
An individual who meets any of the following criteria will be excluded from participation in this 
study:
•
Does not consent to participate, or unable to consent to participate
•
Requires antegrade SESAME access (because of mechanical aortic valve)
•
Prior completed transcoronary alcohol septal ablation, or prior surgical myectomy
•
Pregnant
•
Hemodynamic instability or emergency procedure
•
eGFR < 30 mL/min/1.73m2 
•
Survival despite successful procedure expected < 12months 
8.3
Rationale for selection criteria
The selection criteria identify candidates elaborated in section 5.3 on page 17. 
The selection criteria allow enrollment of the intended population with little anticipated 
selection bias. 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.
Candidates who are eligible, if high risk, for standard transcoronary alcohol septal ablation or 
standard surgical myotomy/myectomy must be willing instead to undergo investigational 
SESAME. 
Septal thickness used for selection criteria are measured at the thickest septal “hump” believed 
to cause LVOT obstruction. Candidates with thin interventricular septa are at increased risk of 
iatrogenic ventricular septal defect from SESAME. Specific septal thickness thresholds are 
estimated according to best available clinical judgement and preclinical data. Planned minimum 
residual septal thickness ≥ 8mm is intended to provide a safety margin against excessively deep 
laceration.  Similarly, candidates with prior transcoronary alcohol septal ablation or prior 
surgical myectomy may have excessive septal fibrosis interfering with successful SESAME 
navigation or splay in this early investigation.
Candidates must have severe (Class III or Class 3) symptoms as specified to justify undergoing 
an early-stage investigational procedure.

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Candidates with hemodynamic instability, such as requiring vasopressor medications, ongoing 
mechanical ventilation, or mechanical circulatory support are excluded.
Candidates with eGFR < 30 mL/min/1.73m2 are excluded because follow-up research contrast 
imaging risks contrast-induced renal injury (after CT) or nephrogenic systemic sclerosis (after 
CMR).
Cognitively-impaired candidates are excluded based on our experience with inability to comply 
with quality-of-life questionnaire instruments, and frequent unwillingness to return for follow-
up in protocols such as this one.
Pregnant candidates are excluded because of the risk of radiation injury to the fetus during the 
research procedure.
Children are excluded because this is an early feasibility study and additional safety information 
is warranted before SESAME is applied to children. There is no maximum eligibility age because 
there is no scientific basis for age-based exclusion per se.
We believe there is no justification to select candidates based on left ventricular ejection 
fraction (LVEF) in the proposed SESAME IDE protocol, which selects subjects with primary or 
secondary LVH and/or small ventricles. These have largely-preserved left ventricular systolic 
function as assessed by LVEF. 
8.4
Inclusion of Vulnerable Participants
8.4.1
Inclusion of Pregnant Women
Pregnant women will be excluded from the enrollment into this study.  
Pregnancy after SESAME will not lead to study discontinuation. The inclusion of pregnant 
women into this protocol is necessary for completion of the study objectives. In addition, 
continuing participation in the study holds out the prospect of direct benefit to the pregnant 
woman during the post-procedure follow up as it ensures subject’s safety. All follow-up visits 
will continue through the 12 month period. Pregnant subject can undergo all follow-up 
procedures through the 12 month except for CT scans to avoid medical radiation exposure to 
the fetus. 
8.4.2
Inclusion of adult subjects who lack capacity to consent to research participation
Cognitively-impaired candidates unable to provide consent will be excluded from the 
enrollment into this study. In the event subjects become cognitively-impaired after the index 
SESAME procedure, they may remain enrolled in the study for the follow up assessments as it is 
necessary for completion of the study objectives. In addition, continuing participation in the 
study holds out the prospect of direct benefit to the subject during the post-procedure follow 
up as it ensures subject’s safety. All post-procedure data, while collected for research, are 
required for clinical care, and the only residual risk is to privacy and confidentiality.  If subjects 
will remain in the study, a Legally Authorized Representative (LAR) will be identified and 
informed consent obtained from the LAR, as described in Section 14.10.3.

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8.5
Lifestyle Considerations
Not applicable
8.6
Screen Failures
Study eligibility is based entirely on clinical records and medically indicated imaging studies.
Subjects consent to participate in the study before undergoing any study-specific activity.
Subjects are classified as screen failures if they undergo study-specific catheterization but NOT 
an attempt at SESAME.
Baseline data acquired for screen failures are retained to facilitate reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities.
In the case of aborted SESAME without evident sequelae, subjects may go off-study as soon as 
they are clinically stable, but will undergo at least 30 day follow-up. Such subjects need not 
undergo additional follow-up for exploratory efficacy or natural history assessment, and will be 
recorded as screen failures.
By contrast, in case of failed SESAME, subjects must complete scheduled follow-up.
Subjects are eligible for repeat screening and enrollment, in which case they are assigned new 
subject specific identifying numbers (SSPIN).
8.7
Strategies for Recruitment and Retention
Subjects will be recruited from the Structural Heart Disease clinical programs of the 
participating medical center(s).
We expect to accrue two subjects per month. There is no subject enrollment at NIH Clinical 
Center.
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.
8.7.1
Costs
Subjects are responsible for the costs of medical care associated with participating in this 
protocol.
NHLBI is the Sponsor, which automatically qualifies sites for CMS reimbursement for costs of 
research-related medical care, according to the CMS Clinical Trial Program (CTP), for CMS 
beneficiaries. The CTP policy is described on
https://www.cms.gov/Medicare/Coverage/ClinicalTrialPolicies/index.html.

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The result is that CMS is “explicitly authorize[d to provide] payment for routine patient care 
costs...and costs due to medical complications associated with participation in clinical trials.”
8.7.2
Compensation
Candidates and subjects receive no compensation for screening or for participating in this 
study.
9
TEST ARTICLES AND INDICATIONS FOR USE
The test articles are commercially available. They are used off-label in this research protocol. 
The manufacturer is not participating in this protocol.
9.1
Asahi-Intecc Astato XS 20, 510(k) K103057, and Astato XS 40, 510(k) K153443
9.1.1
Labeled Indications For Use
Asahi-Intec Astato XS 20 and XS 40: This product is intended to facilitate the placement and 
exchange of diagnostic and therapeutic devices during intravascular procedures. This device 
is intended for peripheral vascular use only.
The two devices differ only in tip load rating (20g vs 40g), and share a common instructions 
for use (IFU) document.
9.1.2
Intended Use in the Protocol
The intended use is traversal and laceration of left ventricular myocardium to accomplish 
transcatheter interventricular septal myotomy.
The intended use is not addressed in the labeled indications for use (above).
The Astato 0.014” guidewires are used for transcatheter electrosurgery in this procedure. The 
midshaft is focally denuded and electrified for the leaflet traversal step. Our group has 
employed this off-label guidewire configuration to lacerate native and bioprosthetic heart valve 
leaflets in patients[5, 6, 15, 32-44]. These LAMPOON- and BASILICA-related procedures have 
become de facto standards of care.
9.2
Asahi-Intecc Confianza Pro 12, 510(k) K171933
9.2.1
Labeled Indications For Use
Asahi-Intecc Confianza Pro 12. ASAHI PTCA Guide Wires are intended to facilitate the 
placement of balloon dilation catheters during percutaneous transluminal coronary 
angioplasty (PTCA) and percutaneous transluminal angioplasty (PTA). The ASAHI PTCA Guide 
Wires are not to be used in the neurovasculature.

