The REDUCE FMR Trial: Safety and Efficacy of the Carillon Mitral Contour System® in Reducing Functional Mitral Regurgitation (FMR) Associated With Heart Failure
Phase: NA
Conditions: Mitral Valve Insufficiency, Heart Failure
Sponsor: Cardiac Dimensions Pty Ltd

 
 
 
Copyright ©2015 Cardiac Dimensions Pty Ltd 
All Proprietary Rights Reserved   
Confidential 
 
 
 
 
INVESTIGATIONAL PLAN 
 
 
The REDUCE FMR Trial:  
Safety and Efficacy of the CARILLON Mitral 
Contour System® in Reducing Functional Mitral 
Regurgitation (FMR) Associated with Heart 
Failure 
 
CVP-1627-01, Revision AD 
12 November 2015 
NCT: 02325830 
 
Product Name: 
CARILLON Mitral Contour System® (XE2) 
Sponsor: 
Cardiac Dimensions Pty Ltd 
5540 Lake Washington Blvd. N.E. 
Kirkland, WA  98033  U.S.A. 
+1 425 605-5900 (Telephone) 
+1 425 739-6161 (Facsimile) 
 
 
 
 
 
 
 
 
 

 
 
 
Copyright ©2015 Cardiac Dimensions Pty Ltd 
All Proprietary Rights Reserved   
Confidential 
This document contains confidential and proprietary information and may not be copied or 
reproduced in whole or in part without the express written permission of Cardiac Dimensions Pty Ltd, 
Kirkland, WA, U.S.A. 

 
 
 
 
REDUCE FMR Trial 
 
CVP-1627-01, Revision AD –12 November, 2015 
Cardiac Dimensions Pty Ltd  
CONFIDENTIAL  
Page 1 of 102 
PROTOCOL SIGNATURE PAGE 
 
The signatures below constitute the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of this protocol including, without limitation, all statements regarding 
confidentiality, ISO 14155, Declaration of Helsinki, MEDDEV 2.7/ 3, Standards of Good 
Clinical Practice, as defined by the International Conference on Harmonization and all 
applicable regulatory requirements. 
 
 
Protocol Title: 
The REDUCE FMR Trial: Safety and Efficacy of the CARILLON 
Mitral Contour System® in Reducing Functional Mitral 
Regurgitation (FMR) Associated with Heart Failure 
 
Protocol Number:  CVP-1627-01 
 
Version:  
 
AD 
 
Date:   
 
12 November 2015 
 
 
 
Clinical Site Name 
 
 
 
Site Principal Investigator Printed Name 
 
_____________________________________ 
 
__________________ 
Site Principal Investigator Signature  
 
 
Date 
 
 
 
 
CDI Representative Printed Name and Title 
 
_____________________________________ 
 
__________________ 
CDI Representative Signature 
 
 
 
Date 
 
 

 
 
 
 
REDUCE FMR Trial 
 
CVP-1627-01, Revision AD –12 November, 2015 
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CONFIDENTIAL  
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Table of Contents 
1 
Introduction ........................................................................................................... 15 
1.1 
Overview of Study ........................................................................................... 15 
1.2 
Rationale for Study ......................................................................................... 16 
1.2.1 
Rationale for the Use of the Device ........................................................... 16 
1.2.2 
Rationale for Subject Population Selection ................................................ 16 
1.2.3 
Rationale for Device Placement ................................................................ 17 
1.3 
Background ..................................................................................................... 17 
1.3.1 
Heart Failure ............................................................................................. 17 
1.3.2 
Morbidity and Mortality Related to Functional Mitral Regurgitation ............ 18 
1.3.3 
Current Treatment of Patients with Mitral Regurgitation............................. 18 
1.3.4 
Novel Therapies for Functional Mitral Regurgitation .................................. 19 
1.3.5 
Summary of Pre-Clinical Studies ............................................................... 20 
1.3.6 
Summary of Clinical Studies...................................................................... 20 
2 
Device Overview ................................................................................................... 23 
2.1 
Device Components ........................................................................................ 23 
2.1.1 
CARILLON Implant ................................................................................... 23 
2.1.2 
Delivery System ........................................................................................ 24 
2.2 
Principles of Operation .................................................................................... 25 
2.3 
Indications for Use .......................................................................................... 26 
2.4 
Contraindications ............................................................................................ 26 
3 
Clinical Study Design ............................................................................................ 27 
3.1 
Study Executive Committee ............................................................................ 27 
3.2 
Study Objectives ............................................................................................. 27 
3.2.1 
Primary Endpoint ....................................................................................... 27 
3.2.2 
Secondary Endpoints ................................................................................ 27 
3.2.3 
Observational Data ................................................................................... 28 
3.2.4 
Subject Follow Up Duration ....................................................................... 29 
3.3 
Subject Eligibility ............................................................................................. 29 
3.3.1 
Inclusion Criteria ....................................................................................... 29 
3.3.2 
Exclusion Criteria ...................................................................................... 30 
3.4 
Informed Consent and Study Enrollment ......................................................... 31 
3.4.1 
Informed Consent ...................................................................................... 31 
3.4.2 
Enrollment and Eligibility ........................................................................... 31 
3.5 
Screening/Baseline Assessments ................................................................... 31 
3.5.1 
Not More than 45 Days Prior to Randomization......................................... 32 

 
 
 
 
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3.5.2 
Not More than Three (3) Days Prior to Randomization .............................. 32 
3.5.3 
Study Procedure - Prior to Randomization ................................................ 33 
3.6 
Randomization ................................................................................................ 34 
3.7 
Study Procedure – Post Randomization .......................................................... 34 
3.7.1 
Index Procedure ........................................................................................ 34 
3.7.2 
Study Subject Follow-up Categories .......................................................... 35 
3.7.3 
Discharge Evaluations............................................................................... 36 
3.8 
Study Follow-up Evaluations ........................................................................... 37 
3.8.1 
Follow-Up Schedule – One (1) Month ....................................................... 37 
3.8.2 
Follow-up Schedule – Six (6) Months ........................................................ 38 
3.8.3 
Follow-Up Schedule – Twelve (12) Months ............................................... 39 
3.8.4 
Unscheduled Follow-Up Procedures and Data Requirements ................... 39 
3.8.5 
Study Exit .................................................................................................. 40 
3.8.6 
Subject Withdrawal ................................................................................... 40 
3.8.7 
Cross-Over Registry .................................................................................. 40 
4 
Blinding ................................................................................................................. 42 
4.1 
Double-Blind Study ......................................................................................... 42 
4.1.1 
Blinded Assessments ................................................................................ 42 
4.1.2 
Subject Training ........................................................................................ 42 
4.1.3 
Site Personnel Training ............................................................................. 43 
4.1.4 
Randomization .......................................................................................... 43 
4.2 
Blinding Procedures ........................................................................................ 43 
4.2.1 
Index Procedure through Discharge .......................................................... 43 
4.2.2 
Study Follow-Up Visits .............................................................................. 43 
4.3 
Unblinding ....................................................................................................... 44 
5 
Adverse Events and Risk Analysis ........................................................................ 46 
5.1 
Adverse Events ............................................................................................... 46 
5.1.1 
Adverse Event Definitions ......................................................................... 46 
5.1.2 
Recording Adverse Events ........................................................................ 48 
5.1.3 
Description of AE Severity ......................................................................... 49 
5.1.4 
Description of AE Causal Relationship ...................................................... 49 
5.1.5 
Reporting SAEs......................................................................................... 49 
5.1.6 
Vigilance reporting (EU sites) .................................................................... 50 
5.1.7 
Data Safety Monitoring Board ................................................................... 50 
5.1.8 
Clinical Events Committee ........................................................................ 50 
5.2 
Risk Analysis ................................................................................................... 50 
5.2.1 
Benefits ..................................................................................................... 50 
5.2.2 
Risks ......................................................................................................... 51 

 
 
 
 
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5.2.3 
Efforts for Risk Minimization ...................................................................... 51 
5.2.4 
Conclusion ................................................................................................ 51 
6 
Statistical Plan ...................................................................................................... 52 
6.1 
Study Populations ........................................................................................... 52 
6.2 
Study Analyses ............................................................................................... 52 
6.3 
Study Objectives ............................................................................................. 53 
6.3.1 
Primary Endpoint ....................................................................................... 53 
6.3.2 
Secondary Endpoints ................................................................................ 53 
6.3.3 
Observational Data ................................................................................... 54 
6.4 
Randomization ................................................................................................ 54 
6.5 
Unblinding ....................................................................................................... 55 
6.6 
Primary Endpoint Evaluation & Sample Size Assumptions .............................. 55 
6.7 
Size and Duration of Trial ................................................................................ 57 
6.8 
Secondary Endpoint & Observational Data Assessment ................................. 57 
6.9 
Supportive Analyses & Missing Data Imputation ............................................. 57 
7 
Ethical, Regulatory, and Administrative Considerations ......................................... 58 
7.1 
Informed Consent ........................................................................................... 58 
7.2 
Institutional Review ......................................................................................... 59 
7.3 
Site Requirements .......................................................................................... 59 
7.3.1 
Individual Responsibilities ......................................................................... 60 
7.3.2 
Sponsor Responsibilities ........................................................................... 60 
7.3.3 
Investigator Responsibilities ...................................................................... 61 
7.3.4 
Study Center Coordinator Responsibilities ................................................ 61 
7.4 
Investigational Plan Compliance ..................................................................... 62 
7.5 
Investigational Plan Amendments ................................................................... 62 
7.6 
Data Completion and Study Monitoring ........................................................... 62 
7.6.1 
Study Monitoring ....................................................................................... 63 
7.6.2 
Completion of Case Report Forms (CRFs) ................................................ 65 
7.6.3 
Central Database ...................................................................................... 65 
7.7 
Study Training ................................................................................................. 65 
7.7.1 
CARILLON Mitral Contour System Procedure Training ............................. 65 
7.8 
Subject Recruitment ........................................................................................ 66 
7.9 
Maintenance of Study Records ....................................................................... 66 
7.9.1 
Records and Reporting ............................................................................. 67 
7.10 
Product Handling & Accountability ................................................................... 70 
7.10.1 
Investigational Product Accountability and Supply ..................................... 71 
7.10.2 
Device Accountability ................................................................................ 71 
7.11 
Confidentiality and Data Protection ................................................................. 71 

