NHLBI DIR Transcatheter Mitral Cerclage Annuloplasty Early Feasibility Study
Phase: NA
Conditions: Functional Mitral Regurgitation
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
 
NHLBI DIR Transcatheter Mitral Cerclage Annuloplasty early feasibility study 
NCT number: 
 
NCT03929913 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
06-14-2021 
 
 

 
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PROTOCOL TITLE: 
NHLBI DIR Transcatheter Mitral Cerclage Annuloplasty early feasibility study 
SHORT TITLE: 
Cerclage EFS study 
INVESTIGATIONAL DEVICE EXEMPTION (IDE) 
G190005 
NHLBI PROTOCOL NUMBER 
19-H-0088 
VERSION HISTORY 
2018-08-27 
NHLBI Cardiovascular Branch Review 
2019-02-06 
Interactive FDA IDE review 
2019-02-27 
Change to single IRB of record 
2019-05-12 
Amendment A: MitraClip Arm, increase in sample size, other study clarifications  
2019-06-27 
Amendment B: Clarifications of, secondary endpoint, ADE, reporting, consent 
2019-09-06 
Amendment C: Additional CT scan, remove NIH as enrolling site 
2019-10-21 
Amendment D: Screening consent, minor cleanup 
2020-02-18 
Amendment E: Additional sites and optional non-invasive tests 
2020-07-09 
Amendment F: Change selection criteria 
2021-06-14 
Amendment G: Add long term FU adverse event recording and reporting criteria; 
 
 
Additional CT scan 
 
SPONSOR INFORMATION: 
 
Sponsor 
NHLBI Office of Clinical Director 
Sponsor Representative 
Robert J. Lederman, MD, Senior Investigator, NHLBI Division of Intramural Research 
 

 
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KEY ROLES 
Role 
Individual 
Affiliation 
FWA If  
applicable 
NIH Principal Investigator, Data 
coordinating center, and IDE 
sponsor representative 
Robert J. Lederman, MD 
NHLBI Division of Intramural Research 
(DIR) 
00005897 
 
 
 
 
 
 
 
Study Manager 
Annette M. Stine, RN 
NHLBI DIR 
 
 
 
 
 
 
Echocardiography core lab 
Vandana Sachdev, MD  
NHLBI DIR 
 
 
 
 
 
CT core lab 
Marcus Chen, MD  
NHLBI DIR 
 
 
 
 
 
Independent Data Monitor 
 
Comprehensive Research Solutions, 
Bethesda, MD; NHLBI Contractor 
 
Independent Clinical Events Adju-
dication Committee 
Hector Garcia-Garcia, MD 
(Chair) 
Medstar Heart and Vascular Institute, 
NHLBI Contractor 
 
Data Safety Monitoring Board 
Jamieson M. Bourque, MD, 
MHS (Chair) 
NHLBI 
 
Study Statistician 
Xin Tian, PhD 
NHLBI Office of Biostatistics Research  
Institutional Review Board (IRB) of 
Record 
— 
Advarra 
00023875 

 
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Role 
Individual 
Affiliation 
FWA If  
applicable 
Site 1 PIs 
Adam B. Greenbaum, MD  
Vasilis C. Babaliaros, MD 
Emory University Hospital 
Atlanta, GA 
00005792 
Site 2 PI 
Toby Rogers, PhD, BM BCh 
 
Medstar Washington Hospital Center 
Washington, DC 
00000504 
Site 3 PI 
Jason Foerst, MD 
Carilion Medical Center 
Roanoke, VA 
00000392 
Site 4 PI 
David V. Daniels, MD 
Christian Spies, MD 
California Pacific Medical Center 
San Francisco, CA 
00000921 
Site 5 PI 
— 
— 
— 
Site 6 (Non-enrolling)  
This site is closed to enrollment in 
Amendment C 
Robert J. Lederman, MD 
NIH Clinical Center 
Bethesda, MD 
00005897 
Associate Investigators 
Jaffar M. Khan, BM BCh 
NHLBI 
00005897 
 
 
Study Site: 
Site Principal Investigator: 
National Heart, Lung and Blood Institute, 
NIH 
FWA #00005897  
(Data Coordinating Center)* 
Robert J. Lederman, MD, Senior Investigator 
National Heart Lung and Blood Institute, 
National Institutes of Health 
Building 10, Room 2c713, MSC 1538 
Bethesda, MD 20892-1538 
Voice: 301-402-6769 
Email: lederman@nih.gov 
Emory University 
FWA #: 00005792 
Adam B. Greenbaum, MD & Vasilis C. Babaliaros, MD 
Emory University 
1364 Clifton Rd. NE, Suite F606 
Atlanta, GA 30322 
Phone: 678-557-4514 
Fax: 404-712-0884 
Email: adam.b.greenbaum@emory.edu & vbabali@emory.edu 
Medstar Washington Hospital Center  
FWA#: 00000504 
Toby Rogers, PhD, MB, BCh, MRCP 
Medstar Washington Hospital Center  
110 Irving Street, NW  
Suite 4B-1  
Washington, DC 20010  
Phone: 202-877-5975  
Fax: 202-877-3339 
E-mail: toby.rogers@medstar.net 
Carilion Medical Center 
FWA#: 00000392 
Jason R. Foerst, MD 
Director of the Adult Structural Heart and Valve Fellowship Program 
Carilion Clinic 
2001 Crystal Spring Ave, Suite 203 
Roanoke, VA 24014 
Phone: 540-632-9220 
Fax: 540-266-6198 
Email: jrfoerst@carilionclinic.org 

 
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California Pacific Medical Center, Sutter 
Health 
FWA#: 00000921 
David V. Daniels, MD and Christian Spies, MD 
1100 Van Ness, #6506 
San Francisco, CA 94109 
Phone: 415-600-5707 
Fax: 415-931-0143 
Email: DanielD2@sutterhealth.org, spiesc@sutterhealth.org 
* No subject enrollment 
ESTIMATED DURATION OF STUDY: 
[6 years] 
ESTIMATED COMPLETION DATE OF STUDY: 
December 31, 2024 
SUBJECTS OF STUDY AND SITES: 
 
 
DISCLOSURES 
RJL and TR are co-inventors on patents, assigned to NIH, on the test article. They may be required to 
receive royalty payments should the test article advance to commercialization. 
The non-NIH site Principal Investigators have the following conflicts of interest: 
ABG serves as a proctor for Edwards Lifesciences, Medtronic, and Abbott Vascular, and is a shareholder in 
Transmural Systems, the manufacturer of the test article.  
VCB is a consultant for Edwards Lifesciences and for Abbott Vascular, and his employer has research con-
tracts from Edwards Lifesciences, Abbott Vascular, Medtronic, and Boston Scientific. 
TR serves as a proctor for Edwards Lifesciences and Medtronic and is a consultant for Medtronic. 
DD serves as a proctor for Edwards Lifesciences, and receives payments from Teleflex for a medical device 
for interventional procedures not tested in this protocol.  
CS serves as a proctor and consultant for Edwards Lifesciences and Medtronic, and is a consultant for Ab-
bott Vascular, Boston Scientific, and Abiomed. NHLBI and Transmural Systems, the manufacturer of the 
cerclage device system, have a collaborative research and development agreement on different cardio-
vascular devices. NHLBI has awarded a Small Business Innovation Research contract to Transmural Sys-
tems to support the early clinical development of this device system. 
 
Subjects 
Sex 
Age range 
Sites 
60 screened 
30 enrolled 
Men & Women  
≥21 years 
Up to 6 

 
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ABBREVIATIONS 
ADE 
Adverse Device Effect 
CIED 
Cardiac implanted electronic device 
CMR 
Cardiovascular magnetic resonance imaging 
CMS 
Centers for Medicare and Medicaid Services 
CRT 
Cardiac resynchronization therapy 
CT 
Computed tomography 
CTP 
CMS Clinical Trial Policy (CTP). 
DIR 
Division of intramural research 
EFS 
FDA Early Feasibility Study under Investigational Device Exemption license 
HFpEF 
Heart failure with preserved ejection fraction 
HFrEF 
Heart failure with reduced ejection fraction 
ICD 
Implanted cardioverter defibrillator 
IEC 
Institutional Ethics Committee 
IRB 
Institutional Review Board 
MVARC 
Mitral valve academic research consortium (criteria) 
MR 
Mitral valve regurgitation 
MS 
Mitral valve stenosis 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SEC 
Study eligibility committee 
TEE 
Transesophageal echocardiography 
TMCA 
Transcatheter Mitral Cerclage Annuloplasty 
TTE 
Transthoracic echocardiography 
UADE 
Unanticipated Adverse Device Effect 
UP 
Unanticipated Problem 
 

 
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TABLE OF CONTENTS 
0.0 
PUBLIC PRÉCIS ................................................................................................................................... 8 
1.0 
Objective ........................................................................................................................................... 8 
2.0 
Background........................................................................................................................................ 8 
3.0 
Clinical and scientific justification ..................................................................................................... 8 
4.0 
Treatment options .......................................................................................................................... 10 
5.0 
Study design .................................................................................................................................... 11 
5.1 
Overview of Study Design .............................................................................................. 11 
5.2 
Evaluation of study Candidates and preparation for the cerclage procedure............... 11 
5.3 
Transcatheter Mitral Cerclage Annuloplasty procedure ................................................ 11 
5.4 
Time and Events Schedule ............................................................................................. 13 
5.5 
CMS Clinical Trial Policy (CTP) on financial coverage of routine medical costs of care in 
this research protocol. ............................................................................................................................ 15 
6.0 
Eligibility assessment ....................................................................................................................... 15 
6.1 
Revised Selection Criteria beginning with Amendment F .............................................. 15 
6.2 
ORIGINAL Selection Criteria BEFORE AMENDMENT F ................................................... 16 
6.3 
Rationale for selection criteria ....................................................................................... 17 
7.0 
Strategies for Recruitment .............................................................................................................. 17 
8.0 
Sample collection, storage and tracking plan ................................................................................. 18 
8.1 
Data transfer to collaborators ........................................................................................ 18 
9.0 
Biostatistical and Analytical considerations .................................................................................... 18 
9.1 
Sample Size .................................................................................................................... 18 
9.2 
Study Analysis ................................................................................................................ 19 
9.3 
Primary endpoint: Technical success ............................................................................. 19 
9.4 
Secondary endpoints...................................................................................................... 20 
9.5 
EXPLORATORY endpoints ............................................................................................... 20 
9.6 
Independent Clinical Events Adjudication ..................................................................... 21 
9.7 
Core laboratories ........................................................................................................... 21 
9.8 
Data Safety Monitoring .................................................................................................. 21 
9.9 
Stopping rules ................................................................................................................ 22 
9.10 
Off study criteria ............................................................................................................ 23 
10.0 
Adverse Event reporting ................................................................................................................. 23 
10.1 
Definitions ...................................................................................................................... 23 
10.2 
Adverse event management: ......................................................................................... 26 
10.3 
Monitoring for specific adverse events.......................................................................... 29 
11.0 
Human subject protection .............................................................................................................. 29 
11.1 
Rationale for Subject Selection ...................................................................................... 29 
11.2 
Risks AND DISCOMFORTS ............................................................................................... 29 
11.3 
Informed consent process: ............................................................................................ 31 
12.0 
Test articles and Indications For Use .............................................................................................. 32 
12.1 
Device description .......................................................................................................... 32 
12.2 
Indications for Use ......................................................................................................... 36 
13.0 
Investigator administrative requirements ...................................................................................... 36 
13.1 
Good Clinical Practice..................................................................................................... 36 
13.2 
IRB Submissions ............................................................................................................. 36 
13.3 
Subject Confidentiality ................................................................................................... 37 
13.4 
Direct Access to Source Data ......................................................................................... 37 
13.5 
Case Report Form Completion ....................................................................................... 37 

 
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13.6 
Record Retention ........................................................................................................... 37 
13.7 
Publication and Presentation of Study Findings and Use of Information ...................... 38 
13.8 
Study Eligibility Committee ............................................................................................ 38 
14.0 
Sponsor regulatory requirements ................................................................................................... 38 
14.1 
Role and General Duties of Sponsor Representative ..................................................... 38 
14.2 
SAFETY MONITORING .................................................................................................... 38 
14.3 
Site Selection and Training ............................................................................................. 39 
References ..................................................................................................................................................... 41 
Appendix A: Risk Analysis............................................................................................................................... 43 
 
 
 