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9.2.2
Intended Use in the Protocol
The intended use is traversal and laceration of left ventricular myocardium to accomplish 
transcatheter interventricular septal myotomy. The intended use is not addressed in the 
labeled indications for use (above).
In SESAME, the ConfianzaPro12 0.014” guidewire is used mechanically to pierce and engage the 
basal septal myocardium. It is modified at the bedside by scissor-amputation of the distal 
~10mm to enhance tip stiffness. This had been standard technique of electrosurgical transcaval 
access to the abdominal aorta in patients[45-49]. Transcaval access has become a standard 
medical practice.
This bedside-modified guidewire configuration has been employed in swine [17] and a small 
number of SESAME procedures in patients. [See Clinical SESAME in section 5.4 on page 19, and 
reference[18]]. The same guidewire configuration, electrified, had been used widely to 
accomplish transcaval access to the abdominal aorta[46, 48-50].
10 STUDY INTERVENTION
10.1 Study Intervention Description
Candidates will be identified by the participating structural heart disease program(s). 
Candidates will undergo clinical evaluation, echocardiography, coronary arteriography, 
contrast-enhanced gated cardiac CT, and (when possible) cardiovascular magnetic resonance. 
Eligibility will be reviewed and proposed by the local multidisciplinary heart teams. The 
multidisciplinary institutional heart team consists of structural interventional cardiologists, 
structural imaging cardiologists, and cardiac surgeon(s). Additional disciplines may also 
participate.
Candidates will then undergo central eligibility review by the sponsor and designated 
investigators (Central Clinical Eligibility Committee). If deemed eligible, candidates will be 
offered participation in the study.
Once enrolled, subjects will undergo baseline assessment and blood tests not already available 
from prior medical care (see Schedule or Activities in section 3.3). 
If CMS or insurance coverage is available, they will undergo optional commercial genetic testing 
for HCM "phenocopies" to determine etiology of primary LV hypertrophy.
10.1.1 SESAME procedure
Subjects will be admitted to the hospital and undergo SESAME.
The SESAME procedure is planned from contrast-enhanced CT to plan a suitable traversal and 
laceration trajectory, projection angles, and radiographic fiducial landmarks. Trajectory plans 
identify basal septal entry points, aligned with the LVOT, and aim to “shave the hump” of 

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excess septal tissue evident on CT. The trajectory plan results in an intended LV- and RV-septal 
depth and length which can be corroborated by intraprocedural echocardiography. 
The SESAME procedure is performed under general anesthesia or under moderate sedation at 
the discretion of the institutional heart team. The SESAME procedure has multiple steps: 
•
Echocardiography to guide septal catheter and guidewire position, and to assess procedural 
myocardial anatomy and performance , including transthoracic echocardiography (TTE), 
transesophageal echocardiography (TEE), and when necessary intracardiac 
echocardiography (ICE) via a deflectable transvenous guiding sheath in the right atrium, 
right ventricle, or positioned trans-septally or retrograde transaortic.
•
Antithrombin anticoagulation at the discretion of the operators, which is typical for 
structural interventional catheterization procedures.
•
Transfemoral arterial retrograde introduction of a deflectable introducer sheath into the 
ascending aorta to position a preshaped guiding catheter across the aortic valve to engage 
the basal interventricular septum. An additional retrograde transfemoral catheter is 
positioned across the aortic valve into the left ventricle as a anatomic marker and to 
exchange for a snare-catheter system.
•
Baseline hemodynamics and echocardiographic gradients and valvular function are 
recorded, typically along with left ventriculography. This includes conductance catheters 
and venous preload-altering balloon catheters when possible, to examine end-diastolic and 
end-systolic pressure-volume relationships.
•
A guidewire test article (amputated stiff 0.014” ConfianzaPro-12 guidewire or AstatoXS-
20/40) is advanced to enter the basal septum and deliver a 0.014” microcatheter. The 
guidewire may then be removed to exchange for a 0.014” AstatoXS-20/40 guidewire (test 
article). Multiple guidewires and microcatheters may be employed.
•
The AstatoXS-20/40 guidewire is navigated through the ventricular septal myocardium and 
the microcatheter advanced in tandem until a suitable endocavitary left ventricular reentry 
is accomplished. Fluoroscopy, echocardiography, intracardiac electrocardiography, and 
contrast left ventriculography are used to guide navigation and confirm guidewire position.
•
Myocardial entry or traversal may be assisted by electrosurgery 5-50W as needed.
•
Navigation guidewires may be connected to hemodynamic monitoring or recording systems 
to display unipolar electrogram morphology, and may also be connected to a marketed 
electroanatomic mapping system.
•
The guidewire is ensnared, and a modified “Flying-V” lacerating surface introduced[15], 
which has been typical for electrosurgical laceration of cardiac leaflets. Operators take care 
to form the “Flying-V” using the blunt edge, not the sharp edge, of a scalpel. The guidewire 
limbs are insulated with coaxial microcatheters and/or catheters and/or balloon catheters.

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•
The guidewire position is examined and confirmed.
•
The modified “Flying-V” is energized while the field is flooded with 5% dextrose or 0.9% 
saline infusion through the guiding catheters to minimize thromboembolism[15], and 
laceration is performed. Care is exerted to assure the aortic valve leaflets are not exposed 
to energized laceration wires. Flush is a least 2mL/s through each catheter. Guidewire is 
energized for maximum of 2s, separated by pause of at least 5s to allow tissue to cool, for 
multiple energy applications until laceration is complete.
•
Concomitant TAVR, if indicated, is allowed during the same interventional catheterization 
encounter as SESAME, at the discretion of the operators
•
Cerebral embolic protection devices are employed at the discretion of the operator.
•
Completion hemodynamics and echocardiographic gradients and valvular function are 
recorded. This includes conductance catheters and venous preload-altering balloon 
catheters when possible, to examine end-diastolic and end-systolic pressure-volume 
relationships.
•
Finally, percutaneous arterial and venous vascular hemostasis is obtained.
10.1.2 Post-Procedure
•
The subject convalesces in the appropriate inpatient recovery unit.
•
Anticoagulation and antiplatelet therapy is prescribed after discharge at the physicians’ 
discretion, and is recorded.
•
For subjects who have permanent pacemakers, devices are interrogated at baseline, before 
discharge, and at 30 days follow-up to determine fraction of paced ventricular beats.
•
Follow-up blood tests, ECG, transthoracic echocardiography, optional CT, exercise exams, 
CMR are recorded as described in the Schedule of Activities (3.3). Clinically-indicated blood 
test results are recorded for research. These are repeated at multiple timepoints.
•
Additional scheduled visits include assessments of adverse events, symptom and functional 
status, and imaging examinations as listed in section 3.3 on page 12.
10.1.3 Termination visits
•
For subjects who die during the study, autopsy evaluation is requested to examine the heart 
at NIH.
•
Subjects’ participation in the study concludes at the 12 months follow-up and off-study visit.
10.1.4 Study duration
Subjects participate through the 12 months follow-up and off-study visit.