 
 
 
 
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7.12 
Study Termination For Cause .......................................................................... 72 
7.13 
Authority to Execute ........................................................................................ 72 
7.14 
Publication Plan .............................................................................................. 72 
8 
Sponsor Personnel and Contacts ......................................................................... 73 
9 
Definitions of Terms, Abbreviations and Acronyms ................................................ 74 
9.1 
Definitions of Abbreviations and Acronyms ...................................................... 74 
9.2 
Definitions of Terms ......................................................................................... 77 
Appendix A – Instructions for Use ........................................................................................ 93 
Appendix B – Sample of Informed Consent ......................................................................... 94 
Appendix C – Subject Study Calendar ................................................................................ 95 
Appendix D – NYHA Classification of Patients with Diseases of the Heart .......................... 96 
Appendix E – Echocardiogram Protocol .............................................................................. 97 
Appendix F – Six Minute Walk Test Protocol ....................................................................... 98 
Appendix G – Definition of Stable Heart Failure Regimen ................................................... 99 
Appendix H – Exercise Echocardiography Protocol Synopsis ........................................... 100 
References ........................................................................................................................ 101 

 
 
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Protocol Synopsis  
Title: 
The REDUCE FMR Trial: Safety and Efficacy of the CARILLON Mitral 
Contour System® in Reducing Functional Mitral Regurgitation (FMR) 
Associated with Heart Failure 
Protocol Number: 
CVP-1627-01, Revision AD –12 November, 2015 
Device: 
CARILLON Mitral Contour System® (CMCS) - Model XE2 
 
The CMCS received CE-Mark on 3 August 2011. 
 
In Australia/New Zealand the CMCS is “For Clinical Trial Use Only”  
Study Objective: 
The objective of this prospective, multi-center, randomized, double-blind 
trial is to assess the safety and efficacy of the CARILLON Mitral Contour 
System in treating functional mitral regurgitation (FMR) associated with 
heart failure, compared to a randomized Control group which is medically 
managed according to heart failure guidelines. 
Number of Centers: Up to 25 centers in Australia/New Zealand and Europe 
Patient Population: Patients with moderate heart failure and functional mitral regurgitation 
Study Population: 
Consent up to 180 subjects suffering from heart failure and presenting with 
functional mitral regurgitation in order to randomize up to 120 subjects 
Study Duration: 
Twenty (20) months (enrollment phase), with long-term subject follow-up 
of one (1) year, for a total of 32 months 
Study Design: 
The REDUCE FMR Trial is a prospective, multi-center, randomized, 
double-blind clinical trial.   
 
Subjects will be randomized between the Treatment Group and a Control 
Group. Subjects will be randomized in a 3:1 ratio (Treatment : Control 
group).   
 
The Treatment group will be implanted with the CARILLON device.  The 
Control group will be medically managed according to current heart failure 
guidelines i,ii. 
 
As this is a double-blinded study, both the patients (Treatment and Control 
groups) and the assessors of key endpoints will be blinded for 12 months.  
 
i  Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure.  J Am 
Coll Cardiol. 2013;62(16):e147-e239. 
ii  McMurray JV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and 
chronic heart failure 2012. European Heart Journal (2012) 33, 1787–1847. 

 
 
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Subjects randomized to the Control or Treatment group will have safety 
and efficacy assessments performed at baseline, one (1), six (6), and twelve 
(12) months after randomization. 
 
Subjects randomized to the Control group may be offered the CARILLON 
device once they have completed the protocol defined follow-up period 
(Cross-Over Registry).  
Inclusion Criteria:  
1. Diagnosis of dilated ischemic or non-ischemic cardiomyopathy  
2. Functional Mitral Regurgitation:  
– 2+ (Moderate), 3+ (Moderate/Severe), or 4+ (Severe)  
3. NYHA II, III, or IV (refer to Appendix D for NYHA Classification) 
4. Six Minute Walk distance of at least 150 meters and no farther than 450 
meters 
5. Subject meets anatomic screening criteria as determined by angiographic 
screening at the time of the index procedure to ensure that implant can be 
sized and placed in accordance with the Instructions for Use 
6. Left Ventricular Ejection Fraction ≤ 50% 
NOTE: Subjects with LVEF of 41- 50% can only be included if baseline 
NYHA is class III/IV AND MR grade is 3+/4+ (moderately-severe/severe) 
7. LV end diastolic dimension (LVEDD) >55mm or LVEDD/BSA > 
3.0cm/m2 
8. Stable heart failure medication regimen for at least three (3) months (refer 
to Appendix G for definition of stable heart failure regimen) 
9. Age ≥ 18 years old and ≤ 85 years old 
10. The subject has read the informed consent, agrees to comply with the 
requirements, and has signed the informed consent to participate in the 
study 
11. Female subjects of child-bearing potential must have a negative serum 
HCG test 
Exclusion Criteria: 
1. Hospitalization in past three (3) months due to myocardial infarction, 
coronary artery bypass graft surgery, and/or unstable angina 
2. Hospitalization in the past 30 days for coronary angioplasty or stent 
placement 
3. Subjects expected to require any cardiac surgery, including surgery for 
coronary artery disease (unprotected left main stenosis greater than or equal 
to 50% or, greater than or equal to 70% stenosis in at least three (3) 
epicardial coronary arteries in the absence of prior bypass surgery), or for 
pulmonic, aortic, or tricuspid valve disease within one (1) year  

 
 
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4. Subjects with echocardiographic documentation of non-compaction 
cardiomyopathy with associated hypercontractility of the cardiac structures 
supporting the mitral annulus 
5. Subjects expected to require any percutaneous coronary intervention within 
30 days of enrollment 
6. Recipient of intravenous positive-inotrope infusion or intra- aortic balloon 
pump support within the past 30 days 
7. Presence of a mechanical mitral heart valve, mitral bio-prosthetic valve or 
mitral annuloplasty ring 
8. Pre-existing device (e.g., pacing lead) in coronary sinus (CS) / great cardiac 
vein (GCV), or anticipated need for cardiac resynchronization therapy 
(CRT) within twelve (12) months 
9. Presence of a coronary artery stent under the CS / GCV in the implant 
target zone 
10. Significant organic mitral valve pathology (e.g., moderate or severe 
myxomatous degeneration, with or without mitral leaflet prolapse, 
rheumatic disease, full or partial chordal rupture) 
11. Presence of severe mitral annular calcification 
12. Presence of left atrial appendage (LAA) clot.   Patients with a 
current/ongoing (documented within the last 12 months) history of atrial 
fibrillation must undergo a trans-esophageal echo prior to the procedure to 
rule-out left atrial appendage clot to minimize the risk of thrombo-
embolism caused by the tissue plication 
13. Cerebral vascular event within the past three (3) months 
14. Presence of primary renal dysfunction or significantly compromised renal 
function as reflected by a serum creatinine > 2.2 mg/dL (194.5 µmol/L) OR 
estimated Glomerular Filtration Rate (eGFR) < 30 ml/min 
15. Allergy to contrast dye that cannot be pre-medicated 
16. Inability to undertake a six-minute walk test due to physical 
restrictions/limitations 
17. Chronic severe pathology limiting survival to less than 12-months 
18. Anticipated need of left ventricular assist device within twelve (12) months 
19. Currently participating in an investigational study that clinically interferes 
with the current study endpoints. 
Primary Endpoint:  
The primary efficacy endpoint is to demonstrate a statistically significant 
improvement in regurgitant volume associated with the CARILLON device 
at twelve (12) months, relative to the Control population. 

 
 
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Secondary Endpoints: 
Safety:  The following secondary safety endpoints will measure the effect of the 
CARILLON Mitral Contour System on clinical safety parameters of 
interest, relative to the Control population  
• To document the difference in the rate of major adverse events between 
randomized groups, at 1 and 12-months post randomization.   
 
Major Adverse Events are defined as a composite of the following: 
– Death 
– Myocardial Infarction  
– Device Embolization 
– Vessel Erosion, requiring percutaneous or surgical intervention 
– Cardiac Perforation, requiring percutaneous or surgical intervention 
– Occurrence of cardiac surgery or percutaneous coronary intervention 
associated with device failure  
• To assess the rate of heart failure hospitalizations (number of 
admissions, and total associated days in the hospital), from the time of 
the index procedure through twelve months of follow-up. 
Efficacy:  The following secondary efficacy endpoints will assess the effect of the 
CARILLON Mitral Contour System on clinical parameters of interest, 
relative to the Control population:  
• To assess the change from baseline to twelve months for six-minute 
walk distance 
• To assess the change from baseline to twelve months in left ventricular 
volumes (end diastolic and end systolic) 
Observational Data:  
• Long-term safety will be evaluated as the comparison of the following 
safety events between the Control and Treatment groups: 
– Mortality through six (6) and twelve (12) months  
– Serious adverse events through six (6) and twelve (12) months 
• NYHA Classification  
• Left ventricular hemodynamicsiii: 
– LV end diastolic (LVEDD) and end systolic (LVESD) dimensions  
– Ejection fraction (LVEF) 
– Forward cardiac output (CO) 
• Functional Mitral Regurgitation echocardiographic assessmentsiii:  
 
iii Left ventricular hemodynamics and FMR assessments will also be assessed during exercise in randomized patients 
at a subset of study sites who have supine bicycle ergometry and echosonographers experienced in imaging 
acquisition during exercise. 