 
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0.0 PUBLIC PRÉCIS 
This research protocol tests a new technique and devices that we have developed to treat functional 
mitral valve regurgitation, called transcatheter mitral valve cerclage annuloplasty, otherwise known as 
“cerclage.” Functional mitral valve regurgitation is a condition caused by damaged heart muscle involving 
the left ventricle which results in mitral valve leakage. This leakage causes heart failure (breathlessness 
and lack of energy especially when walking or exercising, and hospital admissions for fluid buildup). 
This is an early feasibility study (EFS) evaluation of special devices, permanently implanted in the heart, to 
perform mitral cerclage annuloplasty. Mitral cerclage annuloplasty is a catheter procedure performed 
under X-ray and ultrasound guidance without surgery. The cerclage devices compress the mitral valve like 
a purse-string. The cerclage device has a special feature that prevents a coronary artery from getting 
squeezed as part of this purse-string. 
The protocol has been changed to allow patients who have mitral valve regurgitation despite prior Mitra-
Clip treatment. The protocol has been changed to allow patients who have symptomatic heart failure and 
mild mitral regurgitation. 
1.0 OBJECTIVE 
The original objective of this protocol is to evaluate the feasibility and safety of Transcatheter Mitral 
Cerclage Annuloplasty to treat severe functional mitral valve regurgitation in patients with NYHA class II, 
III or IV heart failure symptoms despite optimal medical therapy. 
In Amendment F, the objective of this protocol is changed to evaluate the feasibility and safety of 
Transcatheter Mitral Cerclage Annuloplasty to treat symptomatic heart failure accompanied by mitral 
valve regurgitation despite optimal medical therapy. New subjects may have less severe mitral valve 
regurgitation compared with the first 10 subjects. 
2.0 BACKGROUND 
Functional mitral regurgitation (also known as secondary mitral regurgitation) is a common manifestation 
of left ventricular dysfunction. Ventricular dysfunction leads to dilation, which in turn leads to mitral 
annular dilation and leaflet traction. This causes a failure of coaptation of the otherwise intact leaflets of 
the mitral valve, leading to regurgitation through a central orifice between the mal-coapting leaflet tips. 
Functional mitral regurgitation contributes to heart failure symptoms. 
Annular and/or ventricular restraint are investigational mechanical approaches to mitigate symptoms of 
cardiac dysfunction, that may act by reducing heart failure manifestations during exertion and that may 
induce favorable “negative” chamber remodeling. Transcatheter Mitral Cerclage Annuloplasty is one such 
annular and/or ventricular restraint device strategy. 
3.0 CLINICAL AND SCIENTIFIC JUSTIFICATION 
There is precedent to support the safety of devices that reside in the coronary sinus to treat mitral valve 
regurgitation. But, these so-called ‘partial’ annuloplasty devices and approaches have had mixed results 
with regards to effectiveness. These shortcomings include compression in the commissural more than 
septal-lateral dimensions of the dilated annulus, compression of entrapped circumflex coronary arteries 
inducing myocardial ischemia or infarction predicted in up to two thirds of patient candidates, and 
compression applied far from the annulus when the individual patient coronary sinus anatomically runs 
along the far-left atrial wall.  By contrast, cerclage imparts circumferential compression that reduces the 
septal-lateral dimension, incorporates a protection element to prevent extrinsic compression of 

 
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entrapped coronary arteries, and exhibit planar discordance that achieves annular reduction even when 
the coronary sinus is anatomically located along the posterior left atrial wall. Because it is an entirely 
right-sided procedure and device (i.e. it is not exposed to blood on the left side of the heart), we expect to 
have a similar safety profile to aforementioned partial annuloplasty devices.  
Importantly, cerclage does not preclude other transcatheter mitral valve therapies in the future, including 
edge-to-edge mitral valve repair (e.g. Mitraclip), transcatheter mitral valve replacement (TMVR), or 
surgery. This stands in stark contrast with edge-to-edge repair, that is commonly performed outside the 
US for functional mitral regurgitation. 
Two relevant randomized clinical trials have been published since this study was first proposed, both 
evaluating an alternative transcatheter treatment for functional mitral valve regurgitation. 
The MITRA-FR was a randomized investigator-initiated comparison of Mitra-Clip leaflet apposition or 
medical therapy alone 1. At 12 months, the combined primary endpoint of death or unplanned 
hospitalization was 48.7% versus 47.4% for intervention versus control. The secondary endpoint of death 
was 24.3% versus 22.4% in the intervention and control groups respectively. This study did not support 
the use of Mitra-Clip therapy for functional mitral valve regurgitation. 
The COAPT trial was a randomized pivotal industry comparison of Mitra-Clip leaflet apposition or medical 
therapy alone 2. At 24 months, the primary endpoint of heart failure hospitalization was 35.8% for device 
therapy compared with 67.9% for control (HR 0.53, CI 0.40-0.70). The secondary endpoint of death at 24 
months was 29.1% for device therapy compared with 46.1% for control (HR 0.62, CI 0.46-0.82). This study 
strongly supported the use of Mitra-Clip therapy for functional mitral valve regurgitation. 
These inconsistent randomized trial results are expected not to lead to a definitive (Class I) guideline 
recommendation in favor of Mitra-Clip therapy for functional mitral valve regurgitation.  We therefore 
consider it ethically and medically acceptable to retain the current selection criteria and continue the 
investigational plan of open-label early feasibility evaluation of Cerclage in “all-comer” eligible subjects 
with functional mitral valve regurgitation. 
In Amendment A, we specifically seek patients with symptomatic functional mitral valve regurgitation 
despite treatment with Mitra-Clip transcatheter edge-to-edge leaflet repair. Preliminary data from the 
COAPT randomized comparison of Mitra-Clip versus control on background heart failure therapy suggests 
that both arms show continued left ventricular enlargement and dysfunction.  

 
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We hypothesize that mitral cerclage annuloplasty will complement edge-to-edge leaflet repair and retard 
the progression of ventricular enlargement and dysfunction, analogous to standard surgical practice 
combining leaflet and annuloplasty mitral repairs. 
In Amendments C and E, additional tests were added (see section 5.4). 
In Amendment F, we invite candidates with NYHA Class III or greater symptoms and at least mild mitral 
valve regurgitation. This is based on preliminary findings in the first ten subjects that cerclage caused 
significant improvement in symptoms and functional status but only modest improvement in mitral valve 
regurgitation. This applied equally to patients with “atrial” and “ventricular” functional mitral valve 
regurgitation, which could be alternatively characterized as “heart failure with preserved ejection 
fraction, HFpEF” and “heart failure with reduced ejection fraction, HFrEF,” respectively. 
4.0 TREATMENT OPTIONS 
Candidates for Transcatheter Mitral Cerclage Annuloplasty currently have limited treatment options: 
medical therapy (including cardiac resynchronization therapy) or open surgical mitral valve 
repair/replacement. Because open heart surgery is an invasive procedure, it is typically reserved for the 
patients who are highly symptomatic with severe mitral regurgitation and who have coronary artery 
disease that is likely to benefit from concomitant surgical revascularization. Most patients are therefore 
treated medically, and many will continue to experience heart failure-related symptoms, often leading to 
repeat hospitalizations. MitraClip is a recently approved option for functional mitral valve regurgitation, 
with inconsistent results in two recently reported randomized controlled clinical trials (see section 3.0 
above). 
 
 
Federico ASCH, presented at CRT 2019, Washington DC, March 2019. 

 
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5.0 STUDY DESIGN 
5.1 OVERVIEW OF STUDY DESIGN 
This is an early feasibility study (EFS) of the Transmural Systems Transcatheter Mitral Cerclage 
Annuloplasty device. It is a prospective, open-label, multi-center, investigator-initiated, and 
independently-adjudicated investigation of the cerclage device in patients with symptomatic functional 
mitral valve regurgitation due to underlying cardiomyopathy.  
5.2 EVALUATION OF STUDY CANDIDATES AND PREPARATION FOR THE CERCLAGE PROCEDURE 
Candidates will be identified by the participating structural heart disease programs. Imaging for 
procedural planning will include clinically-necessary imaging studies [specifically contrast-enhanced 
cardiac CT, transesophageal echocardiography (TEE), transthoracic echocardiography (TTE), cardiac 
catheterization and angiography, and if necessary cardiac magnetic resonance imaging (CMR)]. 
Candidates may authorize transmission of medical records and clinical imaging examinations using a 
protocol-specific screening form, if required by the enrolling site. 
Eligibility will be reviewed and proposed by the local multidisciplinary heart teams. Anatomic eligibility 
will be confirmed by the echocardiography and CT analysis Core Laboratories. Candidates will then 
undergo central eligibility review by the Study Eligibility Committee. If deemed eligible, candidates will be 
offered participation in the study. Eligible subjects will be invited to sign the research consent only 
afterwards. 
Candidates will be counseled about the importance of study compliance before enrollment. Once 
enrolled, subjects will undergo protocol baseline assessment. If eligible, subjects will be admitted to the 
hospital and undergo Transcatheter Mitral Cerclage Annuloplasty under this protocol. They will undergo 
follow-up testing including regular transthoracic echocardiography and CT scan before hospital discharge, 
30 days, and 6 months. 
Optionally, subjects may undergo baseline cardiopulmonary exercise testing (CPEX), and/or stress 
(bicycle- or treadmill-) echocardiography, pending local site availability and subject willingness to 
participate. 
5.3 TRANSCATHETER MITRAL CERCLAGE ANNULOPLASTY PROCEDURE 
The Transcatheter Mitral Cerclage Annuloplasty procedure is planned from a time-resolved contrast-
enhanced CT of the heart to confirm suitable coronary venous anatomy.  
The final cerclage implant comprises two components, the cerclage implant with or without a coronary 
artery protection element, and the wishbone lock with coronary sinus and RVOT limbs. 

 
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If the subject is not undergoing therapeutic anticoagulation for another indication (such as atrial fibrilla-
tion), antiplatelet medication is administered on the day of the procedure (aspirin 162-325mg or 
clopidogrel or equivalent daily at the discretion of the treating physician).  
The procedure is performed under general anesthesia or monitored anesthesia care at the discretion of 
the local heart team. The procedure is performed using fluoroscopy and echocardiography (typically 
transesophageal) guidance. The procedure is performed from a transjugular venous approach (preferably 
right side) with a single sheath. Femoral or radial arterial access is also required for selective left coronary 
angiography. After anticoagulation with heparin or equivalent to achieve activated clotting time (ACT) 
>250sec, a balloon wedge end-hole catheter is floated from the internal jugular sheath superior vena cava 
(SVC) to the pulmonary artery. Echocardiography and fluoroscopy are used to ensure the catheter does 
not undermine tricuspid valve chords or the right ventricle moderator band. A guidewire is used to 
exchange the balloon wedge end-hole catheter for the target capture catheter, which is then opened in 
the right ventricular outflow tract (RVOT). This serves as a target and as a snare to capture the septal 
traversal guidewire. 
Using fluoroscopy, a balloon-tip guiding catheter is advanced from the same internal jugular sheath into 
the coronary sinus, the balloon is inflated and a coronary sinus venogram is acquired. Simultaneous 
selective left coronary angiography is acquired to confirm the anatomic relationship of the coronary sinus 
and the left circumflex artery. This serves to confirm the coronary venous anatomy identified on the pre-
procedural CT scan. Coronary guidewires and coronary microcatheters are then used to navigate into a 
suitable coronary vein towards the target capture catheter.  
Once the guidewire is confirmed through the open target capture catheter, the snare is closed to capture 
the guidewire tip. The target capture catheter is then withdrawn from the internal jugular sheath. The 
coronary sinus guidewire is advanced in tandem with the withdrawal of the target capture catheter. This 
creates a wire loop from the internal jugular sheath, along the coronary sinus, through the basal septum 
into the RVOT, through the tricuspid annulus, and back out of the internal jugular sheath. 
The cerclage implant is then attached to the back end of the guidewire and pulled through the internal 
jugular sheath, along the coronary sinus, through the basal septum, through the tricuspid valve, and back 
out of the internal jugular sheath. The cerclage coronary sinus limb is shortened using a scalpel if 
necessary. The position of the cerclage implant is adjusted so that the coronary protection element lies 
directly over any underlying branch of the left coronary artery (typically the left circumflex and/or obtuse 
marginal branch of the circumflex). 
The wishbone lock is then advanced over the two limbs of the cerclage implant and the desired tension is 
titrated to the degree of mitral regurgitation using echocardiography guidance. Selective coronary 
angiography is performed to confirm there is no coronary compression. Once the desired tension has 