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We aim to complete the study in 30 months for enrollment + follow-up.
10.1.5 Number of enrolling sites
Up to 2 site(s) will enroll and treat subjects in this study.
10.2 Preparation/Handling/Storage/Accountability 
Commercial devices will be acquired, maintained, and stored in standard clinical inventory. Lot 
numbers will be recorded in the medical record.
Bedside modification of the test articles will be performed as described above.
10.3 Measures to Minimize Bias: Randomization and Blinding
Not applicable to this open-label study.
10.4 Study Intervention Compliance
Protocol compliance will be assured by source document (medical record) to case-report-form 
data verification by independent data monitors. 
10.5 Concomitant Therapy
There are no restrictions on concomitant therapy.
11 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
11.1 Discontinuation of Study Intervention
SESAME employs single-use disposable devices with no components implanted. 
In general, once a subject consents and undergoes the SESAME catheterization procedure, the 
procedure is either not initiated, it is aborted because of technical failure, or it is completed. 
11.2 Aborted or abandoned SESAME
In the case of aborted SESAME without evident sequelae, subjects may go off-study as soon as 
they are clinically stable, but will undergo at least 30 day follow-up. Such subjects need not 
undergo additional follow-up for exploratory efficacy or natural history assessment, and will be 
recorded as screen failures.
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11.3 Subject Discontinuation/Withdrawal from the Study
Reasonable efforts will be made to undertake protocol-specified safety follow-up procedures to 
capture adverse events and adverse device effects, both serious and not, as well as 
unanticipated problems, through the 30-day follow-up visit.
Subjects are free to withdraw from participation in the study at any time upon request. If a 
subject repeatedly and consistently declines to return for follow-up evaluation, the 
investigators may be forced to withdraw the subject from the study prematurely.
However, since the study intervention (SESAME procedure) will already have been performed, 
withdrawal means these subjects would be withdrawing from follow-up of endpoints and 
adverse events. For the sake of safety, subjects will be advised not to withdraw.
Pregnancy after SESAME will not lead to study discontinuation, although research-related 
radiation (CT) will be avoided to avoid medical radiation exposure to the fetus.
11.4 Loss to Follow-up
A subject will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and despite attempts at contact by the study site staff.
The following actions must be taken if a subject fails to return to the enrollment site for a 
required study visit:
o
The site will attempt to contact the subject and reschedule the missed visit and counsel 
the subject on the importance of maintaining the assigned visit schedule and ascertain if 
the subject wishes to and/or should continue in the study.
o
Before a subject is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the subject (where possible, 3 telephone calls to the 
subject, contact to the referring physician, and, if necessary, a certified letter to the 
subject’s last known mailing address or local equivalent methods). These contact 
attempts should be documented in the study file.
o
Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
12 STUDY ASSESSMENTS AND PROCEDURES
12.1 Screening Procedures
Screening prior to consent is based entirely on clinically-indicated medical encounters, blood 
tests, laboratory and clinical examinations (cardiac catheterization, echocardiography, CT, CMR, 
blood tests), review of medical records, and communication with candidates (in-person, via 
telephone, via telepresence, in writing, or via email). 

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The screening data are reviewed by the local multidisciplinary heart team, and then are 
reviewed by the Central Clinical Eligibility Committee before screening is complete. Candidates 
are only invited to participate if eligible.
Enrolling sites will comply with Health Insurance Portability and Accountability Act (HIPAA) if 
applicable.
12.1.1 Clinical activities performed to screen for eligibility prior to obtaining research 
informed consent
Minimal risk activities that may be performed before the subject has signed a research consent 
include the following: 
•
Email, written, in person or telephone communications with candidates. 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing medical imaging examinations 
These data may be analyzed for the research study after the subjects consents to participate.
12.2 Efficacy Assessments 
Efficacy assessments are performed by qualified laboratories and staff at enrolling sites. 
Standard clinical examinations (such as vital signs and symptom classification), clinical blood 
testing, and clinical cardiac imaging procedures (such as echocardiography, cardiac CT, CMR) 
are performed by clinical laboratories at the enrolling sites. 
Unscheduled clinically-driven imaging exams (echocardiography, CT, CMR) are analyzed for 
efficacy and safety in this study.
CT assessments: septal geometry, septal split geometry, cardiac chamber dimensions and 
function. The schedule of first post-SESAME CT can be altered at the discretion of the attending 
physician, which can be performed before discharge rather than at 30 days. CT exams are 
analyzed by a NHLBI core laboratory. Complications, such as VSD, trigger non-structured 
analysis and reporting not reflected in the case report form..
Fluoroscopy assessments include procedure step clock times extracted from DICOM headers, 
and qualitative assessment of procedure steps such as intramyocardial navigation, distances, 
and ventriculography measurements. Fluoroscopy assessments include accompanying invasive 
hemodynamic measurements. These are analyzed by a NHLBI core laboratory.
Echocardiography assessments include 
-
Procedural assessments: intracameral gradients, and septal split geometry. These are 
analyzed by a NHLBI core laboratory.
-
Function assessments: Chamber size and function, global strain, at baseline and follow-up
-
Complications, such as VSD, trigger non-structured analysis and reporting not reflected in 
the case report form.

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Cardiac magnetic resonance (CMR) assessments include chamber size, function, relaxometry, 
extracellular volume (ECV), late gadolinium enhancement, regional strain, at a single inpatient 
timepoint, felt to combine baseline (morphological, relaxometry) and local iatrogenic (oedema) 
characteristics of the heart immediately following-SESAME. A copy of the FDA medication guide 
will be provided to subjects as part of research-related gadolinium-contrast-enhanced CMR. 
Electrocardiography assessment includes conduction and rhythm assessment, at baseline and 
follow-up. Local site automated measurements are recorded, and ECG records are stored for 
central re-analysis as needed.
Standard research assessments (questionnaires such as KCCQ-23) are performed by qualified 
staff at enrollment sites according to a study Manual of Operations and according to an 
instruction-oriented Case Report Form.
12.3 Safety and Other Assessments
Standard safety assessments (adverse event assessments) are performed by qualified staff at 
enrollment sites according to the Protocol Schedule of Activities and a study Manual of 
Operations and according to an instruction-oriented Case Report Form.
Safety assessments follow a structured adverse event case report form and are corroborated by 
independent data monitors and, for primary endpoints, by an independent clinical events 
adjudication committee.
12.4 Assessment of neurovascular events (stroke and TIA) 
Formally-trained and certified research coordinators will perform baseline and follow-up 
assessments of modified Rankin Score and NIH Stroke Score. 
Training and certification will be obtained from an educational service such as BlueCloud.
12.5 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
12.5.1 Definition of Adverse Event
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 subject’s participation in the research, whether or not considered related to 
the subject’s participation in the research (21 CFR 312.32 (a)).
This includes:
•
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 SESAME cardiac catheterization procedure and 
recovery from the procedure and do not directly result from use of the investigational 
devices.

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12.5.2 Definition of Serious Adverse Events (SAE)
Serious Adverse Event (SAE): A serious adverse event that results in any of the following and 
NOT directly related to the device (21 CFR 812.3(s)). 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.
12.5.3 Definition of Adverse Device Effect (ADE)
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 deployment of the device or any event that is a result of user error.
This includes procedural events directly related to the SESAME procedure and recovery from 
the procedure in addition to use of the investigational devices used for SESAME.
12.5.4 Definition of Serious Adverse Device Effect (SADE), Anticipated Adverse Device Effect 
(AADE), and Unanticipated Adverse Device Effect (UADE)
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.
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. Please refer to the 
list of anticipated adverse device effects (AADE) in section 5.5.1 on page 22.
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 application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects.