 
 
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– Vena Contracta (VC)  
– Effective regurgitant orifice area (EROA) 
– MR Jet area / Left atrial area (MRJA/LAA)  
– MR grade 
• Left atrial size 
• Mitral annular diameter and area 
• Diuretic dose change between baseline and 6 / 12 month follow-up 
• Pulmonary Artery Systolic Pressure (echo derived at rest & during exerciseiii) 
• NT-BNP 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• Quality-of-Life Assessment (SF-12)  
 
 
 

 
 
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Study Design & Flow 

 
 
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Randomization & Study Blinding:  
Randomization will only occur after the following eligibility parameters are 
assessed at the time of the procedure.   
Eligibility Coronary Angiography: Angiography will be performed 
immediately prior to randomization to confirm that the subject will not 
require percutaneous coronary intervention within 30 days from the time of 
randomization (Exclusion criterion #5).  At the Investigator’s discretion, if 
the subject has: 
• non-ischemic dilated cardiomyopathy - an arteriogram performed 
within twelve (12) months prior to eligibility assessment may be 
used to satisfy these criteria.   
• ischemic dilated cardiomyopathy - an arteriogram performed within 
three (3) months prior to eligibility assessment may be used to 
satisfy these criteria. 
If the Investigator determines that an eligibility coronary angiography is 
not required on the day of the index procedure, the subject will minimally 
undergo femoral artery cannulation prior to randomization to obtain 
hemodynamic data and ensure that subject is blinded to the treatment 
assignment. Note: All patients randomized to the Treatment group will 
undergo coronary angiography as part of the CARILLON Mitral Contour 
System procedure. 
Eligibility Coronary Sinus Venogram: A coronary sinus venogram will 
be performed immediately prior to randomization in order to assess 
eligibility for the study (Inclusion Criterion #5).   
If the eligibility arteriogram reveals the need for revascularization, or if the 
study subject does not meet all eligibility criteria, the subject is an enrolled 
screen failure.  Randomization does not occur and the subject is followed 
through discharge only.  The tests and evaluations conducted up to this 
point will be recorded as screening tests. 
Randomization: If eligibility criteria are met, the subject can then be 
randomized to either the Treatment or the Control group.  The Treatment 
group will undergo CARILLON device implant, while the Control group 
will not.  
Subject Blinding (details in Section 4: Blinding): The trial will be double-
blinded to reduce the effect of potential bias.  Consequently, the overall 
time in the lab and perceived interventions (e.g., intra-procedure ECG, 
echo assessments, etc…) should be kept similar to ensure that subjects 
remain blinded to their randomization group.   
If conscious sedation is to be used during the procedure, then the subjects 
should be blindfolded and earplugs provided so that they are not aware of 
any discussions that may reveal their randomization group.  Rigorous 
efforts on the part of the implanting physicians, heart failure physicians, 
and supportive personnel will be implemented during and after the 

 
 
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procedure to ensure that the study subjects remain blinded to treatment 
assignment.   
Assessor Blinding:  The assessors of the NYHA Class, six-minute walk 
test, echo corelab assessors, and Quality of Life Questionnaires (Kansas 
City Cardiomyopathy Questionnaire and SF-12) will not be aware of the 
treatment assignment.   
Cross-Over Registry: 
 
Study subjects randomized to the Control group will be offered the option 
of receiving the investigational device after completing their 1-year follow-
up if they continue to meet all of the study eligibility criteria. 
Cross-Over registry subjects will be followed at discharge and for 30-days 
post the CARILLON procedure.  The discharge and 30-day-up follow-up 
assessments will be identical to those collected in the randomized portion 
of the trial.  On completion of the 30-day follow-up the Cross-Over registry 
subjects will be exited from the study. 
 
 

 
 
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Schedule of assessments: 
 
 
 
PRIMARY STUDY  
CROSS-OVER REGISTRY 
(Treatment & Control pts) 
(Control pts upon primary study completion) 
Study Task 
Screening / 
Baseline 
Index 
Procedure 
Discharge 
1 Month  
(±7 Days) 
6 month 
(±14 Days)  
12 month 
(±30 Days) 
 
Screening / 
Baseline 
CARILLON 
Procedure 
Discharge 
1 month 
(±7 Days) 
Informed Consent 
X 
Randomization
 
 
 
 
 
 
 X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
X 
 
 
 
Past Medical History & 
Physical Exam 
X 
 
 
 
 
 
 
X11,12 
 
 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
X 
 
 
 
TEE1 
X 
 
 
 
 
 
 
X 
 
 
 
Coronary Angiography 
X2 
X2 
 
 
 
 
 
X 
X 
 
 
Coronary Sinus Venogram 
X 
 
 
 
 
 
 
X 
 
 
 
Intraprocedure Echo 
(TTE or TEE) 
 
X 
 
 
 
 
 
 
X 
 
 
Physical Exam 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Coagulation Tests4 
X 
 
 
 
 
 
 
X 
 
 
 
Cardiac Enzymes5 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Chemistries6 
X 
 
X 
X 
X 
X 
 
X12 
 
X 
X 
CBC7 
X 
 
X 
X 
X 
X 
 
X12 
 
X 
X 
12-Lead ECG 
X 
 
X 
X 
X 
X 
 
X12 
 
X 
X 
Complete TTE 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
Exercise TTE8 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
Abbreviated TTE9 (safety) 
 
 
X 
 
 
 
 
 
 
X 
 
CXR or cine fluoroscopy 
 
 
X 
 
X 
X 
 
 
 
X 
 
Six Minute Walk Test 
X10 
 
 
X 
X 
X 
 
X12 
 
 
X 
NYHA Classification  
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
KCCQ 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
SF-12 QoL 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
1. To rule out LAA clot - only required for subjects with a prior history of atrial fibrillation 
2. The eligibility angiography may occur immediately prior to randomization, unless a recent angiogram (see section 3.4.3.2) indicating no CAD requiring 
intervention is available. All Treatment group subjects undergo coronary angiography as part of the CARILLON Mitral Contour System procedure.  
3. Vital signs include: Blood pressure, heart rate, respiratory rate, oxygen saturation, temperature (degrees Celsius), weight, height (baseline only).  
4. Coagulation Tests include: PTT and Prothrombin time. 
5. Cardiac enzymes: cardiac troponin (cTn).  
6. Serum chemistries: sodium, potassium, chloride, BUN, creatinine and NT-BNP.  
7. CBC with differential: hemoglobin, hematocrit, platelets, and WBC.  
8. Exercise TTE will be done only at pre-identified qualified sites with supine bicycle ergometry. 
9. Abbreviated TTE safety assessment to rule out pericardial effusion.  
10. Six-minute walk test will be undertaken for screening and baseline (reference Appendix F: Six Minute Walk Test Protocol).  
11. No past medical history needed, physical exam only. 
12. Data from 12-month follow-up of the primary study may be used if assessments were performed within 45 days to scheduled Cross-Over CARILLON 
 
procedure. 

 
 
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1 
Introduction 
1.1 
Overview of Study 
The American Heart Association (AHA) estimates that there are more than 22 million 
people worldwide with heart failure.1  Functional mitral regurgitation, defined as the 
leakage of the mitral valve caused by global or regional changes in left ventricular 
geometry as well as mitral annular dilation, occurs as a consequence of heart failure.  
Cardiac Dimensions has developed proprietary technology designed to address 
functional mitral regurgitation in a minimally invasive manner. 
 
Cardiac Dimensions plans to conduct a clinical trial of the CARILLON Mitral Contour 
System (XE2) in study subjects with functional mitral regurgitation.  This study is a 
prospective, randomized parallel-group, double-blind, multi-center clinical trial 
designed to examine the safety and efficacy of the CARILLON Mitral Contour System 
in study subjects with functional mitral regurgitation.  The study will consent up to 180 
subjects in order to randomize up to 120 subjects at 25 investigational sites in Europe 
and Australia/New Zealand.  Subjects will be randomized into one of two study groups 
using a 3:1 (Treatment group : Control group) ratio. 
 
Study subjects who are eligible for this clinical study and have consented to 
participating in the study will undergo multiple assessments prior to randomization to 
evaluate the eligibility (inclusion/exclusion) criteria. Subjects who meet all eligibility 
criteria will be randomized into one of two study groups (Treatment or Control).   
 
Study subjects randomized to the Treatment group will undergo a venous angiogram to 
assess the suitability of the coronary sinus/great cardiac vein (CS/GCV) for placement 
of the CARILLON implant.  If the subject meets the anatomic requirements for device 
placement, the CARILLON implant procedure begins.  With the distal aspect of the 
device anchored, incremental tension will be applied to plicate the peri-annular tissue.  
A transesophageal or transthoracic echocardiogram will be obtained during the 
procedure to evaluate the effect on functional mitral regurgitation and to evaluate left 
ventricular function.  After the proximal anchor of the implant is locked in place, safety 
(including assessment of coronary arterial flow) and efficacy will be reconfirmed prior 
to releasing the CARILLON implant from the delivery system.  
 
Subjects randomized to the Control group will experience an index procedure similar to 
the Treatment group, however, without device placement. To ensure that subjects 
randomized to the Control group will not be able to deduce the treatment assignment 
based on the type of intervention or time associated with the procedure, minimal 
interventional procedures, such as femoral arterial pressure monitoring and a jugular 
venous drip.    If a recent (within the last 3 months for ischemic cardiomyopathy or 12 
months for non-ischemic cardiomyopathy) coronary angiogram is available, this 
assessment may be precluded. 
 