 
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been achieved, the wishbone lock is locked and the two limbs of the cerclage implant are cut with a cutter 
catheter. 
Echocardiography assessment of the mitral annulus and mitral regurgitation is again performed, along 
with repeat selective coronary angiography. The internal jugular sheath is then removed, and the patient 
convalesces in the appropriate inpatient recovery unit. 
Before discharge, transthoracic echocardiography is performed. Repeat time-resolved cardiac CT is 
acquired if renal function allows, otherwise it is deferred to the 30-day follow up visit. If renal function 
does not allow contrast by the 30-day follow-up, non-contrast CT is performed for limited geometric 
assessment. 
Anti-platelet medication is continued for 6 months, or longer at the discretion of the attending physician; 
anti-platelet medication is not required if the patient receives therapeutic anticoagulation. 
Optionally, subjects may undergo follow-up cardiopulmonary exercise testing (CPEX), and/or stress 
(bicycle- or treadmill-) echocardiography, as outlined in section 5.4. 
The procedure is unchanged in the presence of prior Mitra-Clip. 
5.3.1 
Pregnancy contingency 
Should a subject become pregnant during the study, CT scans will be omitted but all other study-specific 
follow-up will be unaffected. 
5.4 TIME AND EVENTS SCHEDULE 
 
Screening ± 6 wks 
Baseline ± 6 wks 
Day 0 
Inpatient 
30 d (±14d) FU 
6 mo (± 1 mo) 
12 mo (± 1 mo) 
(range) FU  
2 yrs (± 1 mo) (range) 
FU
3 yrs (± 1 mo) 
4 yrs (± 1 mo) 
5 yrs (± 1 mo) 
Research informed consent 
 
X 
 
 
 
 
 
 
 
 
 
Multidisciplinary heart team eligibility deter-
mination 
X 
 
 
 
 
 
 
 
 
 
 
Baseline clinical assessment 
 
X 
 
 
 
 
 
 
 
 
 
6 minute walk test 
 
X 
 
 
X 
X 
X 
 
 
 
 
Kansas City Cardiomyopathy Questionnaire 
(KCCQ)-23 
 
X 
 
 
X 
X 
X 
 
 
 
 
NYHA Classification 
 
X 
 
 
X 
X 
X 
 
 
 
 
Frailty tests: Katz ADL, 5MW, Albumin 
 
X 
 
 
 
 
 
 
 
 
 
Blood test for pregnancy (hCG) 
X 
X 
 
 
 
 
 
 
 
 
 
Blood tests (see below) 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Vital signs and in-person visit 
 
X 
 
 
X 
X 
X 
 
 
 
 
Cardiac CT contrast-enhanced gated dy-
namic (Baseline may be up to 6 months old) 
Screening or 
baseline 
Screening or 
baseline 
 
Inpatient * 30-90d* X 
X 
 
 
 
 
Transesophageal echocardiogram. May be 
omitted day 0 with SEC concurrence 
Screening or 
baseline 
Screening or 
baseline 
X 
 
 
 
 
 
 
 
 
Transcatheter Mitral Cerclage Annuloplasty 
 
 
X 
 
 
 
 
 
 
 
 
Transthoracic echocardiogram (TTE). Base-
line may be up to 3 months old. 
Screening or 
baseline 
Screening or 
baseline 
 
X 
X 
X 
X 
 
 
 
 
ECG 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Adverse event assessment 
 
 
X 
X 
X 
X 
X 
 
 
 
 

 
EFS Protocol Mitral Cerclage 
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Screening ± 6 wks 
Baseline ± 6 wks 
Day 0 
Inpatient 
30 d (±14d) FU 
6 mo (± 1 mo) 
12 mo (± 1 mo) 
(range) FU  
2 yrs (± 1 mo) (range) 
FU
3 yrs (± 1 mo) 
4 yrs (± 1 mo) 
5 yrs (± 1 mo) 
 Vital status, assessment of SAE and SADE, & 
clinical echo or echo report. Phone call and 
review of records from primary physician 
are acceptable 
 
 
 
 
 
 
 
X 
X 
X 
X 
OPTIONAL: Exercise echocardiogram 
 
X 
 
 
X 
X 
X 
 
 
 
 
OPTIONAL: Cardiopulmonary Exercise Test 
(CPEX) 
 
X 
 
 
X 
X 
X 
 
 
 
 
* follow-up contrast-CT scans may be postponed or omitted as required by patient renal function in 
written coordination with the sponsor representative. 
Subjects would receive continuing care from their primary physicians with consultant input as requested 
from the structural heart disease program. 
For subjects who die, necropsy evaluation is requested to examine the heart at NIH. 
In Amendment C, an additional follow-up CT was added at 30-90 days. 
In Amendment F, additional 6MWT, KCCQ, and proBNP tests were added at 6 months. 
In Amendment G, assessment of and reporting of SAE and SADE is required for long term follow-up.  
5.4.1 
Blood tests 
All of the blood tests specified here are mandatory for routine medical care before, during, and after 
transcatheter mitral valve repair procedure. The results are recorded as research values and in surveil-
lance 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 if change from 
baseline > 10% AND out-of-range: 
Test 
Detail 
Inpatient value 
to record 
Timepoints to 
collect 
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: white blood cell count 
Nonspecific marker of inflammation and infection. 
Highest 
All except 6 mo 
Blood count: platelet 
Nonspecific marker of coagulation and of inflamma-
tion. 
Lowest 
Baseline through 
30d 
Chemistry: Albumin 
Marker of nutritional status and frailty 
 
Baseline only 
Chemistry: Creatinine 
Marker of renal excretion. 
Highest 
All 
Chemistry: Estimated glomerular fil-
tration rate (eGFR) 
Calculated from age, sex, race, and creatinine 
Lowest 
All 
Chemistry: NT-Pro-Brain natriuretic 
peptide (NT-Pro-BNP) 
Marker of volume overload. 
Lowest 
All  
Chemistry: Cardiac troponin 
Marker of cardiomyocyte injury, institution-specific 
subtype (Troponin-I or Troponin-T). 
Highest 
Baseline through 
30 day 
Chemistry: Bilirubin, total 
Used to classify Childs-Pugh status, collected only if 
available from clinical evaluation 
Highest 
Baseline only 
 

 
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5.5 CMS CLINICAL TRIAL POLICY (CTP) ON FINANCIAL COVERAGE OF ROUTINE MEDICAL COSTS 
OF CARE IN THIS RESEARCH PROTOCOL. 
By virtue of NHLBI sponsorship of clinical research protocols, enrolling sites qualify for Centers for 
Medicare and Medicaid Services (CMS) coverage of associated routine costs of medical care under the 
CMS Clinical Trial Policy (CTP). This policy is detailed at 
https://www.cms.gov/Medicare/Coverage/ClinicalTrialPolicies/index.html.  According to this policy, 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… 
“Routine costs of a clinical trial include all items and services that are otherwise generally available to 
Medicare beneficiaries (i.e., there exists a benefit category, it is not statutorily excluded, and there is not 
a national non-coverage decision) that are provided in either the experimental or the control arms of a 
clinical trial except the investigational item…” 
Site billing and reimbursement offices are reminded not to use the IDE number, but instead only bill for 
routine services using the NCT number, which is mandatory. Moreover, site billing and reimbursement 
offices are reminded that under the CTP pathway, the trial is not listed on any CMS web site. 
6.0 ELIGIBILITY ASSESSMENT 
Eligibility criteria were revised in Amendment F to allow patients with symptomatic heart failure (HFrEF 
and HFpEF) accompanied by mitral valve regurgitation. The original criteria are retained below (with text 
struck-out) to allow readers, regulators, and reviewers the opportunity to understand the selection condi-
tions for all subjects. 
6.1 REVISED SELECTION CRITERIA BEGINNING WITH AMENDMENT F 
6.1.1 
Inclusion Criteria  
1. Adults age ≥21 years 
2. Symptomatic functional mitral valve regurgitation 
a. Mild or greater mitral valve regurgitation, LVEF ≤ 0.50,  and NYHA class III - IV 
heart failure  
b. Moderate or greater mitral valve regurgitation and NYHA II - IV heart failure, 
irrespective of LV systolic function  
3. On optimal medical therapy for at least one month (see section 6.3) 
4. Left ventricular ejection fraction ≥0.20 assessed by echocardiography, CT, or CMR 
5. Suitable coronary venous anatomy for Transcatheter Mitral Cerclage Annuloplasty 
based on pre-procedural cardiac CT or coronary venogram 
6. Concordance of the Study Eligibility Committee 
7. If present, a MitraClip was implanted at least 30 days previously 
6.1.2 
Exclusion criteria 
1. Subjects unable to consent to participate 
2. Subjects unwilling to participate or unwilling to return for study follow-up 
activities.  
3. Prior cardiac implanted electronic devices (CIED) likely to be entrapped by 
cerclage. 
o Candidates with coronary sinus or left ventricular pacing or defibrillation 
leads that are not likely to be entrapped by cerclage, evident on baseline CT 
or angiogram, are eligible to participate.  
4. TAVR within 6 weeks 

 
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5. Intended concurrent structural heart procedure, such as aortic or tricuspid valve 
intervention 
6. Aortic stenosis more than mild in severity 
7. Single-leaflet MitraClip detachment, if present 
8. Pregnancy or intent to become pregnant prior to completion of all protocol 
follow-up procedures 
6.2 ORIGINAL SELECTION CRITERIA BEFORE AMENDMENT F 
6.2.1 
Inclusion Criteria  
8. Adults age ≥21 years 
9. Severe functional mitral valve regurgitation defined as: 
a. Effective orifice area ≥20mm2, AND 
b. Regurgitant volume ≥30mL/beat 
10. On optimal medical therapy for at least one month (see section 0) 
11. NYHA class II, III or IV heart failure symptoms 
12. Left ventricular ejection fraction ≥0.20 assessed by echocardiography, CT, or CMR 
13. Suitable coronary venous anatomy for Transcatheter Mitral Cerclage Annuloplasty 
based on pre-procedural cardiac CT or coronary venogram 
14. Concordance of the Study Eligibility Committee 
ADDITIONAL INCLUSION FOR MITRACLIP ARM 
15. Predominantly functional mitral regurgitation as indication for MitraClip 
16. At least 30 days after MitraClip implantation, and at least 24 months after 
MitraClip implantation if enrolled in COAPT trial 
6.2.2 
Exclusion criteria 
9. Subjects unable to consent to participate 
10. Subjects unwilling to participate or unwilling to return for study follow-up 
activities.  
11. TAVR within 6 weeks 
12. Prior cardiac implanted electronic devices (CIED) likely to be entrapped by 
cerclage: Cardiac Resynchronization Therapy (CRT) with coronary sinus lead; 
Implantable Cardioverter Defibrillator (ICD) with lead likely to be entrapped based 
on corelab assessment of baseline CT; or, Single- or dual-chamber pacemaker 
with lead likely to be entrapped based on corelab assessment of baseline CT 
13. Prior Cardiac Resynchronization Therapy (CRT) with biventricular 
pacemaker/Implantable Cardioverter Defibrillator (ICD) and coronary sinus lead 
14. Intended concurrent structural heart procedure, such as aortic or tricuspid valve 
intervention 
15. Aortic stenosis more than mild in severity 
16. Pregnancy or intent to become pregnant prior to completion of all protocol 
follow-up procedures 
ADDITIONAL EXCLUSION FOR MITRACLIP ARM 
17. Single-leaflet detachment of MitraClip 