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12.5.5 Classification Adverse Events
12.5.5.1 Severity of Event
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 
intervention.
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 
requires medical intervention and prolonged hospitalization. 
12.5.5.2 Relationship (Attribution) to Study Intervention
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 
reasonable 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 
reasonable temporal relationship to the research device or research 
procedure, and attribution of the event to the device or procedure cannot 
be excluded. However, alternative causes—such as underlying disease, 
concomitant medications, or concomitant treatments—are presumably 
responsible.
Unlikely
It is doubtful the event is related to the research protocol. The event can 
reasonably be explained by other factures, including underlying disease, 
concomitant 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. 
12.5.5.3 Expectedness
Please see the list of anticipated adverse device effects (AADE) in section 5.5.1 on page 22.
The Principal Investigator and the Site Investigator will be responsible for determining whether 
an adverse event (AE) is expected or unexpected. An AE will be considered unexpected if the 
nature, severity, or frequency of the event is not consistent with the risk information previously 
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12.5.6 Intervals and Frequency for Event Assessment and Follow-Up
Adverse event assessment, recording, and reporting will start on Day (0), upon attempt at a 
SESAME procedure and will continue through the 12 months follow up.
New events or conditions present at baseline that increase in severity will be recorded and 
evaluated and reported on the adverse event case report form. 
Once the subject has completed the 30-day follow-up, only serious adverse events (SAE) serious 
adverse device effects (SADE), unanticipated device effects (UADE) and unanticipated problems 
(UP) will be reported to the Sponsor using study specific case report forms, and then entry into 
the NIH electronic data base, CTDB (or equivalent). Adverse event case report forms and all 
source documentation supporting the adverse event will be transmitted to the Sponsor for 
review prior to entering the event into CTDB. Unanticipated adverse device effects (UADE) and 
Unanticipated problems (UP) must be submitted to the Sponsor for review and approval prior 
to submitting to the Central IRB. Sponsor will review, and if appropriate, provide suggestions to 
the site Primary Investigator. The enrolling site will then enter event into CTDB, and submit the 
report to the IRB using the electronic IRB system. Sponsor will then submit final report to the 
NHLBI Office of the Clinical Director (OCD).
Monitoring visits will be conducted by the Sponsor to review source documentation, and 
accuracy and completion of the adverse event case report forms.
12.5.7 Adverse Event Reporting
Reporting obligations and deadlines are summarized in Appendix A: Tables of Reporting 
Obligations.
12.5.8 Enrolling site reporting to local institutional and ethics bodies 
It is the responsibility of the Site Investigator to report adverse events and adverse device 
effects to their institutional ethics and regulatory bodies according to their local reporting 
requirements.
12.5.9 Events of Special Interest
Not applicable
12.5.10
Reporting of Pregnancy
Pregnancy occurring during follow-up after the initial SESAME procedure, should be reported to 
the enrolling site primary investigator and research coordinator.  Pregnancy after SESAME will 
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(CT) to avoid research radiation exposure to the fetus. All follow-up visits will continue through 
the 12 month period.
12.6 Unanticipated Problems
12.6.1 Definition of Unanticipated Problems (UP)
Any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and
•
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and
•
Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected.
12.6.2  Unanticipated Problem Reporting
The investigator will report unanticipated problems (UPs) to the Sponsor and Institutional 
Review Board (IRB).
12.7 Protocol Deviations and Non-Compliance
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations and/or non-compliance to the Institutional Review Board The investigator is 
responsible for knowing and adhering to the reviewing IRB requirements.
Reporting obligations and deadlines are summarized in Appendix A: Tables of Reporting 
Obligations. All protocol deviations must be reported by the Sponsor to the NHLBI Clinical 
Director as specified.
12.7.1 NIH Definition of Protocol Deviation
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol.
•
Major deviations: Deviations from the IRB approved protocol that have, or may have the 
potential to, negatively impact the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study.
•
Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety or welfare of subjects or others, or the scientific integrity or validity of the 
study.

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13 STATISTICAL CONSIDERATIONS
13.1 Statistical Hypothesis
There are no statistical hypotheses for this single-arm device evaluation study.
13.2 Sample Size Determination
The sample size is not statistically derived.
Up to 30 subjects will be consented until 15 subjects undergo attempted SESAME in this 
protocol.
13.3 Populations for Analyses
The analysis will be per-protocol, and as-treated, of subjects who undergo an attempt at 
SESAME.
13.3.1 Evaluable for toxicity
Complications are reflected in the primary safety endpoint, in secondary endpoints, and 
exploratory endpoints described in section 6.3 beginning on page 27.
13.3.2 Evaluable for objective response
Efficacy is evaluated in the primary efficacy endpoint, in secondary endpoints, and exploratory 
endpoints beginning in section 6.3 beginning on page 27
13.4 Statistical Analyses
Exploratory data analysis will assess for missing values and will generate data clarification 
requests as required.
The primary analyses will be descriptive including demographic values and primary, secondary, 
and exploratory endpoints. Descriptive statistics will include appropriate measures of central 
tendency and variance, and tests of normality as appropriate. Post-hoc analyses will be 
performed as unusual observations and novel questions arise, including those requiring 
additional data abstraction from the source documents or images.
Statistical analysis will be performed or confirmed by the NHLBI DIR study statistical 
investigator.
13.5 Stopping Rule Guidance for Data and Safety Monitoring Board (DSMB)
The study will be monitored to ensure that the mortality within 30-days after the procedure does 
not substantially exceed an anticipated rate. We anticipate the rate of 30-day mortality is 10% or 
less and determine the stopping rule by a Bayesian approach[51]. The stopping boundary is 
reached if the posterior probability that the 30-day mortality rate exceeds 10% is at least 90%. 