After the study subjects are discharged, the subjects’ primary care specialists 
(cardiologist/heart failure physician) and clinical investigation site staff will coordinate 

 
 
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follow-up evaluations.  Subjects will be evaluated at one (1), six (6), and twelve (12) 
months post-implant, to assess long-term safety, and functional and clinical status. 
(Reference Section 3.8-Study Follow-up Evaluations) 
 
This study will provide for an independent Clinical Events Committee (CEC) and an 
independent Data Safety Monitoring Board (DSMB). The CEC will be responsible for 
adjudicating complications reported during the study that are related to study endpoints 
(objectives), the procedure or the device. The DSMB will review the safety data against 
the established criteria and in the context of other safety data accumulated to date and 
the continued validity of the study. 
1.2 
Rationale for Study 
1.2.1 
Rationale for the Use of the Device 
The appeal of percutaneous approaches to treat functional mitral regurgitation is that 
they may provide a sufficient reduction in mitral regurgitation without the morbidity and 
mortality typically associated with surgery.  In addition, for subjects who are high risk 
surgical candidates and in whom medical therapy is suboptimal, a percutaneous 
procedure provides an alternative treatment option. 
 
Cardiac Dimensions has developed a coronary sinus-based technique that involves 
anchoring a device distally in the CS/GCV, plicating the mitral annular tissue through 
external tension, then anchoring the implant in the proximal coronary sinus so as to 
maintain the annular reduction.  The acute and chronic efficacy of this approach has 
been reported in canine and ovine models of heart failure.  In addition to a reduction in 
the degree of mitral regurgitation, increases in cardiac output, a decrease in pulmonary 
capillary wedge pressure, and no untoward effects on cardiac function or hemodynamics 
have been reported.2,3,4,5,6,7,8,9 
1.2.2 
Rationale for Subject Population Selection 
The contribution of mitral regurgitation to the morbidity and mortality of patients 
suffering from heart failure has been well documented.10  Patients with functional mitral 
regurgitation have few options available to them in the treatment of their disease.  
Medical management continues to inadequately address the problem of functional mitral 
valve regurgitation.  The surgical approaches to mitral annuloplasty demonstrate 
improved hemodynamics; however, the high post-operative morbidity and mortality 
associated with surgery in this population does not warrant widespread use of this 
approach, especially for lesser degrees of functional mitral regurgitation.  Percutaneous 
approaches may be able to achieve the same goal without the associated morbidity and 
mortality seen in the surgical approaches.  Therefore, it is this population of subjects 
with functional mitral regurgitation that may benefit the most from the CARILLON 
Mitral Contour System. 

 
 
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1.2.3 
Rationale for Device Placement 
The CARILLON Mitral Contour System received CE-Mark in August 2011 and is 
designed to place a permanent implant in the CS/GCV and to allow the manual 
tensioning necessary to cause mitral annular reduction and thereby decrease mitral 
regurgitation.  The distal end of the CARILLON implant is secured in the GCV, and the 
proximal end is secured in the coronary sinus.  When traction is applied (manually) to 
the delivery system, the CARILLON implant reshapes the mitral annulus in such a way 
as to reduce mitral regurgitation.  It is anticipated that this plication of the mitral annulus 
will lead to improvements in the subject’s functional status and may also improve left 
ventricular hemodynamics. 
1.3 
Background 
1.3.1 
Heart Failure 
Heart failure is defined as a clinical condition in which the heart is unable to pump a 
sufficient amount of blood to meet the metabolic demands of the body.  This 
compromised myocardial contractility triggers a set of compensatory responses whereby 
the heart attempts to accommodate for the altered function.  Included in these 
compensatory responses are increased preload via the Frank-Starling mechanism, 
activation of the neurohumoral systems, and myocardial remodeling.  The enhanced 
preload and increased sarcomere length allow the ventricle to generate more work and 
eject a higher stroke volume.  Although the changes in cardiac anatomy and physiology 
are initially able to minimize the effect of the myocardial dysfunction, the compensatory 
mechanisms are unable to sustain cardiac performance indefinitely, and chronic 
deterioration (decompensation) ensues. 
 
The American Heart Association (AHA) estimates that there are more than 22 million 
people worldwide with congestive heart failure (CHF)1, of these, 85% of subjects have a 
dilated cardiomyopathy.  Based upon the Framingham Heart Study, about 550,000 new 
cases of CHF occur each year.  The incidence approaches 10 per 1,000 people after age 
65.11  The estimated direct and indirect cost of heart failure in the United States for 2009 
is $37.2 billion.1 
1.3.1.1 Prevalence of Mitral Regurgitation in Heart Failure 
In patients with a dilated cardiomyopathy, one of the consequences of chronic cardiac 
deterioration is progressive ventricular dilation.  This dilation not only compromises 
myocardial contractility, but also compromises the efficiency of the ventricle by 
contributing to the development of functional mitral regurgitation (MR).  Functional MR 
refers to leakage of the mitral valve due to dilation of the left ventricle (LV) and the 
annulus that surrounds and supports the mitral valve.  This is in contrast to “organic” 
MR where an abnormality of the valve itself (e.g., myxomatous degeneration) results in 
the leakage.  In patients with severe heart failure, functional MR increases the 
hemodynamic stress on the failing LV resulting in progressive LV dilation, progressive 
systolic dysfunction, higher filling pressures and lower cardiac output.  Between 54% 
and 60% of patients with dilated cardiomyopathy have been reported to have functional 
mitral regurgitation.12,13,14,15 

 
 
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1.3.2 
Morbidity and Mortality Related to Functional Mitral Regurgitation 
Functional mitral regurgitation increases both the morbidity and mortality of subjects 
with heart failure.10  The labile nature of functional mitral regurgitation and its effect on 
exercise tolerance have also been documented.16 
 
If functional mitral regurgitation further strains the failing myocardium, both at rest and 
especially with exercise, then the impact could translate into decreased survival as well.  
A positive correlation between mitral regurgitation and increased mortality has in fact 
been delineated in a variety of recent studies.  Blondheim followed 91 subjects with 
dilated cardiomyopathy longitudinally and found a markedly decreased survival in the 
group with mitral regurgitation (i.e., 22% vs. 60% at 32 months).  The trend also held 
true for mild mitral regurgitation.17 
1.3.3 
Current Treatment of Patients with Mitral Regurgitation 
1.3.3.1 Medical Treatment 
Heart failure patients are routinely managed with a combination of four types of drugs: a 
diuretic, an angiotensin converting enzyme inhibitor (or angiotensin receptor blocker), a 
beta-adrenergic blocker, and an aldosterone blocker.  Patients with evidence of fluid 
retention receive a diuretic until an euvolemic state is achieved.  The diuretic is 
continued to prevent the recurrence of fluid retention.  Even if a patient has responded 
favorably to the diuretic, treatment with an ACE inhibitor and a beta-blocker is initiated 
and maintained in patients who can tolerate them as they have been shown to favorably 
influence the long-term prognosis of heart failure.  Therapy with digitalis may be 
initiated at any time to reduce symptoms and enhance exercise tolerance.18,19 
1.3.3.2 Surgical Treatment 
The efficacy of performing mitral valve repair has been thoroughly studied in subjects 
with organic mitral regurgitation, and the long-term results are encouraging.  Although 
surgical options exist for treatment of organic mitral valve pathologies, surgical repair of 
the mitral valve to treat functional mitral regurgitation is not currently recommended for 
subjects with significant LV dysfunction.  Surgical intervention is warranted in certain 
cases, however as noted in the ACC/AHA Guidelines for the Management of Patients 
with Valvular Heart Disease: 
Furthermore, when chronic severe secondary MR is addressed surgically, it is not 
clear that repair, so valuable in treating primary MR, is even preferred over MVR 
in chronic severe secondary MR. Small RCTs have demonstrated that mitral valve 
surgery reduces chamber size and improves peak oxygen consumption in chronic 
severe secondary MR. Deciding which patients with chronic severe secondary MR 
will benefit from mitral surgery awaits the results of larger RCTs. Ischemic or 
dilated cardiomyopathy presents different challenges for mitral repair. 
Regurgitation is caused by annular dilation as well as apical and lateral 
displacement of the papillary muscles. New techniques have facilitated mitral 
repair in this situation, but durability of the repair is primarily dependent on 
regression or progression of ventricular dilation.20 

 
 
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The paucity of clinical options available to treat functional MR in patients with dilated 
cardiomyopathy has led to the exploration of novel therapeutic modalities.  These novel 
therapeutic approaches include both surgical and percutaneous techniques. 
1.3.4 
Novel Therapies for Functional Mitral Regurgitation 
1.3.4.1 Cardiac Resynchronization 
For patients with CHF and prolonged QRS duration, cardiac resynchronization therapy 
has been shown to improve both quality of life and exercise tolerance.21,22  In a sub-study 
of 24 patients with functional mitral regurgitation and heart failure, the degree of mitral 
regurgitation was quantified before and after biventricular pacemaker implantation.  
Breithardt found that resynchronization therapy was associated with significant 
reduction in mitral regurgitation from moderate to mild.23  Although this observation is 
promising for patients in whom intraventricular conduction delay contributes to their 
pathology, the technique is not applicable to patients with adequate conduction and 
functional mitral regurgitation. 
1.3.4.2 Percutaneous Alfieri Procedure 
A unique approach to mitral valve repair was developed by Alfieri whereby the anterior 
and posterior leaflets of the mitral valve are stitched together to reduce the degree of 
mitral regurgitation.24  A percutaneous form of this therapy was developed by Evalve / 
Abbott where access to the mitral valve was achieved through a transeptal procedure, 
then a clip was positioned on the leaflets to create a double orifice mitral valve.25,26,27,28  
The MitraClip system received CE Mark approval in March 2008, and as a result of 
promising initial clinical experiences with this procedure, this device has been implanted 
as a less invasive treatment alternative to surgery in more than 10,000 patients 
worldwide.  In the United States, the EVEREST II randomized trial was conducted and 
compared treatment with the MitraClip device to treatment with surgery for MR in a 
relatively low-risk group of patients. At 1 year, the rate of death was similar in both 
groups, whereas the degree of residual MR was higher with the percutaneous approach 
compared with surgery. However, major adverse events at 30 days were lower overall 
for percutaneously treated subjects. While the majority of the patients enrolled in the 
EVEREST II High- Surgical-Risk cohort had functional MR, it was a heterogeneous 
group and was not compared to the medical standard of care. The data from this cohort 
did demonstrate positive and consistent results for high-surgical-risk patients in terms of 
safety, reduction of MR, reverse left ventricular remodeling, improvement in heart 
failure symptoms, improvement in quality of life, and reduced rates of rehospitalization, 
albeit in a small number of patients.29 
1.3.4.3 Implications of Percutaneous Therapies 
The contribution of mitral regurgitation to the morbidity and mortality of patients 
suffering from heart failure has been well documented.  Medical management continues 
to inadequately address the problem of functional mitral valve regurgitation.  The 
feasibility studies performed on patients with dilated cardiomyopathy and severe mitral 
regurgitation documenting improved outcomes following mitral annuloplasty are 
encouraging.  The high post-operative morbidity and mortality associated with surgery 