 
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6.3 RATIONALE FOR SELECTION CRITERIA 
The protocol originally selected subjects with severe mitral regurgitation defined according to European 
Society of Cardiology guidelines 3, which define the intended treatment population. Beginning with 
Amendment F, eligibility was extended to patients with severe symptomatic cardiomyopathy (NYHA Class 
III or IV) and any (≥mild) functional mitral valve regurgitation based on evidence in the first ten subjects of 
significant functional and symptomatic benefit out of proportion to reduction in mitral valve 
regurgitation. At the time of the amendment, no subjects had been enrolled with MitraClip and >24 
months had elapse since enrollment completed in the COAPT trial, so enrollment of subjects having 
MitraClip implants was consolidated into a single treatment arm. “Optimal medical therapy” refers to 
guideline-directed medical therapy according to contemporary ACC/AHA/HFSA 4 and/or ESC 5 guidelines. 
This includes pharmacotherapy of atherosclerosis with medications such as antiplatelet medications, lipid-
lowering agents, anti-ischemic medications, and revascularization therapy as indicated. This also includes 
Guideline-Directed therapy for symptomatic left ventricular dysfunction and mitral valve regurgitation as 
tolerated including beta-adrenergic blockade, angiotensin converting enzyme or angiotensin receptor 
blocker or angiotensin receptor–neprilysin inhibitor, diuretics, and additional agents as indicated and as 
tolerated including aldosterone antagonists, hydralazine-nitrate, and cardiac electronic implanted device 
therapy. “Optimal medical therapy” is confirmed by the Study Eligibility Committee.  
The selection criteria allow enrollment of the intended population with little anticipated selection bias. 
Planned concurrent valve procedures such as TAVR are disallowed. Subjects having pre-existing implanted 
devices that might be disturbed or damaged by the cerclage procedure or implant tension are disallowed 
from this early feasibility study (EFS). Conversely, when demonstrated by imaging that CIED follow the 
“outer curvature” of the coronary sinus allowing an “inner curvature” cerclage implant, such candidates 
are allowed to participate in the trial beginning with Amendment F. 
Children are excluded because this is an early feasibility study. Pregnant women are excluded because of 
the research radiation. 
The inclusive selection criteria and geographic extent of enrolling sites are expected to allow recruitment 
of a diverse economic, ethnic, and racial mix of patients that reflects the incident disease. Specifically, the 
results are expected to be generalizable to Medicare and Medicaid beneficiaries because of age and 
disease-related disability. 
The Study Eligibility Committee confirms eligibility before enrollment (see section 13.8). 
7.0 STRATEGIES FOR RECRUITMENT  
Subjects will be recruited from the Structural Heart Disease clinical programs of the participating 
hospitals.  
The distribution of planned enrolling sites assures accessibility of the trial to ethnically, racially, and 
economically diverse populations. The study will track sex, age, ethnicity, and racial background of 
subjects. 
Once recruited, subject retention rate is expected to be high because follow-up activities are not onerous 
and are timed to correspond with routine follow-up medical care, without prohibitively expensive follow-
up testing. 

 
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8.0 SAMPLE COLLECTION, STORAGE AND TRACKING PLAN 
Imaging data (such as from angiography, fluoroscopy, CT, and echocardiography) constitute the only 
information to be collected. CT examinations performed for clinical evaluation prior to signing informed 
consent may be used as the baseline scan. 
CT and fluoroscopy data will be analyzed at the NHLBI DIR Core Laboratory. These data will be transmitted 
on electronic media such as a DVD via carrier or using secure file transfer mechanisms abiding Federal 
Information Security Management Act (FISMA), Health Insurance Portability and Accountability Act of 
1996 (HIPAA) and local institutional standards (such as https://dirweb.nhlbi.nih.gov/oc).  
Imaging data are transmitted to a central facility (NHLBI) using secure HIPAA compliant methods and are 
stored in a secure Picture Archive Computer System (PACS), according to local institutional standards. This 
includes imaging data used for screening eligibility. 
Necropsy specimens will be handled according to local institutional medical standards and will be 
disposed accordingly. 
8.1 DATA TRANSFER TO COLLABORATORS 
De-identified and de-linked data and images will be posted at the NHLBI Cardiovascular Intervention 
Structural Heart Image Data Repository (https://ledermanlab.nhlbi.nih.gov/repository/index.htm or 
equivalent). They are provided for the purpose of medical education and research.  Data are de-identified 
and de-linked, so that patients can not readily be identified, and are therefore not considered human re-
search subjects research data under US 45CFR§46.104(d)(2)(i). 
De-identified images will also be transferred to collaborating investigators at academic and industry sites. 
They are provided for the purpose of medical education and research.  For some, data are de-identified 
and de-linked, so that patients can not readily be identified, and are therefore not considered human re-
search subjects research data under US 45CFR§46.104(d)(2)(i). For others, data are de-identified but 
linked, in case receiving collaborators require additional information. The table below indicates which re-
cipients will receive de-identified but linkable data and which will only receive de-identified and de-linked 
data. 
These recipients include all site Principal Investigators and: 
Recipient 
Organization 
Location 
Linkable 
Nasser Rafiee 
Transmural Systems 
Andover, MA, USA 
Linked 
June-Hong Kim, PhD, MD 
Pusan National University  
Busan, Republic of Korea 
Linked 
Ajit Yoganathan, PhD 
Georgia Institute of Technology 
Atlanta, Georgia, USA 
De-linked 
Martijn Chatrou, PhD 
3mensio Pie Medical Esaote 
Bilthoven, Netherlands 
De-linked 
 
9.0 BIOSTATISTICAL AND ANALYTICAL CONSIDERATIONS 
9.1 SAMPLE SIZE 
This is an early feasibility study of a device not previously used in humans. An arbitrary initial sample size 
of 30 is proposed in coordination with the FDA Centers for Devices and Radiologic Health, which is 
increased from 15 in Amendment A 

 
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Up to 60 subjects will be consented until 30 subjects undergo attempted Transcatheter Mitral Cerclage 
Annuloplasty total in this protocol.  
We will adhere to the extent possible to consensus guidelines that have been established for the analysis 
and reporting of transcatheter mitral valve repair investigational procedures (MVARC).6, 7 
There are no prespecified acceptance criteria for failure rate. 
9.2 STUDY ANALYSIS 
Analyses will be performed using principles both of (1) intention-to-treat, defined as attempting or 
initiating Transcatheter Mitral Cerclage Annuloplasty, and (2) as-treated, defined as completing 
Transcatheter Mitral Cerclage Annuloplasty. We expect these to be the same. 
Clinical events are classified by the site Principal Investigator and confirmed by the NIH Principal 
Investigator. The results of the study will be released within 12 months of study completion. 
The study will be analyzed using descriptive statistics, including a case-by-case narrative summary of 
major adverse events. Representative descriptive statistics include typical demographic features (age, sex, 
comorbidity), symptoms (NYHA heart failure classification), ventricular geometry and function (volumes, 
ejection fraction), hemodynamics (chamber pressures), procedure characteristics (procedure time, 
contrast exposure), etc.  
We will attempt to stratify subjects by various phenotypes (HFrEF vs HFpEF, MR severity, dimensions) and 
associate these with measurements (cerclage geometric shortening), and outcomes (symptom status, 
functional status, change in chamber volumes and regurgitation, adverse events), as allowed by the small 
sample size. 
Afterwards, we will survey for parameters associated with an increased risk of major adverse events. 
9.3 PRIMARY ENDPOINT: TECHNICAL SUCCESS 
The primary endpoint is Technical success. This endpoint is measured at exit from the catheterization 
laboratory. All of the following must be present: 
• 
Alive 
• 
Successful deployment and correct final positioning of a single intended Transcatheter Mitral 
Cerclage Annuloplasty. Repositioning and recapture of the device, if needed, is not classified 
as failure. 
• 
Retrieval of the cerclage delivery system 
• 
Absence of cerclage-related coronary artery compression and absence of additional proce-
dure such as percutaneous coronary intervention (PCI) to relieve coronary artery compression 
• 
No additional unplanned or emergency surgery or re-intervention related to the cerclage or 
delivery system 
The primary endpoint is classified by the NHLBI Principal Investigator and reviewed for possible reclassifi-
cation by the Clinical Events Adjudication Committee. 

 
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9.4 SECONDARY ENDPOINTS 
9.4.1 
Procedural success 
The secondary endpoint is Procedural success This endpoint is measured at 30 days. All of the following 
must be present 
• 
Technical success 
• 
No cerclage device-related Serious Adverse Device Effects, defined as VARC-2 life-threatening 
bleeding, major vascular or cardiac complications related to the cerclage requiring unplanned 
reintervention or surgery 
Such reinterventions are directly related to the valve. Pacemaker implantation, for example, is consistent 
with procedural success. 
The secondary endpoint is classified by the NHLBI Principal Investigator and reviewed for possible reclassi-
fication by the Clinical Events Adjudication Committee. 
9.5 EXPLORATORY ENDPOINTS 
Exploratory endpoints include:  
• 
MVARC6 30-day Device Success 
• 
MVARC6 1-year Patient Success 
• 
Change from baseline in degree of mitral regurgitation post-procedure, at 30 days, 6-months, 
and 12-months 
• 
Change from baseline in left ventricular dimensions/volumes post-procedure, at 30 days, 6-
months, and 12-months 
• 
Change in symptoms assessed by New York Heart Association heart failure classification and 
by Kansas City Cardiomyopathy Questionnaire 
• 
Mortality, all-cause, cardiovascular vs non-cardiovascular, peri- vs non-periprocedural, includ-
ing Transcatheter Mitral Cerclage Annuloplasty relatedness) 
• 
Neurological events as reported by the site clinicians only 
• 
Procedural9 Myocardial infarction 
• 
VARC-28 vascular complications 
• 
MVARC6 bleeding complications, which includes pericardial bleeding 
• 
AKI acute kidney injury 
• 
Arrhythmia and conduction disturbances 
• 
Infection related to the cerclage 
• 
Device related technical failure: Device Failure, Pericardial effusion, Conversion to open sur-
gery, Device mal-positioning or migration or detachment, Device fracture, Unintended dam-
age to native mitral valve or tricuspid valve apparatus 
• 
Device thrombosis 

 
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• 
Change in optional exercise endpoints including mitral regurgitation severity, pulmonary ar-
tery pressure estimated from tricuspid regurgitation jet velocity, and gas exchange, when 
available. 
Procedural myocardial infarction will rely on the updated Fourth Universal Definition Type II (supply-de-
mand mismatch) within 48 hours of cerclage. This definition most closely applies to the presumed etiology 
of myocardial infarction theoretically attributable to cerclage. Application of this definition requires rise 
and fall of cardiac troponin above the 99th upper limit of normal, combined with any of: symptoms of 
acute myocardial ischemia; new ischemic ECG changes; development of pathologic Q waves, imaging evi-
dence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent 
with an ischemic etiology 9. 
9.6 INDEPENDENT CLINICAL EVENTS ADJUDICATION 
An independent Clinical Events Adjudication Committee will review all of the following that occur in the 
first year: 
• 
Deaths 
• 
Technical success (primary endpoint) 
• 
Procedure success (secondary endpoint) 
The CEAC will classify relatedness of the above events to the Transcatheter Mitral Cerclage Annuloplasty 
procedure and to the cerclage device. 
9.7 CORE LABORATORIES 
The NHLBI CT and Echocardiography Core Laboratories will analyze all imaging and compare post-
procedure imaging with baseline (pre-procedure) imaging. Analysis will include but will not be limited to 
the following: 
• 
Assessment of baseline eligibility 
o Likelihood of entrapment of Cardiac Implanted Electronic Devices (CIED) by the cerclage 
system 
o Suitability of coronary venous anatomy for the cerclage procedure 
o Geometry of likely cerclage trajectory 
• 
Assessment of cerclage device post-implantation characteristics 
o Cerclage position 
o Cerclage integrity 
o Cerclage-related compression of underlying coronary arteries 
o Cerclage-related tricuspid valve dysfunction 
• 
Assessment of impact of cerclage on heart function 
o Cardiac chamber size and function 
o Severity of mitral valve regurgitation 
o Impact of cerclage on function of non-target valve function (tricuspid and aortic) 
9.8 DATA SAFETY MONITORING 
A Data Safety and Monitoring Board (DSMB) appointed by the NHLBI Division of Intramural Research will 
monitor the safety of subjects in the study as described in the investigational plan, as required for 
interventional studies at NHLBI Division of Intramural Research. All members of the DSMB are unaffiliated 