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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 = 0.3, 
b =2.7. Hence when we make decisions about stopping the study, the data from the study will 
dominate over the prior opinion. 
The following table summarizes the threshold numbers for the stop rule boundary, which would 
lead to a recommendation to stop the study due to the excess 30-day mortality.
Number of subjects in the stratum
Consider stopping if the number of deaths within 30 
days reaches
2 - 5
2
6 - 11
3
12 - 15
4
We investigated the performance of the above stopping rule by a simulation study. In each 
simulation run, we generated a study with 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%
Proportion of Stopped Studies
4%
20%
46%
71%
87%
96%
Average number of subjects
29.2
26.2
21.6
16.9
12.8
9.7
Average number of 30-day mortality
1.5
2.6
3.3
3.4
3.2
2.9
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.
14 STUDY GOVERNANCE AND OTHER OPERATIONAL CONSIDERATIONS
14.1 Sponsor Representative
As the study Sponsor representative of this clinical study, Dr. Robert Lederman has the overall 
responsibility for the conduct of the study, including assurance that the study meets the 
regulatory requirements of the appropriate regulatory bodies.
The Sponsor Representative is the point of contact for enrolling sites to report all events of 
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14.1.1 General Sponsor Duties
The Sponsor's general duties consist of submitting the appropriate regulatory applications, 
selecting investigators and enrolling sites, obtaining their signed agreement, providing them 
with the information necessary to conduct the study, assuring proper clinical protocol conduct, 
ensuring proper clinical site monitoring, and ensuring study subject informed consent is 
obtained.
14.1.2 Data Coordinating Center
NHLBI will serve as data coordinating center (DCC) for the study. The DCC will provide study 
protocol, questionnaires, data collection forms, and data analysis; will collaborate in manuscript 
preparation; and will provide overall study training, coordination and quality assurance, 
including coordination of the activities of the Data and Safety Monitoring Board (DSMB) and the 
Study Central Clinical Eligibility Committee.
14.2 Site Selection and Training
14.2.1 Site selection:
Site selection is based on
•
Physician expression of interest and availability of suitable study candidates at the site.
•
Site prior participation in IDE protocols evaluating a treatment of structural heart disease, 
with investigators willing and able to comply with the requirements of this protocol.
•
Preference is given to sites with high volume structural heart intervention programs, 
operators with high technical proficiency, and successful prior collaboration with NHLBI 
Division of Intramural Research.
•
Further preference is given to sites that have achieved high volume and proficiency with 
SESAME-related procedures such as LAMPOON.
•
Sites must demonstrate ability to obtain CT examinations that are technically satisfactory 
for consideration of SESAME.
•
Sites should have biplane fluoroscopy available to conduct SESAME procedures until 
alternative image guidance modalities are available
Site(s) must have telepresence transmission capability for remote biplane viewing and 
teleproctoring (such as Medinbox, Toulouse), at no cost to the sponsor
14.2.2 Site training:
The Sponsor Representative will ensure appropriate training in the technique of SESAME prior 
to enrollment at any participating institution.
Site training will consist of
•
NHLBI Investigator and/or Sponsor didactic training about the technique, preclinical, and 
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•
When logistically feasible, site investigator observation of SESAME procedures at a luminary 
site such as Emory University.
•
Proctored conduct of SESAME procedures in subjects at the study site, at the discretion of 
the Sponsor representative, in-person or via telepresence.
Completion of training, and suitability for independent SESAME enrollment, will be certified by 
the NHLBI Principal Investigator and Sponsor Representative.
14.3 Study Central Clinical Eligibility Committee
Clinical data for all research candidates are confirmed by the study Central Clinical Eligibility 
Committee in telepresence or in-person meetings before enrollment.
The Study Central Clinical Eligibility Committee consists of the NHLBI Principal Investigator and 
associate investigators, the site Principal Investigators, a non-interventional cardiologist, and a 
NHLBI core lab representative. A quorum of the committee requires a site Principal Investigator 
where the candidate is not to be enrolled, as well as at least two NHLBI investigators. In 
addition, at least one member at each Eligibility meeting must be free of actual or perceived 
financial conflict of interest. The considerations and determination of the Study Central Clinical 
Eligibility Committee will be recorded.
14.4 Core Laboratories
CT, Fluoroscopy, and CMR, and Echocardiography Core Laboratories will analyze baseline, 
procedure, and follow-up exams. Their activity is summarized in section 12.2.
14.5 Clinical Events Adjudication Committee (CEAC)
An independent CEAC will review monitored data to assure accuracy. The CEAC will be an 
independent contractor, and the charter will be agreed between the NHLBI Principal 
Investigator and the CEAC after the contract is awarded, which will be after final IRB approval.
The CEAC will review all of the following events that occur in the 30-day follow-up interval
-
Primary (Efficacy) and (Safety) Endpoints
The CEAC will classify relatedness of the above events to the SESAME system devices. CEAC 
adjudication prevails over Principal Investigator classifications.
14.6 Data and Safety Monitoring Board (DSMB)
The standing Data and Safety 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. For oversight of this protocol, DSMB will employ full-time or ad hoc 
members with expertise in transcatheter structural heart disease intervention. Members of 
the DSMB are independent from the study conduct and free of conflicts of interest.

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The NHLBI DSMB charter is on file with NHLBI and is approved by the NHLBI Director and/or 
NHLBI Clinical Director.
The NHLBI DSMB will review the protocol progress report at pre-specified intervals, or more 
frequently upon request of PI, IRB, and/or NHLBI Clinical Director. These progress reports are 
prepared by the NHLBI Principal Investigator and study staff. The DSMB may recommend early 
termination of the study for considerations of safety and efficacy. Unanticipated Adverse 
Device Effects (UADEs) will be reported to the DSMB following the same timelines as the IRB 
(See section 12.5.7 on page 43.
In the case of death or serious UADE, if the Sponsor and the NHLBI Principal Investigator or 
DSMB 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 Sponsor first receives notice of the effect. [21 CFR 812.46]. 
All sites will be notified of this action.
A “stopping rule” is described in section 13.5 on page 45 as non-binding guidance for the 
Investigators and the DSMB to assure subject safety. This is based on anticipated 30-day 
mortality. This is intended to assist and not automate decision-making.
14.7 Publications Committee
The study publications committee consists of the NHLBI Principal Investigator and the local site 
Principal Investigators.
Investigators may not independently publish, present, or disclose study results, in whole or in 
part, without permission of the Publications Committee.
14.8 Publication and Data Sharing Policy
14.8.1 Human Data Sharing Plan
Results of the study will be presented at scientific meetings and/or published in a peer 
reviewed scientific or medical journal. The results of the study will be released within 12 
months of study completion.
Investigators may not independently publish or disclose study results without permission of the 
Publications Committee (See section 14.7).
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication.

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This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. All dataset(s) that can be 
shared will be deposited in NIH Biomedical Translational Research Information System (BTRIS).
Data from this study may be requested by other researchers indefinitely, beginning one year 
after the completion of the study by contacting the NHLBI Principal Investigator.
14.8.2 Posting of anonymized image data on public data repository
Anonymized (personally identifiable information and linking codes removed) data and images 
may 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. Data are de-identified, so that 
patients can not readily be identified, and are therefore not considered human research 
subjects research data under US 45CFR§46.104(d)(2)(i).
14.8.3 Data transfer to collaborators
De-identified images (with linking codes retained) will be transferred to collaborating 
investigators at academic and industry sites, for the purposes of research, education, and 
quality assurance. These collaborators include
Recipient
Organization
Location
Linkable
D. Korel Yildirim
NHLBI Division of Intramural 
Research
Bethesda, MD
Linked
Nasser Rafiee
Transmural Systems
Andover, MA
Linked
Rebecca Hahn
Columbia University
New York, Y
Linked
14.9 Intellectual Property
The Sponsor has full rights over any invention, discovery, or innovation, patentable or not, that 
may occur when performing the study.
14.10Informed Consent Process
14.10.1
Consent/Assent Procedures and Documentation
Subjects who are UNABLE to provide consent may NOT be enrolled. The use of a legally 
authorized representative (surrogate), or telephone consent is not permitted.
The method of obtaining and documenting the informed consent and the contents of the 
consent complies with ICH- GCP and all applicable regulatory requirement(s). Informed consent 
will be obtained by the enrolling site Principal Investigator and enrolling site personnel who are 
listed on the Delegation of Authority Log. The most recent IRB-approved consent will be used. 