 
 
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in this patient population makes widespread acceptance of this approach uncertain.  
With no single treatment regimen resonating as the gold standard for treatment and 
correction of functional mitral regurgitation, there remains room for new therapies to 
yield better results in this patient population.  
1.3.5 
Summary of Pre-Clinical Studies 
In addition to extensive bench-top safety testing, Cardiac Dimensions has conducted 
several pre-clinical animal studies designed to evaluate the feasibility, efficacy and 
safety of the CARILLON Mitral Contour System.  Studies have been performed in large 
animal species, in healthy and diseased animals, and in acute and chronic settings.  Proof 
of concept studies and preliminary safety studies in combination with bench-top and 
cadaver work have led to the current design of the CARILLON implant.  The results of 
these studies indicate that the investigational device can be safely and reliably loaded, 
deployed, locked, tensioned, recaptured and removed.  Pre-clinical use of the device did 
not result in any vein damage including perforation, thrombus or occlusion 
1.3.6 
Summary of Clinical Studies 
1.3.6.1 Multi-Center Study of the CARILLON Mitral Contour System, Europe – The 
AMADEUS Trial 
In 2005, Cardiac Dimensions initiated a safety study of the CARILLON Mitral Contour 
System in thirty (30) subjects in seven (7) clinical investigation sites in Germany, the 
Netherlands, and Poland.  The primary objective of the “AMADEUS Trial: A Safety and 
Efficacy Study of the CARILLON Mitral Contour System for the Treatment of Mitral 
Regurgitation” was to evaluate the safety of deploying and implanting the Cardiac 
Dimensions CARILLON implant in the coronary sinus and great cardiac vein of 
subjects with functional mitral regurgitation (FMR).  The secondary objectives were to 
determine the long-term safety of the device and the effect of the device on 
hemodynamics and subject function. 
Patients with dilated cardiomyopathy, moderate to severe FMR, ejection fraction < 40%, 
and six minute walk distance between 150 and 450 meters were enrolled in the 
AMADEUS Trial.  Echocardiographic FMR grade, exercise tolerance, New York Heart 
Association (NYHA) class, and quality of life (QOL) were assessed at baseline, one, and 
six months.  Of the 48 subjects enrolled in the trial, 30 were permanently implanted with 
the CARILLON device.  Eighteen (18) subjects did not receive a device due to access 
issues, insufficient acute FMR reduction, or coronary artery compromise.  The major 
adverse event rate was 13% at 30 days.  At six months, the degree of FMR reduction 
among five different quantitative echo measures ranged from 22 – 32%.  Six minute 
walk distance improved from 307 ±87 meters at baseline, to 403 ±137 meters at six 
months (p<0.001).  QOL, measured by the Kansas City Cardiomyopathy Questionnaire, 
improved from 47 ±16 points at baseline, to 69 ±15 points at six months (p<0.001).  The 
results of the AMADEUS study have been published in a peer-reviewed journal – 
Circulation in 2009.30 Follow-up in the study was completed in 2007. 

 
 
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1.3.6.2 Pilot Safety Study of the CARILLON Mitral Contour System, Europe – The TITAN 
Trial 
The European feasibility trial of the CARILLON Mitral Contour System, named 
TITAN, is a multi-center, safety study for the treatment of functional mitral 
regurgitation.  The primary objective of the study is to evaluate the safety of deploying 
and implanting the CARILLON device in the coronary sinus/great cardiac vein in 
patients with functional mitral regurgitation.  The secondary objectives are to determine 
the long-term safety of the device, and the effect of the device on hemodynamics and 
patient function. 
 
The TITAN Trial Investigational Plan was reviewed and approved by the appropriate 
medical ethics committees and notification was made to the Competent Authorities.  The 
TITAN Trial was initiated in April 2008.  Three (3) sites in Germany, two (2) sites in 
Poland, and two (2) sites in France were ultimately initiated.   
  
Patients with dilated ischemic or non-ischemic cardiomyopathy, moderate to severe 
FMR, ejection fraction < 40%, and six minute walk distance between 150 and 450 
meters were enrolled in the TITAN Trial.  Echocardiographic FMR grade, exercise 
tolerance, NYHA class, and Quality-of-Life (QOL) were assessed at baseline, one, six 
and twelve months.  Of the 65 subjects enrolled in the trial, 12 subjects did not meet the 
study eligibility criteria.  Of the 53 subjects who underwent a procedure to implant the 
CARILLON device, 36 ultimately received the CARILLON device.  Seventeen subjects 
did not receive a device due to access issues, insufficient acute FMR reduction, or 
coronary artery compromise.   
  
The major adverse event rate was 1.9% at 30 days.  Analysis of the TITAN study 
indicates that at 12 months, the degree of FMR reduction among four different 
quantitative echo measures ranged from 32 – 46%, with regurgitant volume showing a 
the greatest reduction between baseline and 12 months.  NYHA grade improved by 32% 
from baseline to 12 months, six minute walk distance improved by over 125 meters 
(41% increase from baseline) and QOL, as measured by the Kansas City 
Cardiomyopathy Questionnaire, improved by 53% at twelve months.  Left ventricular 
dimensions in the implanted population also showed a significant trend toward reverse 
remodeling, with end diastolic and systolic volumes decreasing by 9% and 12%, 
respectively at 12 months. The results of the TITAN study have been published in a 
peer-reviewed journal - European J. Heart Failure in 2012.31 
1.3.6.3 Safety Study of the CARILLON Mitral Contour System, Europe – The TITAN II 
Trial: 
The European safety trial of the CARILLON Mitral Contour System (modified XE2), 
named TITAN II, is a multi-center, safety study for the treatment of functional mitral 
regurgitation.  The primary objective of the study is to evaluate the safety of deploying 
and implanting the CARILLON device in the coronary sinus/great cardiac vein in 
patients with functional mitral regurgitation.  The secondary objectives are to determine 
the long-term safety of the device, and the effect of the device on hemodynamics and 
patient function. 
 

 
 
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The TITAN II Trial Investigational Plan has been reviewed and approved by the 
appropriate medical ethics committees and notification was made to the Competent 
Authorities.  The TITAN II Trial was initiated in July 2011.  Three (3) sites in Germany, 
one site in Poland, and one site in France have been initiated and have enrolled patients. 
As of August 28, 2013, a total of 30 patients have been implanted with the CARILLON 
device and patient enrollment is now complete.  Per the study protocol, all implanted 
patients were followed for 12-months post procedure.   
 
Of the 43 subjects enrolled in the trial, seven (7) subjects did not meet the study 
eligibility criteria.  Of the 36 subjects who underwent a procedure to implant the 
CARILLON device, 30 ultimately received the CARILLON device.  Six (6) subjects did 
not receive a device due to access issues or coronary artery compromise. 
 
The major adverse event rate in the intent-to-treat population at 30 days (the primary 
endpoint for the study) was 2.8%.  Although a complete analysis of the data is awaiting 
complete monitoring of all the follow-up information, the preliminary analysis of the 
mitral regurgitation (MR Grade and Regurgitant Volume) and functional parameters (six 
minute walk distance and NYHA class) shows improvements that are comparable to that 
found in the TITAN study. 
 
 
 
10. 
15. 
20. 
25. 
30. 
35. 
40. 
Baseline 
1 Month 
6 Month 
12 Month 
RV (ml) 
Regurgitant Volume 
TITAN II: Baseline n=24, 1mo n=22, 6mo n=18; 12mo n=14 
TITAN:    Baseline n=36, 1mo n=33, 6mo n=31. 12mo n=25 
0.00 
1.00 
2.00 
3.00 
4.00 
Baseline 
1 Month 
6 Month 
12 Month 
MR Grade 
MR Grade 
TITAN II: Baseline n=25, 1mo n=24, 6mo n=23; 12mo n=16 
TITAN:    Baseline n=36, 1mo n=33, 6mo n=31. 12mo n=25 
250 
300 
350 
400 
450 
500 
Baseline 
1 Month 
6 Month 
12 month 
6 MWD (m) 
6 Minute Walk Distance 
1 
2 
3 
4 
Baseline 
1 Month 
6 Month 
12 month 
NYHA Class 
NYHA 
 TITAN II
 
 TITAN  
TITAN II: 6MWD Baseline n=29, 1mo n=25, 6mo n=18; 12mo n=19                   TITAN II: NYHA Baseline n=30, 1mo n=29, 6mo n=23; 12mo n=21 
TITAN:   6MWD Baseline n=36, 1mo n=32, 6mo n=27; 12mo n=23                    TITAN:    NYHA Baseline n=36, 1mo n=32, 6mo n=29; 12mo n=25 

 
 
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2 
Device Overview 
The CARILLON Mitral Contour System (XE2) is a Class III medical device and is 
manufactured by Cardiac Dimensions, Inc., in Kirkland, Washington, USA.  The device 
received CE-Mark on 3rd August 2011.  In Australia/New Zealand, the CARILLON 
device is intended “For Clinical Trial Use Only”. 
2.1 
Device Components 
The CARILLON Mitral Contour System (XE2) consists of the following components:  
• 
An implant intended for permanent placement in the coronary sinus (CS)/great 
cardiac vein (GCV)  
• 
A delivery system which consists of a custom 9F delivery catheter and a handle 
assembly.  
 