 
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to the study. The NHLBI DSMB will review the protocol progress report at six-month intervals. The DSMB 
may recommend early termination of the study for considerations of safety and efficacy, using proposed 
Stopping Rules (section 9.9) as a guidance. Unanticipated Adverse Device Effects (UADEs) will be 
submitted to the DSMB following the same timelines as the IRB (See section 9.2.4). 
In all cases of death or serious UADE, the sponsor and the NIH Principal Investigator will make a 
determination whether the event presents an unreasonable risk to the participating subjects. If this 
determination is affirmative, 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 clinical sites will be notified of this action. 
The IRB will review all Unanticipated Adverse Device Effects, and Unanticipated Problems, and may 
choose to suspend or terminate the protocol based on those findings. We believe this will protect subject 
safety. The IRB will review Serious Adverse Events and Serious Adverse Device Effects during continuing 
review. 
9.9 STOPPING RULES  
The study will be monitored to ensure that the mortality within 30-days after the procedure does not sub-
stantially exceed an anticipated rate. We anticipate the rate of 30-day mortality is 10% or less and deter-
mine the stopping rule by a Bayesian approach 10. The stopping boundary is reached if the posterior prob-
ability that the 30-day mortality rate exceeds 10% is at least 85%.  We take our prior distribution to be a 
beta distribution so that our prior clinical opinion is worth 20% of the weight we will place on the new data. 
This gives the prior parameters a = 0.6, b =5.4. Hence when we make decisions about stopping the study, 
the data from the study will dominate over the prior opinion.  
The following table summarizes the threshold numbers for the stop rule boundary, which may lead to a 
recommendation to stop the study due to the excess 30-day mortality. 
Number of subjects 
Stop if the number of deaths 
within 30 days reaches 
2-5 
2 
6-12 
3 
13-20 
4 
21-28 
5 
28-30 
6 
We investigated the performance of the above stopping rule by a simulation study. In each simulation run, 
we generated a study with 15 independent Bernoulli trials, each with a true certain 30-day mortality, and 
compared these outcomes with the above stopping boundary to determine whether the study was stopped.  
We repeated the simulation 100,000 times and computed the proportion of stopped studies using the 
above stopping rule.  The following table summarizes the performance of this stopping rule: 
True 30-day mortality rate 
2.5% 
5% 
10% 
15% 
20% 
25% 
30% 
35% 
Proportion of Stopped Studies (%) 
1 
4 
24 
52 
76 
90 
97 
99 
Average number of subjects (n) 
29.8 
29.1 
25.8 
21 
16.1 
12.2 
9.4 
7.4 
Average number of 30-day mortality (n) 
0.7 
1.5 
2.6 
3.2 
3.2 
3.1 
2.8 
2.6 
These simulation results suggest that our stopping rule has a low probability of stopping a study when the 
true 30-day mortality rate is 10% or less, and the probability of stopping a study is high when the true 30-

 
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day mortality rate exceeds 10%.  There, we believe that our stopping rule for 30-day mortality has satis-
factory statistical properties. 
9.10 
OFF STUDY CRITERIA 
• 
Completion of the 5-year follow-up 
• 
The subject voluntarily withdraws 
• 
The cerclage procedure fails and no implant is left behind, after the first 30 day assessment 
• 
Significant subject non-compliance with follow-up visits, despite repeated site Principal 
Investigator effort to assure compliance including telephone encouragement and registered letter 
reminders if necessary.  
• 
Death 
Confirmation of survival will be sought from all subjects, even after they voluntarily withdraw, by contact-
ing their physicians, the social security death index, and the subjects themselves. 
10.0 
ADVERSE EVENT REPORTING 
10.1 
DEFINITIONS 
Adverse events: Any untoward medical occurrence in a human subject, including any abnormal sign (e.g., 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the 
subject’s participation in the research, whether or not considered related to the subject’s participation in 
the research. 
This will include: 
• 
Expected events related to the subject’s disease process during active enrollment in the research 
protocol and do not directly result from use of the investigational device or study. 
• 
Procedural events directly related to the cardiac catheterization procedure and recovery from the 
procedure and do not directly result from use of the investigational device. 
Serious Adverse Event (SAE): A serious adverse event that results in any of the following and NOT directly 
related to the device. This includes any event that 
• 
Results in death 
• 
Is life-threatening (places the subject at immediate risk of death from the event as it occurs); 
• 
results in in-patient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant incapacity; 
• 
results in a congenital anomaly/birth defect (not relevant to this study); or 
• 
based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition. 
Adverse Device Effect (ADE): Any untoward or unintended response to a medical device. This definition 
includes any event resulting from insufficiencies or inadequacies in the instructions for use or the 
deployment of the device or any event that is a result of user error. 
During this clinical investigation an event should be considered related to the device when it is the result 
of: 
• 
Transcatheter Mitral Cerclage Annuloplasty procedure 
• 
Transcatheter Mitral Cerclage Annuloplasty device 

 
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An event will be considered NOT related to the Transcatheter Mitral Cerclage Annuloplasty procedure 
when it is the result of a pre-existing medical condition. 
Anticipated Adverse Device Effects (AADEs): An AADE is an adverse event with a reasonable possibility that 
the device or procedure caused or contributed to the event. The following AADEs are considered 
anticipated based on judgement and clinical experience: 
• 
Death 
• 
Cardiac arrhythmia including ventricular tachycardia, ventricular fibrillation, supraventricular 
tachycardia, and atrial fibrillation and including cardiac arrest 
• 
Cardiopulmonary resuscitation (CPR) in response to cardiac arrhythmia, cardiac arrest, or 
cardiogenic shock 
• 
Anaphylactic or toxic reaction to anesthesia, medications, or contrast media, or device materials 
• 
Hypersensitivity or immune reaction to the test article(s) or their components 
• 
Complications of vascular access including bleeding (hemorrhage), fistula, dissection, pseudoan-
eurysm, retroperitoneal hematoma, pneumothorax, hemothorax, site hematoma or bruising and 
requiring transcatheter or surgical repair or further medical evaluation or management.  
• 
Conduction system injury including atrio-ventricular conduction block, high-degree atrio-
ventricular block, partial and complete bundle branch block, requiring CPR or temporary or 
permanent pacemaker. At present we believe there is a high chance of needing a pacemaker after 
the cerclage procedure. 
• 
Coronary artery compression which may cause angina, myocardial ischemia, myocardial 
infarction, or ventricular arrhythmia, caused either by the cerclage device or by coronary 
arteriography during or after implantation, and that may require percutaneous or surgical 
intervention 
• 
Embolization of air, thrombus, or debris to coronary arteries, brain, limbs, or viscera causing 
myocardial infarction, stroke, transient ischemic attack, etc 
• 
Transcatheter Mitral Cerclage Annuloplasty device failure including failure to traverse, to deliver, 
to position, or to lock catheters or guidewires 
• 
Malposition, embolization, dislocation, migration, or deployment in an unintended location of the 
cerclage device or its components, or surgical retrieval 
• 
Myocardial or coronary vein perforation during the implantation procedure causing pericardial 
effusion or tamponade, including requiring percutaneous or surgical intervention. 
• 
Bleeding (hemorrhage) caused by the cerclage implantation procedure apart from vascular access 
complications, including blood transfusion  
• 
Bleeding (hemorrhage) caused by vascular access for the cerclage implantation procedure, 
including causing low blood pressure and requiring vasopressor support or requiring blood 
transfusion 
• 
Anemia requiring blood transfusion, such as from procedural blood loss 
• 
Coronary vein dissection or thrombosis caused by the cerclage implantation procedure 
• 
Mechanical injury to the myocardium or heart valves that may cause elevation of myocardial 
biomarkers (Troponin) other than myocardial infarction 
• 
Mechanical injury to, or decline in function of, tricuspid or aortic heart valves or subvalvular 
apparatus causing valve regurgitation including requiring mechanical intervention 
• 
Chest pain 
• 
Cardiogenic shock or hypotension caused by valvular, subvalvular, or myocardial injury during or 
after cerclage implantation procedure requiring vasopressor support or mechanical circulatory 
support or other mechanical or surgical intervention 

 
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• 
Myocardial erosion which may cause myocardial perforation, intracardiac shunt, pericardial 
effusion or tamponade and which may require surgical or transcatheter intervention 
• 
Renal injury or failure, including contrast-induced nephropathy, requiring temporary or 
permanent hemodialysis or medical treatment 
• 
Volume overload, congestive heart failure, dyspnea, pulmonary edema, or pleural or pericardial 
effusion from procedure-related volume perturbations  
• 
Congestive heart failure, cardiomyopathy, cardiogenic shock, respiratory failure, BNP elevation 
• 
Narrowing the mitral valve too much, causing a condition called mitral valve stenosis. This can re-
sult in lung congestion causing shortness of breath, similar to symptoms of leaky (regurgitant) mi-
tral valve. 
• 
Respiratory failure requiring oxygen or mechanical support or mechanical ventilation 
• 
Endocarditis or endarteritis or sepsis related to the cerclage device 
• 
Venous thrombosis or thromboembolism including deep vein thrombosis, and pulmonary 
thromboembolism 
• 
Ecchymoses or gastric bleeding related to anti-platelet medications. 
• 
Other infection related to access site or procedure including urinary or pulmonary or sepsis 
• 
Pain including back pain and access site pain and generalized pain 
• 
Low or high blood pressure values, or low or high heart rate values, whether related to anesthesia 
or not 
• 
Abnormal blood cell tests including hemoglobin, hematocrit, platelets and white blood cells 
• 
Abnormal blood chemistries including creatinine, troponin, and NT-pro-BNP 
• 
Radiation injury including intractable skin injury 
• 
Emergency cardiovascular surgery 
 
Serious Adverse Device Effect (SADE): An adverse effect that may have been or is attributed to the use of 
the device and produce an injury or illness that is life-threatening, results in permanent impairment or 
damage to the body, or requires medical or surgical intervention to prevent permanent harm to the body.  
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
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 (21 CFR 812.3(s)). 
Unanticipated Problem (Up): An unanticipated problem is any incident, experience, or outcome that 
meets ALL of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency in relation to: 
a. the research risks that are described in the IRB-approved research protocol and informed consent 
document, Investigator’s Brochure or other study documents, and  
b. the characteristics of the subject population being studied, and  
• 
Related or possibly related to participation in the research, and  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) related to the research than was previously known or 
expected.  
Unanticipated Problem that is not an Adverse Event: An unanticipated problem that does not fit the 
definition of an adverse event, but which may, in the opinion of the NIH and site Principal Investigators, 

 
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involves risk to the subject, affect others in the research study, or significantly impact the integrity of 
research data. For example, report occurrences of breaches of confidentiality, or accidental destruction of 
study records. 
Protocol Deviation: A protocol deviation is any change, divergence, or departure from IRB-approved 
research protocol. 
Major Deviations - Deviations from the IRB approved protocol that have, or may have the poten-
tial 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. 
Non-compliance: Failure of investigator(s) to follow the applicable laws, regulations, or institutional poli-
cies governing the protection of human subjects in research, or the requirements or determinations of 
the IRB, whether intentional or not.  
Serious non-compliance: Non-compliance, whether intentional or not, that results in harm or 
otherwise materially compromises the rights, welfare and/or safety of the subject. Non-
compliance that materially effects the scientific integrity or validity of the research may be 
considered serious non-compliance, even if it does not result in direct harm to research subjects. 
Continuing non-compliance: A pattern of recurring non-compliance that either has resulted, or, if 
continued, may result in harm to subjects or otherwise materially compromise the rights, welfare 
and/or safety of subjects, affect the scientific integrity of the study or validity of the results. The 
pattern may comprise repetition of the same non-compliant action(s), or different noncompliant 
events. Such non-compliance may be unintentional (e.g. due to lack of understanding, knowledge, 
or commitment), or intentional (e.g. due to deliberate  choice to ignore or compromise the re-
quirements of any applicable regulation, organizational policy, or determination of the IRB). 
10.2 
ADVERSE EVENT MANAGEMENT: 
The following adverse event management guidelines are intended to ensure the safety of each subject 
while on the study. Adverse events and adverse device effects will be attributed to study procedure and 
graded by severity according to the following tables: 
10.2.1 Grading of adverse events and adverse device effects 
Category 
Description 
Mild 
Awareness of symptom. Not expected to have a clinically significant effect on 
the subject’s condition. Not surpassing the expected standard medical 
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.  
 

 
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10.2.2 Attribution of adverse events to the research protocol 
The relatedness of adverse events will be classified as: 
Classification 
Description 
Definite 
The event is clearly related to the research protocol. 
Probable 
The event is likely related to the research protocol. The event has a 
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.  
 