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The candidate will be asked to consider participating (consent) during a clinical encounter to 
discuss structural heart disease treatment. 
The investigational nature and objectives of the trial, the procedures and treatments involved, 
and the risks and discomforts and potential benefits will be carefully explained in person to the 
candidate. The consenting process will be a verbal review of the IRB-approved consent in a 
language understandable to the subject, free of any exculpatory language to avoid any 
possibility of coercion. Candidates will be given ample opportunity to read the study consent in 
private and to discuss with family, personal physicians, or others as desired; to ask questions; 
and to allow sufficient time to determine whether or not to participate in the research study. 
The informed consent document will be signed and dated in the presence of the authorized 
study staff, who will also sign and date as appropriate. The subject will then receive a hard copy 
of the informed consent document.
The research consenting process will be documented in the subjects medical record with the 
signed and dated IRB research consent. Electronic consent will not be employed in this research 
study. 
Subjects participating at covered entities will provide written Privacy Rule Authorization (aka 
“HIPAA Authorization”) to use and disclose individually identifiable health information for this 
protocol. Subjects will be counseled about privacy and confidentiality protections and 
provisions as part of the informed consent process.
14.10.2
Informed consent for non-English speaking subjects
Enrolling sites will follow IRB processes for short form consent of non-English speaking research 
participants. This includes use of pre-approved short form consent templates. If no short form 
consent is pre-approved in the candidate’s native language, or if a different short form consent 
is used, the certified translation must be submitted for IRB review. The IRB approved long form 
English consent is used as the written summary of what the investigator presents orally
14.10.3
Consent of Subjects who lose decision-making ability during the study
Adults with decisional impairment are not eligible to enroll in the study.
In the event subjects lose the ability to consent after the index SESAME procedure, they will 
remain in the study, because the main risk of investigation is confined to the index procedure. 
All additional data, while collected for research, are required for clinical care, and the only 
residual risk is to privacy and confidentiality.
Decision-making is assessed during scheduled follow-up events. When subjects lose decision-
making ability, affirmation of consent is sought directly from the Legally Authorized 
Representative (LAR) at the enrolling site. Local State laws apply.

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If the study team is unable to identify a Legally Authorized Representative, the team will seek 
guidance from the local institutional ethics service.
Having failed to obtain affirmation of consent, the subject is withdrawn from the study. 
14.11Unscheduled Study Discontinuation and Closure
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to affected regulatory 
bodies including enrolling site Investigators, central IRB, Sponsor (NHLBI Office of Clinical 
Director), NHLBI Principal Investigator, Device Manufacturer, and FDA. 
If the study is prematurely terminated or suspended, the NHLBI Principal Investigator (PI) will 
promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension. 
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
 Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IRB and, as applicable, the Food and Drug Administration 
(FDA).
14.12Confidentiality and Privacy
In order to maintain subject privacy, accountability records, study reports, and communications 
will identify the subject by initials and the assigned subject number.
However, medical records will be transmitted and stored as source documents and will retain 
patient names and/or medical record numbers, to allow physician-investigators to 
recommend medical therapies as appropriate, to avoid risk of mis-identification.
In addition, electronic (DICOM-format) medical images transmitted for the purpose of this 
study will retain patient identifiers.
The study monitor, other authorized representatives of the Sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 

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records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
enrolling study site will permit access to such records.
The study participant’s contact information will be securely stored at each enrolling site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
Sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the NHLBI. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will 
be identified by a unique study identification number. The study data entry and study 
management systems used by enrolling sites and by NHLBI research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and 
archived at the NHLBI.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help 
achieve the research objectives and promote participation in studies by helping assure 
confidentiality and privacy to participants.
14.13Future use of Stored Specimens and Data
Data may be stored indefinitely. Imaging data in PACS may be stored indefinitely.
Subjects are asked consent to future use of their clinical and imaging data indefinitely. 
Following analyses of data for primary research purposes as described in the protocol, images 
suitable for future research will be stored. Any future research use of identifiable data not 
defined in the research protocol will occur only after IRB review and approval.
Upon withdrawal of consent, we undertake diligently to destroy imaging data that might be 
used for future research.
Autopsy specimens will be handled according to local institutional medical standards and will 
be disposed accordingly. We do not intend to store these specimens for future use.
See also Section 14.12, Confidentiality and Privacy and Section 14.16, Data Handling and Record 
Keeping, for further information on future use of study records.
14.14Clinical Monitoring
As per ICH-GCP 5.18 and FDA 21 CFR 312.50 clinical protocols are required to be adequately 
monitored by the study sponsor. Clinical site monitoring is conducted to ensure that the rights 

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and well-being of trial participants are protected, that the reported trial data are accurate, 
complete, and verifiable, and that the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).
14.14.1
Independent Data Monitor:
Independent data monitors will visit sites in-person or using remote telepresence with the 
following visit objectives:
•
to verify the existence of signed informed consent form and documentation of the informed 
consent process for each monitored subject;
•
to verify the prompt and accurate recording of all monitored data points, and prompt 
reporting of all SAEs;
•
to compare abstracted information with individual subjects’ records and source documents 
(subjects’ charts, laboratory analyses and test results, physicians’ progress notes, nurses’ 
notes, and any other relevant original subject information); and
•
to help ensure investigators are in compliance with the protocol.
The monitors also will inspect the enrolling site regulatory files to ensure that regulatory 
requirements (Office for Human Research Protections, OHRP), FDA and applicable guidelines 
(ICH-GCP) are being followed. During the monitoring visits, the site Principal Investigator 
(and/or designee) and other study personnel will be available to discuss the study progress and 
monitoring visit. The site Principal Investigator (and/or designee) will make study documents 
(e.g., consent forms and pertinent hospital or clinical records readily available for inspection by 
the IRB, the FDA, the site monitors, and the NHLBI staff for confirmation of the study findings.
The Sponsor and sites will be provided copies of monitoring reports within 30 days of visit.
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP 
describes in detail who will conduct the monitoring, at what frequency monitoring will be done, 
at what level of detail monitoring will be performed, and the distribution of monitoring reports.
14.14.1.1
Schedule of Monitoring Activities
Monitoring visits will be conducted after the first subject is treated and returns for 30-day 
follow up. Remote monitoring visits will conducted wherever possible using remote access to 
electronic medical records, transmitted source documents, associated emails, and monitoring 
reports. Electronic data queries from the Sponsor to the enrolling site must be resolved within 7 
days of site notification.
14.14.1.2
Extent of monitoring activities
The monitors will provide 100% source-data verification of case report forms including adverse 
event reports.
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14.14.2
NHLBI Principal Investigator Monitoring:
Accrual and safety will be monitored by the NHLBI Principal Investigator, seeking unusual or 
unexpected events, morbidity, or mortality.
14.14.3
Institutional Review Board (IRB) of Record:
Accrual and safety data will be monitored and reviewed annually by the IRB of Record. Prior to 
implementation of this study, the protocol, and subject research consents will be reviewed and 
approved according to Protection of Human Subjects Research Title 45 CFR Part 46 of the Code 
of Federal Regulations (45 CFR 46). The IRB must approve all amendments to the protocol or 
informed consent, and conduct continuing annual review so long as the protocol is open to 
accrual or follow up of subjects.
14.14.4
Data and Safety Monitoring Board (DSMB) Monitoring
DSMB activities are described in section 14.6 on page 48
14.15Quality Assurance and Quality Control
Quality assurance measures include
-
Diligent investigator procedure training in SESAME technique and device operation
-
Sponsor and investigator participation (when available) and review of SESAME 
procedures
-
Site initiation visit by NHLBI Principal Investigator, NHLBI Study Manager, and 
independent data monitors
Quality control measures include
-
Site Principal Investigator review of completed case report forms
-
Study Manager review of case report forms with data clarification request reconciliation
-
Data entry into an auditable electronic case report database
-
Independent data monitor source-data verification with data clarification request 
reconciliation
-
NHLBI Principal Investigator review of case report form data
-
Independent core lab review of imaging endpoints
-
Study Statistician review of case report form data. Errors will be corrected by 
investigators and data manager
-
Independent Clinical Events Adjudication committee adjudication of primary endpoints
14.16Data Handling and Record Keeping
Clinical data (including adverse events (AEs), concomitant medications, and adverse reactions 
data) and clinical laboratory data will be entered into a 21 CFR Part 11-compliant data capture 
system provided by the study Sponsor. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear 
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14.16.1
Case Report Form Completion
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The site investigators are responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported.
All source document worksheets should be prepared in a neat, legible manner to ensure 
accurate interpretation of data.
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study. Data recorded in the 
electronic case report form (eCRF) derived from source documents should be consistent with 
the data recorded on the source documents.
Case Report Forms (CRFs) will be completed for each study subject. It is the site Principal 
Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the data 
reported in the subject’s Case Report Forms. Source documentation supporting the Case Report 
Forms 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 site Principal Investigator or designated representative, should complete the Case Report 
Forms screens as soon as possible after information is collected, preferably on the same day 
that a study subject is seen for an examination, treatment, or any other study procedure but no 
more than 5 days post procedure. An explanation should be given for all missing data.
14.16.2
Direct Access to Source Data
Site investigators will follow Sponsor monitoring and auditing procedures to assure compliance 
with GCP guidelines.
The site Investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and 
regulatory authority (ies) access to the subject’s original medical records for verification of data 
gathered on the CRFs and to audit the data collection process. The subject’s confidentiality will 
be maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations.
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 site Investigator, who must provide support at all times for these activities.
14.16.3
Data transmission and storage
Medical records source documents will be copied and transmitted electronically to the study 
Sponsor representative.