The implant is attached to the handle assembly and is delivered through the delivery 
catheter to the coronary vein along the posterolateral aspect of the mitral annulus. 
2.1.1 
CARILLON Implant 
The CARILLON implant (XE2) is made of nitinol and titanium and is manufactured in 
different lengths and with different anchor sizes to accommodate individual venous 
anatomy.  The implant is composed of a distal anchor (positioned in the GCV), proximal 
anchor (positioned in the CS), ribbon connector (joining the anchors), proximal crimp 
tube and distal crimp tube.  The implant is designed to be deployed, tensioned, and 
locked in the coronary vein in order to reshape the mitral annulus and thus reduce mitral 
annular dilation and mitral regurgitation. 
 
 
 
Figure 2.1  CARILLON Implant (XE2) 
 

 
 
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2.1.2 
Delivery System 
2.1.2.1 Delivery Catheter 
The delivery catheter is curved at its distal end and has a 9F (3.0 mm) outer diameter 
and 70 cm effective length.  The inside diameter is 2.5 mm and will accept a 0.035” 
(0.89 mm) guidewire or a 7F (2.3 mm) outer diameter diagnostic or deflectable catheter. 
 
The delivery catheter is used to introduce a graded measuring device (e.g., marker 
catheter), to inject radiopaque contrast for venograms, to connect to the cartridge of the 
handle assembly to help deliver the implant, to engage the locking mechanism of the 
distal anchor, and to recapture the implant.  The straight port allows for advancement 
and removal of a measuring device and introduction of the implant.  The side port may 
be used for injection of radiopaque contrast medium. 
 
Figure 2.2  CARILLON 9F Delivery Catheter 
2.1.2.2 Handle Assembly 
The handle assembly is composed of a cartridge, a sheath/pusher assembly and a handle 
assembly with cartridge window, rotating knobs, and release safety. 
 
The cartridge contains the implant, which is folded in the unlocked position within the 
cartridge lumen.  During delivery, the implant is manually advanced from the cartridge 
into the delivery catheter.  The handle facilitates deployment, locking, decoupling and 
recapture of the implant.  This is accomplished by rotating knobs that enable controlled 
movements of the delivery catheter, the implant, the sheath/pusher and the decoupling 
mechanism.  The release safety must be removed prior to decoupling the implant from 
the handle assembly. 

 
 
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Figure 2.3  Handle Assembly 
2.2 
Principles of Operation 
The CARILLON implant is implanted through transvenous placement (jugular 
cannulation) under fluoroscopy following standard percutaneous cannulation/ 
catheterization procedures. 
 
After catheterization of the coronary venous system, an assessment of the size of the 
CS/GCV is made to determine the proper sizing of the CARILLON implant.  This is 
accomplished by performing a venogram to assist in measurement of vein diameter and 
length.  An angiogram is also performed to determine the location of the coronary 
arteries in relation to the CS/GCV. 
 
The CARILLON implant is comprised of distal and proximal anchors joined with a 
ribbon connector.  The design of the distal portion of the implant (described as the 
“distal anchor”) enables it to be anchored in the distal portion of the GCV.  This is 
accomplished by expanding the anchor in the vein and locking it in place with the tip of 
the delivery catheter.  The pressure applied on the vein wall by the expanded and locked 
anchor enables secure anchoring of the CARILLON implant.  The delivery catheter is 
then withdrawn proximally to expose the ribbon connector. 
 
Tension is applied manually to the delivery system, pulling the proximal portion of the 
CARILLON implant (described as the “proximal anchor”) toward the CS ostium.  
Fluoroscopy and echocardiography guide the tensioning process.  The proximal anchor 
is deployed and locked in the CS by advancing the sheath component of the delivery 
system, thus reshaping the mitral annulus.  After determining that no coronary artery 
flow is compromised (assessed by coronary angiography), that there is some reduction 

 
 
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in the mitral regurgitation characteristics (assessed by echocardiography) and ensuring 
that the proximal anchor is locked (assessed by fluoroscopic imaging), the operator may 
then decouple the handle assembly from the implant and remove the catheter. 
 
 
Figure 2.4  Deployment of the CARILLON Implant and Plication of the Mitral Valve Annulus 
 
The CARILLON Mitral Contour System is designed to enable acute recapture during 
the implantation procedure (prior to decoupling) if for any reason the implant cannot be 
successfully deployed, or for other clinical or safety reasons.  The implant is recaptured 
by advancing the sheath to the proximal anchor arrowhead.  The delivery catheter is then 
advanced over both the proximal and distal anchors by turning the control knob.  Both 
anchors will be completely recaptured into the delivery catheter 
2.3 
Indications for Use 
The CARILLON Mitral Contour System is indicated for use in patients with secondary 
(functional) mitral regurgitation.   
2.4 
Contraindications 
The CMCS is contraindicated for use in: 
• Patients with existing devices in the CS/GCV 
• Patients who have had a mitral valve replacement or a mitral annuloplasty ring 
implant 
 

 
 
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3 
Clinical Study Design 
3.1 
Study Executive Committee 
The REDUCE FMR study has an Executive Committee which provides oversight for the 
overall direction and strategy of this clinical trial. The Executive Committee will 
contribute to the design of the study, increase information exchange at an early stage of 
trial development, increase the efficiency of clinical trial collaboration and contribute to 
the publication of the study data. 
The Executive Committee consists of the following individuals: 
• 
Prof. Ian Meredith, Prof. Horst Sievert and Prof. David Kaye – overall 
REDUCE FMR Study Principal Investigators 
• 
Dr. Steve Goldberg – Medical Monitor for the REDUCE FMR study 
• 
Prof. Tomasz Siminiak and Dr. Janusz Lipiecki – site Principal Investigators  
 
3.2 
Study Objectives 
3.2.1 
Primary Endpoint 
The primary efficacy endpoint is to demonstrate a statistically significant improvement 
in regurgitant volume associated with the CARILLON device at twelve (12) months, 
relative to the Control population. 
3.2.2 
Secondary Endpoints 
The secondary objectives of the REDUCE FMR Trial are to determine the procedural 
safety of the device and the effect of the CARILLON implant on hemodynamics, subject 
function and long-term safety, further defined as follows. 
3.2.2.1 Safety  
The following secondary safety endpoints will measure the effect of the CARILLON 
Mitral Contour System on clinical safety parameters of interest, relative to the Control 
population  
• 
To document the difference in the rate of major adverse events between 
randomized groups, at 1 and 12-months post randomization.   
Major Adverse Events are defined as a composite of the following: 
• 
Death 
• 
Myocardial Infarction  
• 
Device Embolization 
• 
Vessel Erosion, requiring percutaneous or surgical intervention 
• 
Cardiac Perforation, requiring percutaneous or surgical intervention 
• 
Occurrence of cardiac surgery or percutaneous coronary intervention 
associated with device failure  

 
 
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• 
To assess the rate of heart failure hospitalizations (number of admissions, and 
total associated days in the hospital), from the time of the index procedure 
through twelve months of follow-up. 
3.2.2.2 Efficacy  
The following secondary endpoints will measure the effect of the CARILLON Mitral 
Contour System on clinical parameters of interest, relative to the Control population:  
• 
To assess the change from baseline to twelve months for six-minute walk 
distance  
• 
To assess the change from baseline to twelve months in left ventricular volumes 
(end diastolic and end systolic) 
3.2.3 
Observational Data 
The following observational data will provide additional safety, clinical and/or 
mechanistic data: 
• 
Long-term safety will be evaluated as the comparison of the following safety 
events between the Control and Treatment groups: 
– Mortality at six (6) and twelve (12) months  
– Serious adverse events at six (6) and twelve (12) months 
• 
NYHA Classification  
• 
Left ventricular hemodynamicsiv: 
– LV end diastolic (LVEDD) and end systolic (LVESD) dimensions  
– Ejection fraction (LVEF) 
– Forward cardiac output (CO) 
• 
Functional Mitral Regurgitation echocardiographic assessmentsiv:  
– Vena Contracta (VC)  
– Effective regurgitant orifice area (EROA),  
– MR Jet area / Left atrial area (MRJA/LAA)  
– MR grade 
• 
Left atrial size 
• 
Mitral annular diameter and area 
• 
Diuretic dose change between baseline and 6 / 12 month follow-up 
• 
Pulmonary Artery Systolic Pressure (echo derived at rest & during exerciseiv) 
• 
NT-BNP 
 
iv Left ventricular hemodynamics, FMR assessments and pulmonary artery pressure (echo derived) will also be 
assessed during exercise in randomized patients at a subset of study sites who have supine bicycle ergometry and 
echosonographers experienced in imaging acquisition during exercise. 
 

 
 
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• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
Quality-of-Life Assessment (SF-12) 
3.2.4 
Subject Follow Up Duration 
Subjects will be followed for 12 months from the time of randomization to meet primary 
and secondary endpoints in accordance with the follow-up periods as defined in this 
Investigational Plan and the Subject Study Calendar (reference Appendix C).   
 