10.2.3 Adverse Event Reporting 
Adverse event recording will start on Day (0) of the Transcatheter Mitral Cerclage Annuloplasty procedure 
and will continue through the 12 month Follow Up. Assessment, recording and reporting of serious 
adverse events (SAE) and serious adverse device effects (SADE) will continue at annual visits 
thereafter. 
New events or conditions present at baseline that increase in severity will be recorded and evaluated and 
reported on the case report form. Once the subject has completed the 30 day follow up, only serious 
adverse events (SAE), serious adverse device effects (SADE), unanticipated device effects (UADE) and 
unanticipated problems (UP) will be reported to the Sponsor . It is the responsibility of the site Principal 
Investigator to report adverse events and adverse device effects to the IRB of record, to the study 
sponsor, and to other regulatory bodies according to their reporting requirements. Monitoring visits will 
be conducted by the Sponsor to review source documentation, and accuracy and completion of the 
adverse event case report forms. 
Section 5.4.1 enumerates blood tests that are monitored for adverse events.  No other blood test are 
reported as adverse events. 
10.2.4 Adverse event reporting timeframes  
The tabular summaries are provided below to aid investigators and staff.  Further detail is provided below 

 
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Reporting obligations of site Principal Investigator 
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 
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 
Immediately but within 3 
working days 
Sponsor 
Serious Unanticipated Problems (UP) 
Within 3 working days 
Sponsor 
Unanticipated Problems, non-serious (UP) 
Within 3 working days 
Sponsor 
Protocol Deviations (PD), serious 
Within 3 working days 
Sponsor 
Protocol Deviations, non-serious (PD) 
Within 7 working days 
Sponsor 
Non-compliance, Serious 
Within 3 working days 
Sponsor 
Non-compliance, Continuing 
Within 7 days 
Sponsor 
Non-compliance, Non-serious 
Within 7 days 
Sponsor 
 
Reporting obligations of NIH Principal Investigator 
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 (CD) 
FDA; IRB;  
CD 
Anticipated Adverse Device effect (ADE) 
Annual summary 
FDA; IRB 
Serious Adverse Events (SAE-not directly re-
lated to the device) 
Annual progress report; 
Within 14 days (CD) 
IRB; FDA 
CD; 
Adverse Events 
Annual summary 
IRB; CD; FDA 
Death 
Possibly related to research: within 
24 hours of ascertainment otherwise 
within 7 days (CD) 
Annual Progress Report 
CD; 
IRB; FDA 
Unanticipated Problems (UP) involving sub-
ject risk 
Within 7 days (CD) otherwise 10 days 
IRB; CD 
Major Protocol Deviations (PD) 
Annual progress report 
Within 7 days (CD) 
FDA; IRB;  
CD 
Minor Protocol Deviations (PD) 
Annual progress report; 
Within 14 days(CD) 
FDA; IRB; 
CD;  

 
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Serious or Continuing Non-compliance 
Within 10 days 
Within 7 days (CD) 
IRB;  
CD 
 
 
 
Informed consent (use of a device without 
obtaining informed consent) 
Within 5 working days  
FDA 
Withdrawal of IRB approval 
Within 5 working days 
FDA; IRB; All PIs 
Withdrawal of FDA approval 
Within 5 working days 
All PIs; IRB 
New information that might affect willing-
ness of subjects to enroll or continue par-
ticipation 
Within 7 days 
CD 
Recall and Device disposition 
Within 30 working days 
All PIs; IRB; FDA 
Sponsor suspend or terminate protocol 
If UADE increases risk to subjects, 5 
days after determination and ≤ 15 
working days after sponsor first noti-
fied 
All PIs; IRB; FDA 
Final Report (enrollment complete & termi-
nation) 
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 = Principal Investigator 
All other adverse events are reported collectively at time of IRB continuing review. 
10.2.5 Interim reporting to FDA CDRH for Early Feasibility Study 
For each sequential cohort of 5 subjects, we will summarize and transmit the 30-day data to FDA CDRH. 
10.3 
MONITORING FOR SPECIFIC ADVERSE EVENTS 
Because non-clinical tests of complement activation have not been completed on the cerclage delivery 
system, there is a remote possibility of complement activation-mediated immune reactions such as 
angioedema and anaphylaxis. We will therefore observe subjects for manifestations of immune-mediated 
reactions such as angioedema and anaphylaxis after the procedure and before hospital discharge. 
11.0 
HUMAN SUBJECT PROTECTION 
11.1 
RATIONALE FOR SUBJECT SELECTION 
11.1.1 Study population: 
Subjects are selected for being adults who are determined otherwise likely to benefit from Transcatheter 
Mitral Cerclage. The determination will be made by the local institutional multidisciplinary Heart Team . 
No patient will be excluded from participation based on gender, race or ethnicity.  
11.2 
RISKS AND DISCOMFORTS 
The enumeration of risks has been harmonized to match the list of anticipated adverse device effects, ex-
cept for the risks below identified with [SR] to denote subject risk that would not be adverse device effect. 
A formal risk analysis is provided in Appendix A: Risk Analysis. 
• 
Death 
• 
Cardiac arrhythmia including ventricular tachycardia, ventricular fibrillation, supraventricular 
tachycardia, and atrial fibrillation and including cardiac arrest 

 
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• 
Cardiopulmonary resuscitation (CPR) in response to cardiac arrhythmia, cardiac arrest, or 
cardiogenic shock 
• 
Anaphylactic or toxic reaction to anesthesia, medications, or contrast media, or device materials 
• 
Hypersensitivity or immune reaction to the test article(s) or their components 
• 
Complications of vascular access including bleeding (hemorrhage), fistula, dissection, pseudoan-
eurysm, retroperitoneal hematoma, pneumothorax, hemothorax, site hematoma or bruising and 
requiring transcatheter or surgical repair or further medical evaluation or management.  
• 
Conduction system injury including atrio-ventricular conduction block, high-degree atrio-
ventricular block, partial and complete bundle branch block, requiring CPR or temporary or 
permanent pacemaker. At present we believe there is a high chance of needing a pacemaker after 
the cerclage procedure. 
• 
Coronary artery compression which may cause angina, myocardial ischemia, myocardial 
infarction, or ventricular arrhythmia, caused either by the cerclage device or by coronary 
arteriography during or after implantation, and that may require percutaneous or surgical 
intervention 
• 
Embolization of air, thrombus, or debris to coronary arteries, brain, limbs, or viscera causing 
myocardial infarction, stroke, transient ischemic attack, etc 
• 
Transcatheter Mitral Cerclage Annuloplasty device failure including failure to traverse, to deliver, 
to position, or to lock catheters or guidewires 
• 
Malposition, embolization, dislocation, migration, or deployment in an unintended location of the 
cerclage device or its components, or surgical retrieval 
• 
Myocardial or coronary vein perforation during the implantation procedure causing pericardial 
effusion or tamponade, including requiring percutaneous or surgical intervention. 
• 
Bleeding (hemorrhage) caused by the cerclage implantation procedure apart from vascular access 
complications, including blood transfusion  
• 
Bleeding (hemorrhage) caused by vascular access for the cerclage implantation procedure, 
including causing low blood pressure and requiring vasopressor support or requiring blood 
transfusion 
• 
Anemia requiring blood transfusion, such as from procedural blood loss 
• 
Coronary vein dissection or thrombosis caused by the cerclage implantation procedure 
• 
Mechanical injury to the myocardium or heart valves that may cause elevation of myocardial 
biomarkers (Troponin) other than myocardial infarction 
• 
Mechanical injury to, or decline in function of, tricuspid or aortic heart valves or subvalvular 
apparatus causing valve regurgitation including requiring mechanical intervention 
• 
Chest pain 
• 
Cardiogenic shock or hypotension caused by valvular, subvalvular, or myocardial injury during or 
after cerclage implantation procedure requiring vasopressor support or mechanical circulatory 
support or other mechanical or surgical intervention 
• 
Myocardial erosion which may cause myocardial perforation, intracardiac shunt, pericardial 
effusion or tamponade and which may require surgical or transcatheter intervention 
• 
Renal injury or failure, including contrast-induced nephropathy, requiring temporary or 
permanent hemodialysis or medical treatment 
• 
Volume overload, congestive heart failure, dyspnea, pulmonary edema, or pleural or pericardial 
effusion from procedure-related volume perturbations  
• 
Congestive heart failure, cardiomyopathy, cardiogenic shock, respiratory failure, BNP elevation 
• 
Narrowing the mitral valve too much, causing a condition called mitral valve stenosis. This can re-
sult in lung congestion causing shortness of breath, similar to symptoms of leaky (regurgitant) mi-
tral valve. 

 
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• 
Respiratory failure requiring oxygen or mechanical support or mechanical ventilation 
• 
Endocarditis or endarteritis or sepsis related to the cerclage device 
• 
Venous thrombosis or thromboembolism including deep vein thrombosis, and pulmonary 
thromboembolism 
• 
Ecchymoses or gastric bleeding related to anti-platelet medications. 
• 
Other infection related to access site or procedure including urinary or pulmonary or sepsis 
• 
Pain including back pain and access site pain and generalized pain 
• 
Low or high blood pressure values, or low or high heart rate values, whether related to anesthesia 
or not 
• 
Abnormal blood cell tests including hemoglobin, hematocrit, platelets and white blood cells 
• 
Abnormal blood chemistries including creatinine, troponin, and NT-pro-BNP 
• 
Radiation injury including intractable skin injury 
• 
Emergency cardiovascular surgery 
 
Risks Related to Radiation 
In this research protocol, subjects will be exposed to radiation from 4 research CT scans (increase from 3 
CT scans in Amendment G). The CT scans are performed for surveillance of transcatheter heart valve 
dysfunction. It is estimated that the amount of research radiation that a subject will be exposed to during 
participation in this research protocol will be approximately 3.2 Rem from the three CT scans, and 
36mSv11 from approximately 30-50 minutes of fluoroscopy during performance of Transcatheter Mitral 
Cerclage Annuloplasty. This is equivalent to 900 chest X-rays. 
The dosimetry per full-function cardiac CT scan was reduced in Amendment G from 1.8 Rem per scan to 
0.79 Rem per full-function exam based on continued evolution of scanners used. Therefore the estimated 
total CT-related radiation was reduced from 5.4 to 3.2 Rem.  The number of chest X-ray equivalents was 
left unchanged, in order to be conservative.We believe the total fluoroscopy exposure to be justifiable in 
this setting, given the seriousness of their cardiovascular disease and limited options. We estimate the 
benefit to the research subjects for these procedures to outweigh the risks.  
11.2.1 Personal Identifiable Information 
Clinical data from subjects participating in this trial will retain personally identifiable information. This in-
cludes CT scans, echocardiograms, fluoroscopy, and medical records. 
Abstracted data will be coded and de-identified for transmission to participating subcontracting investiga-
tors, such as core imaging laboratories, clinical events adjudication committee, and statistician. 
DICOM data will be stored in a secured NIH research PACS system for analysis, including personally 
identifiable information.  
See also section 13.3 (“subject confidentiality”). 
11.3 INFORMED CONSENT PROCESS: 
Candidates may authorize transmission of medical records and clinical imaging examinations using a 
protocol-specific screening form, if required by the enrolling site. After the study has been fully explained, 
written informed consent will be obtained from the subject prior to study participation. The method of 
obtaining and documenting the informed consent and the contents of the consent will comply with ICH-
GCP and all applicable regulatory requirement(s). 

 
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Subjects who are UNABLE to provide consent may NOT be enrolled. The use of a legally authorized 
representative, or telephone consent for any subject enrolling in this study is not acceptable to the 
Sponsor.  
Subjects participating at covered entities will provide written Privacy Rule Authorization (aka “HIPAA Au-
thorization”) 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.  
11.3.1 
Informed consent for non-English speaking subjects. 
Translation of the full consent document will occur per institutional guidelines and standards of practice. 
Enrolling sites will follow Advarra processes for short form consent of non-English speaking research par-
ticipants. This includes use of Advarra-approved short form consent templates posted by Advarra CIRBI 
system, which require no additional IRB approval. If no Advarra short form consent is pre-approved in the 
candidate’s native language, or if a different short form consent is used, the certified translation from 
Advarra 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. 
12.0 
TEST ARTICLES AND INDICATIONS FOR USE 
12.1 
DEVICE DESCRIPTION 
The Transmural Systems Mitral Cerclage Annuloplasty system is designed to treat heart failure symptoms 
including with secondary mitral regurgitation. It is fully retrievable during the implant procedure and post 
deployment.   
The Transmural Systems Mitral Cerclage Annuloplasty system consists of four main parts:  
1. a guidewire capture target and snare  
2. an implant which consists of radiopaque tether with or without a coronary artery protection ele-
ment 
3. straightening catheter 
4. wishbone lock 
5. tether cutter 
12.1.1 Guidewire capture target and snare 
Transmural Systems guidewire capture target and snare are used at the beginning of the procedure to 
capture the guidewire after it has traversed the interventricular septum and consist of an adjustable and 
retrievable braided Nickel Titanium (NiTi) basket attached to a flexible inner push rod with a guidewire 
lumen. The basket is housed inside of a 10F delivery catheter and can be deployed and positioned in the 
RVOT to serve as a target for the septal traversal guidewire. The combination of both push rod and 
braided structure allows for adjustability and manipulation of the capture basket shape and profile which 
can better adapt to the variable shapes of the RVOT anatomy.   
This is intended to prevent trabecular or sub-valvar entrapment of the traversal guidewire. Once the tra-
versal guidewire advances into the capture basket, the capture basket can be collapsed into the delivery 
catheter and externalized to the venous access site.  Now, the implant can be connected to the guidewire 
and exchanged. 
The primary features of the guidewire capture target and snare are:  
a) Radiopaque braided structure is visible and provides a target for traversal guidewire 
b) Adjustable braided basket conforms to various RVOT anatomies  

 
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c) Helps to prevent implant from interacting with or entrapping tricuspid subvalvular structures  
 
Figure 1. Transmural Systems Guidewire capture target and snare 
12.1.2 Implant with or without Coronary artery protection element: 
The implant consists of a braided flat radiopaque tether made of Polyester which incorporates a coronary 
artery protection element, where required.  Loaded over the length of the implant tethers on either side 
of the protection element are removable polymer delivery tubes, which aid in delivery of the implant.  On 
the end of the distal removable delivery tube is a 0.014” guidewire compatible connector, which connects 
the implant to the proximal end of the traversal guidewire. These features enable the exchange of the tra-
versal guidewire for the implant. When the implant delivered to the site and positioned, the connector 
and the delivery tubes are removed from the implant.  The radiopaque tether is long enough on both 
ends to exit through the Superior Vena Cava (SVC).  The implant can be repositioned or completely re-
moved at any time during the procedure, or after completion of the procedure.   
In patients whose cardiac vein does not cross the coronary artery a version of the implant is available 
which does not utilize a coronary artery protection element.  A loading tube is used to facilitate smooth 
delivery of the implant and protection element through the introducer sheath. 
 