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These documents will include the entire electronic health record for the inpatient SESAME 
encounter. They also will include the physician notes for all baseline and follow-up visits, and 
site interpretations of all relevant medical imaging examinations.
Source documents also include the following medical imaging data in DICOM format. These are 
collected as obtained both for clinical and/or research purposes. They include cardiac 
catheterization fluoroscopy images, echocardiography, cardiac CT, and CMR. These all will 
retain patient identifiers. Examinations performed for clinical evaluation prior to signing 
informed consent may be used as the baseline images.
As indicated in section 14.12 (confidentiality):
medical records will be transmitted and stored as source documents and will retain 
patient names and/or medical record numbers, to allow physician-investigators to 
recommend medical therapies as appropriate, to avoid risk of mis-identification.
Imaging data will be transmitted electronically to NHLBI for central laboratory analysis. Imaging 
data will be transmitted via secure file transfer mechanisms abiding FIPS 140-2, HIPAA and local 
institutional standards (such as https://nih.box.com). Imaging data are stored in a secure 
Picture Archive Computer System (PACS) or vendor-neutral archive, according to local 
institutional standards.
14.17Study Records Retention
The site Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(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 applicable regulatory requirement(s). If the site 
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.
14.18Collaborative Agreements
Not applicable.
14.19Conflict of Interest Policy
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in 
the design and conduct of this trial. The study leadership in conjunction with the NHLBI has 
established policies and procedures for all study group members to disclose all conflicts of 

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interest and will establish a mechanism for the management of all reported dualities of 
interest.
15 ABBREVIATIONS
ADE
Adverse device effect 
AE
Adverse Event
AR
Aortic valve regurgitation
AS
Aortic valve stenosis
BASILICA
Bioprosthetic or native Aortic Scallop Intentional Laceration to prevent 
Iatrogenic Coronary Artery obstruction
CI
Confidence Interval
CMR
Cardiovascular magnetic resonance
CRF
Case Report Form
CT
Computed tomography
CTDB
Clinical Trials electronic Data Base for case report form capture
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
ECV
Extracellular volume, typically measured at CMR
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act of 2007
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act 
ICE
Intracardiac echocardiography
IDE
Investigational Device Exemption
IRB
Institutional Review Board
LAMPOON
Intentional Laceration of the Anterior Mitral leaflet to Prevent left ventricular 
Outflow tract ObstructioN
LVOT(O)
Left ventricular outflow tract (obstruction)
MACE
Major adverse clinical events
MVARC
Mitral Valve Academic Research Consortium endpoint definitions
mRS
Modified Rankin Scale of stroke disability
NHLBI
National Heart Lung and Blood Institute
OHSRP
NIH Office of Human Subjects Research Protections
PI
Principal Investigator
SADE
Serious adverse device effect
SAE
Serious adverse event
SESAME
SEptal Scoring Along Midline Endocardium
TAVR
Transcatheter aortic valve implantation
TMVR
Transcatheter mitral valve implantation
TEE
Transesophageal echocardiography
TEER
Transcatheter edge-to-edge repair (of the mitral valve)

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THV
Transcatheter heart valve
TTE
Transthoracic echocardiography
UADE
Unanticipated adverse device effect
UP
Unanticipated problem
VARC
Valve academic research consortium (criteria)

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16 REVISIONS
2023-02-17
Initial NIH IRB Review Submission after CDRH issues IDE license
2023-03-13
Response to NIH IRB Pre-Review
2023-09-12
Response to NHLBI DSMB stipulations, including changes to the selection 
criteria and consent.
Response to additional NIH IRB Pre-Review and housekeeping revisions
2023-12-19
Response to stipulations from NIH IRB
Attendant changes to: Schema diagram
2024-01-22
Response to stipulations from NIH IRB
2024-12-04
Add a second site in response to poor enrollment at a single site;
Remove TMVR as an allowable inclusion criterion to focus enrollment on a 
single disease entity, hypertrophic cardiomyopathy (HCM); delete the 
TMVR-related informed consent document; 
Some optional endpoints changed to non-optional
2024-12-30
Change selection criteria to increase required septal thickness
2025-01-06
Change Risk Analysis Outcomes Classification 
Change procedure detail in attempt to reduce risk of steam pop
2025-02-14
Changes stipulated by NHLBI DSMB

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49.
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Caval-aortic access to allow transcatheter aortic valve replacement in otherwise ineligible 
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Biostatistics, N.L. Geller, Editor 2003, Chapman & Hall / CRC Press.

67
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
Template version date 05.06.2021
18 Appendix A: Tables of Reporting Obligations
Reporting obligations of NHLBI Principal Investigator
Reports from NHLBI PI
Submission or event
Reporting Time Frame
Regulatory 
Body
Current Investigator list
Every 6 months
FDA
IDE Progress Report or 
Continuing Review
Annual
FDA; IRB
Deviations from the investigational plan 
(emergency)
Within 5 working days
IRB; FDA
Unanticipated Adverse Device Effects (UADE)
As soon as possible but within 10 
working days.
Within 7 days 
FDA;
IRB; CD
Anticipated Adverse Device effect (ADE)
Annual summary
FDA; IRB
Serious Adverse Events (SAE-not directly related to 
the device)
Annual progress report;
Within 14 days (CD)
IRB; FDA
CD;
Adverse Events
Annual summary
IRB; FDA
Death of a research subject at least possibly 
related to research
Within 24 hours
IRB; CD
Death unlikely or unrelated to research
At continuing review
Report within 7 calendar days (CD)
IRB; FDA
CD
Unanticipated Problems (UP) involving subject risk
Within 7 calendar days 
IRB; CD
Major Protocol Deviations (PD)
Within 7 days
Annual progress report
IRB; CD
FDA
Minor Protocol Deviations (PD)
Annual progress report;
Within 14 days(CD)
FDA; IRB;
CD; 
Serious or Continuing Non-compliance
Within 7 days 
IRB; CD
Use of a device without obtaining informed 
consent
Within 5 working days 
FDA
Withdrawal of IRB approval
Within 5 working days
FDA; All 
PIs
Withdrawal of FDA approval
Within 5 working days
All PIs; IRB
New information that might affect willingness of 
subjects to enroll or continue participation
Within 7 days
IRB; CD
Recall and Device disposition
Within 30 working days
All PIs; IRB; 
FDA
Sponsor suspend or terminate protocol
Within 7 calendar days
All PIs; IRB; 
FDA
Final Report (enrollment complete & termination)
Within 30 working days 
(termination)
Within 6 months (final report)
FDA; 
Abbreviations: CD = NHLBI Clinical Director. FDA = United States Food and Drug Administration; 
IRB = Institutional Review Board; PI = NHLBI Principal Investigator / Sponsor Representative