3.3 
Subject Eligibility 
This study intends to enroll patients with moderate heart failure and functional mitral 
regurgitation. All evaluations assessing eligibility criteria for this study must be 
performed within 45 days prior to randomization and the index procedure, unless 
otherwise noted.   
 
All subjects will require informed consent for enrollment in this clinical study. 
 
Many of the evaluations at eligibility will have been collected as part of a subject’s 
standard chronic heart failure treatment regimen, prior to the subject being consented for 
the study.  If these tests or examinations were completed as standard of care for the 
subject, and timing of the test or exam is within 45 days prior to randomization and the 
index procedure, the results are acceptable for use as satisfying eligibility requirements. 
 
In cases when key evaluations have occurred more than 45 days prior to randomization, 
the subject must undergo new assessments for qualifying the subject for the clinical 
study.   
3.3.1 
Inclusion Criteria 
The subject must meet all of the following criteria at the time of eligibility for 
randomization and the index procedure: 
1. Diagnosis of dilated ischemic or non-ischemic cardiomyopathy  
2. Functional Mitral Regurgitation:  
2+ (Moderate), 3+ (Moderate/Severe), or 4+ (Severe)  
3. NYHA II, III, or IV (refer to Appendix D for NYHA Classification) 
4. Six Minute Walk distance of at least 150 meters and no farther than 450 meters 
5. Subject meets anatomic screening criteria as determined by angiographic screening 
at the time of the index procedure to ensure that implant can be sized and placed in 
accordance with the Instructions for Use 
6. Left Ventricular Ejection Fraction ≤ 50% 
NOTE: Subjects with LVEF of 41- 50% can only be included if baseline NYHA is 
class III/IV AND MR grade is 3+/4+ (moderately-severe/severe) 

 
 
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7. LV end diastolic dimension (LVEDD) >55mm or LVEDD/BSA > 3.0cm/m2 
8. Stable heart failure medication regimen for at least three (3) months (refer to 
Appendix G for definition of stable heart failure regimen) 
9. Age ≥ 18 years old and ≤ 85 years old 
10. The subject has read the informed consent, agrees to comply with the requirements, 
and has signed the informed consent to participate in the study 
11. Female subjects of child-bearing potential must have a negative serum HCG test 
 
3.3.2 
Exclusion Criteria  
The following must NOT be present at the time of eligibility for randomization and the 
index procedure:  
1. Hospitalization in past three (3) months due to myocardial infarction, coronary artery 
bypass graft surgery, and/or unstable angina 
2. Hospitalization in the past 30 days for coronary angioplasty or stent placement 
3. Subjects expected to require any cardiac surgery, including surgery for coronary 
artery disease (unprotected left main stenosis greater than or equal to 50% or, greater 
than or equal to 70% stenosis in at least three (3) epicardial coronary arteries in the 
absence of prior bypass surgery), or for pulmonic, aortic, or tricuspid valve disease 
within one (1) year  
4. Subjects with echocardiographic documentation of non-compaction cardiomyopathy 
with associated hypercontractility of the cardiac structures supporting the mitral 
annulus 
5. Subjects expected to require any percutaneous coronary intervention within 30 days 
of enrollment 
6. Recipient of intravenous positive-inotrope infusion or intra- aortic balloon pump 
support within the past 30 days 
7. Presence of a mechanical mitral heart valve, mitral bio-prosthetic valve or mitral 
annuloplasty ring 
8. Pre-existing device (e.g., pacing lead) in coronary sinus (CS) / great cardiac vein 
(GCV), or anticipated need for cardiac resynchronization therapy (CRT) within 
twelve (12) months 
9. Presence of a coronary artery stent under the CS / GCV in the implant target zone 
10. Significant organic mitral valve pathology (e.g., moderate or severe myxomatous 
degeneration, with or without mitral leaflet prolapse, rheumatic disease, full or 
partial chordal rupture) 
11. Presence of severe mitral annular calcification 
12. Presence of left atrial appendage (LAA) clot.   Patients with a current/ongoing 
(documented within the last 12 months) history of atrial fibrillation must undergo a 

 
 
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trans-esophageal echo prior to the procedure to rule-out left atrial appendage clot to 
minimize the risk of thrombo-embolism caused by the tissue plication 
13. Cerebral vascular event within the past three (3) months 
14. Presence of primary renal dysfunction or significantly compromised renal function 
as reflected by a serum creatinine > 2.2 mg/dL (194.5 µmol/L) OR estimated 
Glomerular Filtration Rate (eGFR) < 30 ml/min 
15. Allergy to contrast dye that cannot be pre-medicated 
16. Inability to undertake a six-minute walk test due to physical restrictions/limitations 
17. Chronic severe pathology limiting survival to less than 12-months 
18. Anticipated need of left ventricular assist device within twelve (12) months 
19. Currently participating in an investigational study that clinically interferes with the 
current study endpoints. 
3.4 
Informed Consent and Study Enrollment 
3.4.1 
Informed Consent 
To protect the rights and welfare of subjects, this clinical study will be conducted in 
conformance with ISO 14155:2011 Section 4 – Ethical Considerations.  
 
The subject will be provided with ample time to read, ask questions as needed, be 
provided with all appropriate answers, and to understand the study before making 
decision to participate in the study or not.  
 
For additional details on the Informed Consent process, please see section 7.1 – 
Informed Consent. 
3.4.2 
Enrollment and Eligibility 
Once the subject has provided their consent, the subject is enrolled in the study. 
Once the subject has completed the required baseline assessments and met all eligibility 
criteria (with the exception of the final anatomic eligibility), the subject can then be 
scheduled for angiographic/venogram to assess final eligibility prior to randomization. 
Recruitment will continue in a consecutive manner until enrollment for the study is 
complete.  In order to provide traceability for each subject enrolled in this study, unique 
study numbers will be assigned according to Cardiac Dimensions standard operating 
procedures, including study sites, study number, and a unique subject number. 
3.5 
Screening/Baseline Assessments 
The following examinations and tests will be completed according to the schedule as 
shown.  These will be completed prior to randomization and the index procedure for 

 
 
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those study subjects who continue to be eligible.  This set of examinations and tests will 
be considered the study subject’s baseline evaluations.   
3.5.1 
Not More than 45 Days Prior to Randomization 
The following evaluations must be performed within 45 days prior to the index 
procedure.  Subjects who continue to meet all of the inclusion and none of the exclusion 
criteria will be scheduled for randomization and the index procedure.  Subjects who are 
found ineligible will be categorized as screen failures. 
• 
Complete past medical history, physical exam (history to include details of original 
diagnosis and review of current and prior heart failure treatment) 
• 
Transthoracic echocardiogram (TTE) 
Note: Study sites that have experience and necessary equipment may undertake exercise 
echocardiography in addition to the standard resting echocardiographic assessment 
required by the protocol.  
• 
Functional assessments:  
– NYHA Classification (reference Appendix D: NYHA Classification) 
– Six minute walk test. To minimize any training effect, the screening and 
baseline tests must be two separate assessments at least two hours apart 
(reference Appendix F: Six Minute Walk Test Protocol) 
– Kansas City Cardiomyopathy Questionnaire (KCCQ) 
– SF-12 Quality-of-Life Assessment Questionnaire  
• 
Electrocardiogram (12-lead ECG) 
• 
Serum chemistries: sodium, potassium, chloride, glucose, BUN, creatinine, and 
NT-BNP  
• 
CBC with hemoglobin, hematocrit, platelets, and WBC  
• 
Serum pregnancy test (if subject is a female of child-bearing potential) 
• 
Other information to be recorded between eligibility and the study procedure:  
– Current medications  
– Adverse events including newly diagnosed infections, organ dysfunction, etc. 
3.5.2 
Not More than Three (3) Days Prior to Randomization 
The following safety evaluations must be performed within three (3) days prior to the 
index procedure to ensure that subjects continue to be eligible for randomization and the 
index procedure:  
• 
Vital signs: blood pressure, heart rate, respiratory rate, oxygen saturation, 
temperature, weight and height  
• 
PTT and PT 
• 
Cardiac enzymes: cardiac troponin (cTn) 

 
 
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• 
Serum creatinine  
• 
Transesophageal echocardiogram (TEE) - to rule out left atrial appendage clot  
Note: only required in subjects with existing atrial fibrillation. 
Note: if TEE is done on the day of the study procedure and an LAA clot is 
identified (subject is ineligible), no study discharge evaluations are necessary. 
These subjects are regarded as screen failures. 
3.5.3 
Study Procedure - Prior to Randomization 
3.5.3.1 Cardiac Catheterization Requirements 
All subjects brought into the catheterization lab on the day of the index procedure will 
be pre-medicated according to institutional procedures for cardiac catheterization.  
Additionally, subjects will be heparinized prior to the angiographic procedure according 
to institutional policies.  Anti-platelet therapy is not required in the trial, however, 
individual Investigators may prescribe such medications in accordance with their 
institution’s standard of care or as necessary to treat other concurrent cardiac conditions.  
The use of anti-platelet therapy will be noted on the case report forms.   
3.5.3.2 Eligibility Coronary Angiography 
Coronary angiography will be performed immediately prior to randomization to confirm 
that the subject will not require percutaneous coronary intervention within 30 days from 
the time of randomization (Exclusion Criteria #5).  At the Investigator’s discretion, if the 
subject has: 
• non-ischemic dilated cardiomyopathy - an arteriogram performed within twelve 
(12) months prior to eligibility assessment may be used to satisfy these criteria.   
• ischemic dilated cardiomyopathy - an arteriogram performed within three (3) 
months prior to eligibility assessment may be used to satisfy these criteria. 
 