Figure 2. Transmural Systems Implant with coronary artery protection element 
The primary features of the implant system are:   
a) A connector feature to provide a smooth and secure connection between the traversal guidewire 
and the implant.  
b) Removable delivery tubes to aid in the delivery of the implant. 
c) A radiopaque implant tether that is designed to provide visibility and circumferential tension. 
d)  A coronary artery protection element which prevents the implant from causing extrinsic com-
pression of an entrapped coronary artery.  The implant is packaged with a loading tube which the 
covers the coronary artery protection element to facilitate insertion into the introducer sheath.  
12.1.3 Straightening Catheter 
The straightening catheter consists of a dual lumen polymer tube with tri-adaptor hemostasis valve.  One 
lumen is loaded with a CS snare (white) and the other lumen is loaded with a RVOT snare (green).    The 
tri-adaptor has a port with a one-way flush valve to allow connection to an active flush.  The tip of the 
catheter has a radiopaque marker band to allow for visibility under fluoroscopy.   

 
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Once the delivery tubes of the implants are removed,  each end of the implant tether is loaded into the 
corresponding snare openings and pulled through the lumen of the straightening catheter.  The straight-
ening catheter is loaded into the introducer sheath and visualized with fluoroscopy.  If twists in the im-
plant tether are visible,  the straightening catheter is rotated to untwists the implant.  Once all twists are 
removed the straightening catheter can be carefully removed from the body and the implant tethers are 
separated to prevented from further twisting.  Parallel implant tethers allow of easy introduction of the 
wishbone lock and delivery system. 
 
Figure 3.  Transmural Systems straightening catheter 
The primary features of the Straightening Catheter are:   
• 
The snares are color coded to allow easy identification of CS and RVOT sides of the implant.  
• 
Pre-loaded implant tether snares extending from the tri-adaptor hemostasis valve to distal end of 
the catheter.  These snares are utilized to easily load and the implant through the straightening 
catheter.  
• 
An active flush port with one-way valve.  
• 
Radiopaque tip for ease of visualization under fluoroscopy. 
 
12.1.4 Wishbone Lock and delivery system 
The Transmural Systems lock consists of an adjustable implantable lock with an attached wishbone exten-
sion that is packaged in a peel-away delivery sheath, a delivery system with pre-loaded tether snares, and 
a handle to manage the tension applied to the implant tethers.   
Each end of the implant tether is looped through the pre-loaded tether snares and externalized at the 
proximal end of the delivery system handle.  The lock system is advanced over the implant tethers to a 
position within the right atrium.  Once the lock is in place, tension can be applied and released repeatedly 
to one or both implant tethers as required.   This allows the user to fine tune the final position of the im-
plant as well as assess and adjust mitral annular circumferential reduction.   
When the desired results are achieved, the lock can then be permanently released from the delivery sys-
tem by removing the lock retaining suture and withdrawing the delivery system. 

 
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Figure 4. Transmural Systems wishbone lock and delivery system 
The primary features of the wishbone lock and delivery system are:   
a) An adjustable lock that allows for repositioning and is designed so that no slippage occurs after it 
is closed.  
b) A pre-shaped wishbone is attached to the distal end of the lock.  The wishbone is comprised of 
two Limbs which are shaped to conform to the anatomy.  The Coronary Sinus Limb (CS Limb) pro-
tects the coronary sinus.  The Right Ventricular Outflow Tract Limb (RVOT Limb) straddles and 
protects the septal tricuspid leaflet and coronary conduction system and incorporates a distal 
bumper to create an atraumatic interface with the RVOT wall.  The wishbone lock is packaged in a 
peel-away sheath to aid in insertion into the introducer sheath. 
c) A delivery system which is includes a lock housing for securing the wishbone lock to the delivery 
system, and a retention suture to ensure the lock remains secure in the housing until final deploy-
ment. 
d) Pre-loaded tether snares extending from the delivery system handle through the wishbone lock.  
These snares are utilized to load the implant through the wishbone lock, delivery system and han-
dle.  
e) A handle attached to the delivery system to individually or collectively manage implant tether and 
the lock retention suture tension. 
 
12.1.5 Tether cutter 
After removing the delivery system from the lock, the back ends of the tethers are threaded through the 
supplied pre-loaded snare and drawn through the cutter housing.  The cutter is then advanced along the 
length of the tethers, until it reaches a position at the proximal end of the lock.  A spring-loaded actuation 
button on the handle is pressed, cutting the tethers.  The cut end of the tethers and the cutting device are 
then withdrawn from the body. 
 
Figure 5. Transmural Systems tether cutter. 

 
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The primary features of the Tether cutter are:   
a) An inner shaft is attached to a forward facing “V” shaped blade at the distal end, to facilitate cut-
ting the radiopaque tethers. 
b) A blade housing with through holes and pre-loaded snare for threading the tethers through the 
cutter. 
c) A spring-loaded actuation handle to minimize the likelihood of inadvertently cutting the implant 
tether prematurely, and to retract the blade.  
 
12.2 
INDICATIONS FOR USE 
The Transmural Mitral Cerclage Annuloplasty is indicated to treat heart failure symptoms including with 
secondary mitral valve regurgitation by reducing mitral annular dimensions.   
13.0 
INVESTIGATOR ADMINISTRATIVE REQUIREMENTS 
13.1 
GOOD CLINICAL PRACTICE 
The study will be conducted in accordance with the International Conference on Harmonisation (ICH) E6 
(Guideline for Good Clinical Practice), Title 21 of the Code of Federal Regulations, Parts 50 (Protection of 
Human Subjects), and 56 (Institutional Review Boards), and other appropriate regulatory requirement(s). 
The Investigators will be thoroughly familiar with the Transcatheter Mitral Cerclage Annuloplasty 
technique as described in the protocol and the Investigational plan. Essential clinical documents will be 
maintained to demonstrate the validity of the study and the integrity of the data collected. Regulatory 
files should be established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations. 
The site Principal Investigator must sign and date the Investigator’s Agreement provided by the Sponsor 
to endorse the recorded data. 
13.2 
IRB SUBMISSIONS 
The IRB/IEC and other appropriate institutional regulatory bodies will review all appropriate study 
documentation in order to safeguard the rights, safety, and well-being of the subjects. The study will only 
be conducted at sites where IRB/IEC and other appropriate institutional regulatory body approval have 
been obtained. The protocol, informed consent, safety updates, annual progress reports, and any 
Figure 6. Transmural Systems final deployed Implant 

 
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revisions to these documents will be provided to the IRB/IEC and other appropriate institutional 
regulatory bodies by the site Principal Investigator. 
13.3 
SUBJECT CONFIDENTIALITY 
Clinical data from subjects participating in this trial will retain personally identifiable information. This in-
cludes CT scans, echocardiograms, fluoroscopy, and medical records. 
We believe medical safety in this protocol is more important than the privacy benefits of masking patient 
identity in research documentation. Therefore, many subject-specific research documents will retain 
patient identifiers. This includes medical images and medical records retained for source documentation, 
case report forms, and medical communications.   
Abstracted data will be coded and de-identified for transmission to participating subcontracting investiga-
tors, such as core imaging laboratories, clinical events adjudication committee, and statistician. Privacy 
will be protected in all public communications such as scientific presentations and manuscripts.  
See also section 11.2.1 (“Personal Identifiable Information”). 
13.4 
DIRECT ACCESS TO SOURCE DATA 
Monitoring and auditing procedures developed by the Sponsor will be followed, in order to comply with 
GCP guidelines. 
Regulatory authorities, the IRB/IEC and other appropriate institutional regulatory bodies, and/or the 
Sponsor may request access to all source documents, CRFs, and other study documentation for on-site 
audit or inspection. Direct access to these documents must be guaranteed by the site Principal 
Investigator, who must provide support at all times for these activities. Monitor(s) and auditor(s) from 
the Sponsor or its designee and regulatory authority (ies) are provided direct access to the local 
electronic health record. 
The subject’s confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations. 
13.5 
CASE REPORT FORM COMPLETION 
CRFs will be completed for each study subject no more than 7 days after procedures, visits, or events. It is 
the site Principal Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the subject’s CRF. Source documentation supporting the CRF data should indicate the 
subject’s participation in the study and should document the dates and details of study procedures, AEs, 
and subject status. Source documents will be provided to the Sponsor electronically according to provided 
Source Document Transmittal List within 7 days of subject discharge or out-patient visit. 
An explanation should be given for all missing data. Accompanying source documents should be 
assembled and scanned and may retain subject identifiers. 
The Principal Investigator must sign and date the Investigator’s Statement at the end of the CRF to 
endorse the recorded data. 
13.6 
RECORD RETENTION 
The site Principal 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 

 
EFS Protocol Mitral Cerclage 
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or according to applicable regulatory requirement(s). If the Investigator withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person willing to accept the responsibility. 
The Sponsor must be notified in writing if a custodial change occurs. 
The Sponsor has full rights over any invention, discovery, or innovation, patentable or not, derived from  
performing the study. 
13.7 
PUBLICATION AND PRESENTATION OF STUDY FINDINGS AND USE OF INFORMATION 
It is anticipated that the results of this study will be presented at scientific meetings and/or published in a 
peer reviewed scientific or medical journal. A Publications Committee comprised of the NIH Principal 
Investigator and Investigators participating in the study, as appropriate, will be formed to oversee the 
publication and presentation of the study results, which will reflect the experience of all investigational 
sites. No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between NIH Principal Investigator and the non-NIH 
Investigator and/or the Investigator's institution. 
Upon request, the primary study publication will be provided to research subjects. 
13.8 
STUDY ELIGIBILITY COMMITTEE 
Clinical data for all research candidates are confirmed by the Study Eligibility Committee before 
enrollment. The Committee confirms the candidate has been adequately treated with optimal medical 
therapy, and that the candidate meets the study selection criteria. 
The Study Eligibility Committee consists of the NIH Principal Investigator and associate investigators, the 
site Principal Investigators, 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 NIH 
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 Eligibility 
Committee will be recorded 
14.0 
SPONSOR REGULATORY REQUIREMENTS 
14.1 
ROLE AND GENERAL DUTIES OF SPONSOR REPRESENTATIVE 
Dr. Robert Lederman is the NIH Principal Investigator and sponsor representative on behalf of NHLBI and 
the NHLBI Office of Clinical Director. Dr. 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 NIH Principal Investigator’s general duties consist of submitting the appropriate regulatory 
applications, selecting investigators, obtaining their signed agreement, providing them with the 
information necessary to conduct the study, ensuring proper clinical site monitoring, and ensuring study 
subject informed consent is obtained.  
14.2 
SAFETY MONITORING 
14.2.1 Principal Investigator (PI):  
Accrual and safety data will be monitored by the NIH PI. The protocol will be continuously evaluated for 
any unusual or unpredicted complications with the aim of detecting and preventing unacceptable in-
crease in morbidity and mortality over and above that anticipated from the procedure.  