68
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
Template version date 05.06.2021
All other adverse events are reported collectively at time of IRB continuing review.
Reporting obligations of Enrolling Site Principal Investigator to the Sponsor*
Site PI Obligation:
Submission or event
Reporting Time Frame
Recipient
Deviations from the investigational plan 
(emergency)
Immediately, but no later than 3 working 
days
Sponsor
Unanticipated Adverse Device Effects (UADE)
Immediately, but no later than 10 
working days
Sponsor, 
IRB
Serious Anticipated Adverse Device Effect (SADE) Within 3 working days
Sponsor
Anticipated Adverse Device effect (ADE)
Within 7 working days
Sponsor
Serious Adverse Events (SAE-not directly related 
to the device)
Within 5 working days
Sponsor
Adverse Events (AE)
Within 7 working days
Sponsor
Death unlikely or unrelated to research 
Immediately but within 3 working days
Sponsor
Death of a research subject at least possibly 
related to research
Within 24 hours
Sponsor, 
IRB
Unanticipated Problems (UP) involving subject 
risk
Within 3 working days, Within 7 days
Sponsor, 
IRB
Major Protocol Deviations (PD)
Within 3 working days
Within 7 days
Sponsor
IRB
Minor Protocol Deviations (PD)
Within 7 working days
Sponsor
Non-compliance, Serious
Within 3 working days
Within 7 days
Sponsor
IRB
Non-compliance, Continuing
Within 3 days working days
Sponsor

69
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
19 Appendix B. Risk Analysis

70
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation

71
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation
Electro-
surgery
Ventricular 
fibrillation
Life-threatening but 
reversible
3
2
6
VF from electrosurgical 
and/or mechanical 
stimulation of septum 
during laceration
Data: Observed in ~5% of clinical 
SESAME, responding promptly to 
defibrillation
Strategy: Monitor rhythm, apply 
defibrillation pads before SESAME 
procedures.

72
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation
Iatrogenic aortic 
regurgitation
From errant 
electrosurgery
4
1
4
Aortic injury has been 
observed in tip-to-base 
LAMPOON by 
inexperienced operator
Prevent: ensheath laceration 
surface below aortic valve. Slow 
traction during electrosurgical 
laceration. Discontinue application 
of energy before withdrawing 
retrograde laceration catheters 
across aortic valve

73
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation
SESAME
Ventricular Septal 
Defect from 
excessively deep 
cut
Acute VSD with 
left-to-right shunt 
causing 
hemodynamic 
compromise
5
2
10
This is a known 
complication of surgical 
myectomy and of trans-
coronary alcohol septal 
ablation
Prevention: Image-guidance 
(echocardiography, EDEN 
intracardiac electrograms), limit 
duration of RF application
Therapy: Conservative, 
transcatheter VSD device 
implantation, or conversion to 
cardiac surgery, as indicated

74
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation
Free wall ventricular 
perforation from 
excessively deep 
and non-target cut 
or from catheter 
manipulations 
including during 
SESAME-induced 
tachycardia
Pericardial effusion 
and tamponade
5
2
10
This is a catastrophic 
complication that would 
be difficult to remedy.
Imaging guidance
Treatment: bailout pericardial 
drainage, transcatheter or surgical 
repair.
Withdraw ICE probe from LV 
before electrosurgery.
“Steam pop”
Intramyocardial 
tissue disruption 
contributing to VSD 
or free-wall 
perforation
5
1
5
Serious complication of 
cardiac electrosurgery
Limit duration of intramyocardial 
radiofrequency ablation without 
traction to allow communication 
with blood pool
Insufficiently deep 
laceration
Clinical failure of 
procedure
2
2
4
Analogous to 
insufficiently deep 
surgical myectomy or to 
coronary-target 
mismatch after alcohol 
septal ablation
Would require an alternative 
therapy such as radiofrequency or 
alcohol or surgical ablation, or a 
repeat attempt at SESAME

75
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation
Mitral chordal 
laceration
Mitral valve 
regurgitation
4
1
1
Mitral valve 
regurgitation
Strategy: Snare in apical position 
below chordal apparatus. Use 
imaging to assure freedom from 
chordal entrapment. Use traction 
to assure freedom from chordal 
entrapment.
Treatment: TEER, surgery, or 
conservative as indicated.
Thromboembolism
Electrosurgery may 
cause intravascular 
coagulation and 
char
3
1
3
Thromboembolism 
including stroke
Prevent: Anticoagulation; limit 
electrosurgery duration and 
energy; Use dextrose flush to 
displace blood from the LV 
catheter; Ensheath both free ends 
of the laceration guidewire; 
Consider analogy to LV 
endocardial radiofrequency 
ablation for EP
High-degree 
atrioventricular 
conduction defect
Requires temporary 
or permanent 
pacemaker therapy
3
2
6
Catheter or surgical 
ventriculotomy is 
performed near the 
Bundle of His and Left 
Bundle; the latter often 
induces left anterior 
fascicle block or more 
advanced conduction 
defects
Observe for electrocardiographic 
conduction abnormalities and offer 
cardiac pacing therapy as 
indicated

76
Abbreviated Title: SESAME IDE Protocol
Version Date: Amendment B 2025-02-14
KEY LEVEL
1
2
3
4
5
Probability
Rare
Uncommon
Common
Normal
Severity
Easy to correct, no anticipated harm to 
patient
Difficult to correct, no anticipated 
harm to patient
Potentially harmful to patient
Likely harmful, even with 
immediate correction
Life threatening
Risk Score
1-4
5-9
10-20
>20
Risk Interpretation
Negligible
Tolerable 
Undesirable
Intolerable
Category
Failure
Impact
Severit
y
Likelihood 
/ 
frequency
Scor
e
Available evidence to 
consider risk
Mitigation
Coronary cameral 
procedure
This is an expected 
complication of 
surgical or 
transcatheter 
myotomy across 
septal perforator 
coronary artery 
branches
1
4
4
Septal perforator 
coronary cameral fistula 
into the left ventricular 
cavity has been 
observed and is 
expected to have little or 
no clinical consequence
Observation
Catheter 
mechanical
Laceration 
guidewire fracture 
and separation
May require device 
replacement
1
1
1
One case of “flying V” 
guidewire fracture was 
observed in the 
LAMPOON IDE trial 
2017, attributed to over-
aggressive 
denuding/kinking, not 
observed in clinical 
LAMPOON or 
BASILICA thereafter
Operator training on proper 
bedside preparation of “flying-V”
Per-
cutaneous 
procedures
ATN from 
procedural contrast 
and from follow-up 
contrast CT
Temporary or 
permanent 
hemodialysis
3
2
6
Temporary or 
permanent hemodialysis
Minimize contrast exposure. 
Request low-energy and low-
contrast time-resolved CT to 
minimize contrast. Follow operator 
discretion about timing of contrast 
exposure