 
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14.2.1 Institutional Ethics Committee (IEC) Submissions:  
Sites will rely on a single IRB of record.  
14.2.2 IRB of Record:  
Accrual and safety data will be monitored and reviewed annually by the IRB of Record.  Prior to imple-
mentation of this study, the protocol, and subject research consents will be reviewed and approved ac-
cording 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 con-
tinuing annual review so long as the protocol is open to accrual or follow up of subjects.  
14.2.3 DSMB:  
The NHLBI Data Safety and Monitoring Board (DSMB) will review the protocol at six and twelve month in-
tervals. A progress report will be forwarded to the DSMB at these times. The DSMB may recommend early 
termination of the study for considerations of safety and efficacy.  
14.2.4 Independent Data Monitor: 
As per ICH-GCP 5.18 and FDA 21 CFR 312.50 clinical protocols are required to be adequately monitored by 
the study sponsor.  
The objectives of a monitoring visit will be:  
1) to verify the existence of signed informed consent form and documentation of the informed con-
sent process for each monitored subject;  
2) to verify the prompt and accurate recording of all monitored data points, and prompt reporting of 
all SAEs;  
3) to compare abstracted information with individual subjects’ records and source documents (sub-
ject’s charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, and 
any other relevant original subject information); and  
4) to help ensure investigators are in compliance with the protocol.  
The monitors also will inspect the clinical site regulatory files to ensure that regulatory requirements (Of-
fice 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. 
On-site monitoring visits will be conducted after the first 3 subjects are treated and return for 30-day fol-
low 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 study site must be resolved within 7 days of site notification.   
In this study, we plan 100% source-data verification. 
14.3 
SITE SELECTION AND TRAINING 
The NIH Principal Investigator or his designee will ensure appropriate training in the technique of 
Transcatheter Mitral Cerclage Annuloplasty prior to enrollment at any enrolling site. 
14.3.1 Site selection: 
Site selection will be based on  
• 
Physician expression of interest and need to apply this treatment approach to patients at the site. 

 
EFS Protocol Mitral Cerclage 
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2021-06-14 
• 
Physician prior experience with transcatheter mitral valve therapies (e.g. Mitraclip edge-to-edge 
repair, transcatheter mitral valve replacement). 
• 
Site prior participation in IDE protocols, especially sponsored by NHLBI DIR, evaluating a 
treatment of structural heart disease 
• 
Site ability to obtain CT examinations that are satisfactory for consideration of Transcatheter 
Mitral Cerclage Annuloplasty. 
• 
Record of research support team conduct in the performance of structural heart disease research 
protocols 
• 
Site investigators willing and able to comply with the requirements of this protocol. 
14.3.2 Site training: 
Site training will consist of 
• 
NIH Principal Investigator and NIH PI-designee didactic training about the technique, preclinical, 
and clinical experience to date. 
• 
Proctored conduct of Transcatheter Mitral Cerclage Annuloplasty procedures in patients at the 
local site, at the sole discretion of the NIH Principal Investigator.  
• 
Completion of training, and suitability for independent Transcatheter Mitral Cerclage 
Annuloplasty enrollment, will be certified by the NIH Principal Investigator. 
 
 

 
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REFERENCES 
1. 
Obadia JF, Messika-Zeitoun D, Leurent G, Iung B, Bonnet G, Piriou N, Lefevre T, Piot C, Rouleau F, Carrie D, 
Nejjari M, Ohlmann P, Leclercq F, Saint Etienne C, Teiger E, Leroux L, Karam N, Michel N, Gilard M, Donal E, Trochu 
JN, Cormier B, Armoiry X, Boutitie F, Maucort-Boulch D, Barnel C, Samson G, Guerin P, Vahanian A, Mewton N and 
Investigators M-F. Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. The New England 
journal of medicine. 2018. 
2. 
Stone GW, Lindenfeld J, Abraham WT, Kar S, Lim DS, Mishell JM, Whisenant B, Grayburn PA, Rinaldi M, 
Kapadia SR, Rajagopal V, Sarembock IJ, Brieke A, Marx SO, Cohen DJ, Weissman NJ and Mack MJ. Transcatheter 
Mitral-Valve Repair in Patients with Heart Failure. New England Journal of Medicine. 2018;0:null. 
3. 
Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, Iung B, Lancellotti P, Lansac E, Rodriguez 
Munoz D, Rosenhek R, Sjogren J, Tornos Mas P, Vahanian A, Walther T, Wendler O, Windecker S, Zamorano JL and 
Group ESCSD. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2017;38:2739-
2791. 
4. 
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, 
Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW and Westlake C. 
2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A 
Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines 
and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70:776-803. 
5. 
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, 
Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, 
Ruschitzka F, Rutten FH, van der Meer P and Authors/Task Force M. 2016 ESC Guidelines for the diagnosis and 
treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic 
heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure 
Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-200. 
6. 
Stone GW, Adams DH, Abraham WT, Kappetein AP, Genereux P, Vranckx P, Mehran R, Kuck KH, Leon MB, 
Piazza N, Head SJ, Filippatos G, Vahanian AS and Mitral Valve Academic Research C. Clinical Trial Design Principles 
and Endpoint Definitions for Transcatheter Mitral Valve Repair and Replacement: Part 2: Endpoint Definitions: A 
Consensus Document From the Mitral Valve Academic Research Consortium. J Am Coll Cardiol. 2015;66:308-21. 
7. 
Stone GW, Vahanian AS, Adams DH, Abraham WT, Borer JS, Bax JJ, Schofer J, Cutlip DE, Krucoff MW, 
Blackstone EH, Genereux P, Mack MJ, Siegel RJ, Grayburn PA, Enriquez-Sarano M, Lancellotti P, Filippatos G, 
Kappetein AP and Mitral Valve Academic Research C. Clinical Trial Design Principles and Endpoint Definitions for 
Transcatheter Mitral Valve Repair and Replacement: Part 1: Clinical Trial Design Principles: A Consensus Document 
From the Mitral Valve Academic Research Consortium. J Am Coll Cardiol. 2015;66:278-307. 
8. 
Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip 
DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, 
Windecker S, Serruys PW and Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve 
implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60:1438-54. 
9. 
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD and Executive Group on behalf 
of the Joint European Society of Cardiology /American College of Cardiology /American Heart Association /World 
Heart Federation Task Force for the Universal Definition of Myocardial I. Fourth Universal Definition of Myocardial 
Infarction (2018). J Am Coll Cardiol. 2018;72:2231-2264. 

 
EFS Protocol Mitral Cerclage 
Page 42 of 46 
2021-06-14 
10. 
Geller NL, Follman D, Leifer ES and Carter SL. Design of Early Trials in Stem Cell Transplantation: A Hybrid 
Frequentist-Bayesian Approach In: N. L. Geller, ed. Advances in Clinical Trial Biostatistics: Chapman & Hall / CRC 
Press 2003. 
11. 
Uniyal SC, Chaturvedi V, Sharma SD and Rawat A. Patient Dosimetry during Interventional Cardiac 
Procedures in a Dedicated Catheterization Laboratory. Radiat Prot Dosimetry. 2016. 
12. 
Fischer R. Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket 
Approval and De Novo Classifications. 2012. 
 
 

 
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APPENDIX A: RISK ANALYSIS 
This is a patient-centered risk analysis12 in accordance with 21 CFR 812.25(c). It considers probable and not possible risk. This risk analysis applies to candidates 
for Transcatheter Mitral Cerclage Annuloplasty on optimal medical therapy and with few or no further therapeutic options.  

 
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Failure 
Impact 
Sever-
ity 
Likeli- 
hood 
Score Available evidence  
to consider risk 
Mitigation 
Coronary artery 
compression 
Myocardial ische-
mia, infarction 
4 
2 
8 
Preclinical and early clini-
cal experience in Korea 
Up to two-thirds of patients are expected to have a coronary 
artery run underneath the cerclage system. 
The cerclage system integrates a dedicated coronary protec-
tion device to prevent compression of underlying coronary 
artery. 
Coronary compression is assessed carefully during applica-
tion of cerclage tension using intra-procedural selective cor-
onary angiography. 
Tricuspid valve 
leaflet or sub-val-
vular entrapment 
Tricuspid regurgita-
tion 
3 
3 
9 
Preclinical and early clini-
cal experience in Korea 
Echo assessment of tricuspid valve during procedure 
Tricuspid valve 
leaflet or sub-val-
vular laceration 
Tricuspid regurgita-
tion 
4 
2 
8 
Early preclinical experi-
ence. Introduction of tar-
get-capture system 
through other-than-ma-
jor tricuspid orifice could 
lead to subvalvular tri-
cuspid chordal laceration 
that could cause or exac-
erbate tricuspid regurgi-
tation. 
Careful advancement of the balloon wedge end-hole cathe-
ter across the tricuspid major orifice before exchange for 
the target-capture catheter. 
Atrioventricular 
node compres-
sion and/or injury 
Heart block 
3 
2 
6 
Preclinical experience 
Intra-procedural rhythm monitoring, ECGs obtained post-
procedure and at follow up visits 
If observed during procedure, tension can be reduced, or 
whole device can be removed 
If it persists, it may require permanent pacemaker implanta-
tion 

 
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Myocardial ero-
sion 
Cardiac perforation, 
loss of therapeutic 
effect 
3 
1 
1 
Preclinical experience 
Preclinical evaluation strategy to assure freedom from ero-
sion 
Clinical feasibility evaluation using serial CT to assure free-
dom from erosion 
Device designed to redistribute erosive force along “thicker” 
prosthesis 
Imperfect or miss-
ing basal septal 
perforator coro-
nary vein 
Aborted procedure, 
no permanent harm 
expected 
2 
2 
4 
Preclinical and early clini-
cal experience in Korea 
Target/capture system and crossing systems designed to op-
erate from any anatomic position even if there is no suitable 
septal perforator vein.  Has been demonstrated in pigs. 
Epicardial coro-
nary artery injury 
from vein-to-RV 
crossing 
Myocardial ischemia 
or infarction. 
 
5 
1 
5 
Preclinical and early clini-
cal experience in Korea 
Use coronary arteriography during cerclage to assure vein 
crossing point does not threaten epicardial coronary artery 
(LAD) 
Interference with 
coronary sinus 
leads used for car-
diac resynchroni-
zation therapy 
Cerclage compres-
sion leads to lead 
erosion and failure. 
4 
2 
8 
Theoretical 
Exclude candidates from initial EFS in whom CIED leads are 
threatened based on core lab evaluation of CT. 
Coronary sinus 
position is far 
from mitral annu-
lar plane 
Reduction/loss of 
therapeutic effect 
3 
2 
6 
Theoretical 
Abort procedure, remove implant, no permanent harm ex-
pected, or intermediate-phase failure to improve mitral 
valve regurgitation after otherwise successful procedure. 
Procedural coro-
nary sinus injury, 
dissection, perfo-
ration  
Pericardial effusion, 
or tamponade 
3 
2 
6 
Theoretical, prior experi-
ence with coronary sinus 
pacing leads 
Coronary sinus injury, disruption, dissection, or perforation 
is common in CRT lead implantation procedures and is usu-
ally benign. Pericardial effusion is uncommon and drainage, 
although infrequently required, is definitive. 
Occluded superior 
vena cava, jugular 
vein, subclavian 
vein 
Unable to deliver 
device 
1 
1 
1 
Theoretical 
Abort procedure, no permanent harm expected   

 
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Excessive cerclage 
tension causing 
mitral valve ste-
nosis 
Hemodynamic com-
promise, heart fail-
ure symptoms, myo-
cardial ischemia or 
infarction 
4 
1 
4 
Preclinical experience 
Careful titration of system tension using intraprocedural 
echocardiography 
Reverse lock, reduce tension, if necessary abort procedure 
and remove implant, no permanent harm expected 
Mitral regurgita-
tion reduced after 
initial application 
of tension, but re-
appears later with 
exercise 
Loss of therapeutic 
effect 
2 
3 
6 
Prior clinical experience 
with both surgical and 
transcatheter mitral 
valve repair techniques 
Serial observation for at least 12 months after cerclage. 
Failure of cerclage 
tension lock 
mechanism 
Loss of therapeutic 
effect 
3 
2 
 
Theoretical 
Lock has been designed to tighten with every heartbeat, 
permanent implant has been bench tested to withstand 
much more tension than will be required in clinical practice