If the Investigator determines that the eligibility angiography is not required on the day 
of the index procedure, the subject will minimally undergo femoral artery cannulation 
prior to randomization to obtain hemodynamic data and ensure that subject is blinded to 
the treatment assignment. 
 
If the eligibility angiography reveals the need for revascularization, or if the study 
subject does not meet all eligibility criteria, the subject is an enrolled screen failure.  
Randomization does not occur and the subject is followed through discharge only.   
3.5.3.3 Eligibility Venogram 
A coronary sinus venogram will be performed immediately prior to randomization in 
order to assess eligibility for the study (Inclusion Criteria #5).   
 

 
 
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If the study subject does not meet the final venogram eligibility criteria, the subject is an 
enrolled screen failure.  Randomization does not occur and the subject is followed 
through discharge only.   
3.5.3.4 Fully Eligible Subjects 
If the study subject meets all eligibility criteria, then the subject will be randomized.  
The test and evaluation results captured to date will become the study subject’s baseline 
measurements. 
3.6 
Randomization 
Randomization will occur in a 3:1 allocation to the Treatment (CARILLON) or Control 
group.  Randomization will be stratified according to investigational center in a 
randomized permuted blocks design.  
 
The study statistician will generate randomization schedules (independent of the 
Sponsor) and the randomization will be identified either through a web-based portal or 
by randomization envelopes provided for each center. 
3.7 
Study Procedure – Post Randomization 
3.7.1 
Index Procedure 
3.7.1.1 Sponsor Support of Procedure 
Cardiac Dimensions will provide a trained field clinical technician to support the 
investigational team during the procedure.  Cardiac Dimensions may additionally 
provide a physician proctor, as needed. 
3.7.1.2 Treatment Group 
For subjects randomized to the Treatment group, the CARILLON Mitral Contour 
System procedure will be performed.  The implant procedure is described in Appendix 
A: Instructions For Use.  
Pre-medication will be according to institutional procedures for cardiac catheterization.  
Additionally, subjects will be heparinized prior to the angiographic procedure according 
to institutional policies.  Anti-platelet therapy is not required in the REDUCE FMR 
Trial, however, individual Investigators may prescribe such medications in accordance 
with their institution’s standard of care or as necessary to treat other concurrent cardiac 
conditions.  The use of anti-platelet therapy will be noted on the case report forms.   
 
Either Transesophageal Echocardiogram (TEE) or Transthoracic Echocardiogram (TTE) 
may be used during the implant procedure to evaluate the safety and effectiveness of 
device placement.  If TEE is used during the index procedure, the assessment of the left 
atrial appendage clot exclusion criteria (required for subjects with existing atrial 

 
 
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fibrillation) may be made immediately prior to randomization and the index procedure 
(i.e., a separate TEE is not required.)   
 
All subjects randomized to the Treatment group will have coronary angiography 
performed prior to the CARILLON implant attempt.  This is in order to establish the 
baseline flow characteristics of the coronary arterial vessels in the same location (AV 
groove) as the coronary sinus/great cardiac vein. If coronary artery flow compromise is 
noted during the CARILLON implant procedure, the CARILLON device can be 
recaptured.  At the investigator and proctor’s discretion, another CARILLON device 
attempt can occur if the device can be placed in a portion of the coronary sinus/great 
cardiac vein where coronary flow is not compromised. 
 
However, if there is clinically significant coronary artery compromise, mitral stenosis, 
systolic anterior motion or other safety issues, the CARILLON implant will be 
recaptured and the procedure ended.   
 
If the patient becomes hemodynamically unstable and/or no CARILLON device implant 
is attempted, the subject will be classified as a Procedural Screen Failure in the 
Treatment group and will be followed through 1-month with a safety assessment only 
(full 1-month follow-up assessments are not necessary), then exited from the study.  
 
If CARILLON device implant attempt(s) occur but the CARILLON device is ultimately 
recaptured and no implant takes place, the subject is classified as Non-implanted in the 
Treatment group and will be followed through the 12-month primary endpoint.   
3.7.1.3 Control Group 
Since eligibility angiography (if indicated, see section 3.5.3.2 - Eligibility Coronary 
Angiography) and venography will be performed in all subjects prior to randomization, 
subjects ultimately randomized to the Control group will experience a procedure similar 
to the Treatment group to ensure that they will not be able to deduce their treatment 
assignment.  In addition to the femoral arterial (for the eligibility angiography) and 
jugular venous punctures (for the eligibility venogram), subjects will undergo 
electrocardiographic and echocardiographic examinations similar to those performed 
during the CARILLON implant procedure.  These subjects will not undergo placement 
of the CARILLON implant. 
3.7.2 
Study Subject Follow-up Categories  
SCREEN-FAILURE → Subject consented but did not meet baseline eligibility criteria 
(including TEE, if applicable). No study discharge evaluations are necessary.  
ENROLLED SCREEN-FAILURE → Subject consented, met all baseline eligibility 
criteria, but did not meet final angiographic eligibility. Implant was not attempted.  
Limited study discharge evaluations are necessary, but no follow-up visits are required. 
PROCEDURAL SCREEN-FAILURE → Randomized to treatment group, but 
procedure discontinued before an implant attempt.  Full study discharge evaluations are 
required and the subject is followed through 1-month. 

 
 
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NON-IMPLANTED → Randomized to treatment group, implant attempted, but not 
successful.  Full study discharge evaluations are required and the subject is followed 
through 12-months. 
IMPLANTED → Randomized to treatment group, device successfully implanted. Full 
study discharge evaluations are required and the subject is followed through 12-months. 
CONTROL → Randomized to control group, implant not attempted.  Full study 
discharge evaluations are required and the subject is followed through 12-months. 
3.7.3 
Discharge Evaluations 
3.7.3.1 Randomized Subjects  
Immediately following the index procedure, all randomized subjects will be observed 
overnight for complications related to the final eligibility assessments and/or procedure.  
This includes Procedural Screen Failures, Treatment subjects (non-implanted and 
implanted) and Control subjects.  
 
Prior to hospital discharge, the following assessments will be performed: 
• 
Physical examination 
• 
Vital signs 
• 
Abbreviated Echocardiogram (TTE) safety assessment  
• 
Chest X-ray (PA and lateral) or cine fluoroscopy (for assessment of pulmonary 
congestion and assessment of implant integrity in implanted subjects) 
• 
ECG (12-lead) 
• 
Serum creatinine 
• 
NT-BNP 
• 
Cardiac enzymes: cardiac troponin (cTn) 
Cardiac enzymes will be monitored 6-8 hours post procedure (or the following 
morning if procedure time was late in the day).  If a clinically significant elevation 
in cardiac enzymes is noted then a repeat measurement should be undertaken for 
confirmation. 
• 
CBC with differential, includes hemoglobin, hematocrit, platelets, and WBC  
• 
Clinical assessments by the physician and other information to be evaluated and 
recorded as they occur including:   
– Concomitant medications 
– Adverse events 
If the index procedure was discontinued before a CARILLON implant was attempted in 
a Treatment group subject, they are considered a Procedural Screen Failure and are 
followed through discharge and 1-month (safety assessment only), then exited from the 
study. 

 
 
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3.7.3.2 Enrolled Screen Failures 
The following safety evaluations will be performed prior to discharge for subjects who 
were brought into the catheterization lab but do not meet final eligibility criteria or for 
any other reason device implant is not attempted:  
• 
Vital signs 
• 
ECG (12-lead) 
• 
Serum creatinine 
• 
Cardiac enzymes: cardiac troponin (cTn) 
Enrolled screen failure subjects are followed through discharge and then exited from 
the study. 
3.8 
Study Follow-up Evaluations  
Randomized subjects (Treatment and Control groups) will be required to complete all 
scheduled follow-up visits as outlined below:   
• 
1, 6 and 12 months 
Subjects randomized to the Control group may be offered the CARILLON device once 
they have completed the 1-year protocol defined follow-up period (reference Section 
3.8.7: Cross-Over Registry). 
 
Reference Appendix E: Echocardiogram Protocol and Appendix F: Six Minute Walk 
Test for all study follow-up visits.  
3.8.1 
Follow-Up Schedule – One (1) Month 
One (1) month (30 days  seven (7) days) after the index procedure, the study subject 
will return to the study site for follow-up evaluations.  The evaluations at this visit will 
include: 
• 
Physical examination 
• 
Vital signs 
• 
Echocardiogram (TTE) 
Note: Study sites that have experience and necessary equipment may undertake 
exercise echocardiography in addition to the standard echocardiographic 
assessment required by the protocol.  
• 
ECG (12-lead)  
• 
Serum chemistries: sodium, potassium, chloride, glucose, BUN, creatinine, and 
NT-BNP  
• 
Cardiac enzymes: cardiac troponin (cTn) 
• 
CBC with differential, includes hemoglobin, hematocrit, platelets, and WBC  
• 
Quality of Life questionnaires:  

 
 
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– KCCQ 
– SF-12 
• 
NYHA Classification assessment 
• 
Functional assessment: 
– Six minute walk test 
• 
Clinical assessments by the physician and other information to be evaluated and 
recorded as they occur including:   
– Concomitant medications 
– Adverse events 
 
If the index procedure was discontinued before a CARILLON implant was attempted in 
a Treatment group subject, they are considered a Procedural Screen Failure and are 
followed through 1-month, then exited from the study. 
3.8.2 
Follow-up Schedule – Six (6) Months 
Six (6) months (180 days  14 days) after the index procedure, the study subject will 
return to the study site for follow-up evaluations.  The evaluations at this visit will 
include: 
• 
Physical examination  
• 
Vital signs 
• 
Echocardiogram (TTE)  
Note: Study sites that have experience and necessary equipment may undertake 
exercise echocardiography in addition to the standard echocardiographic 
assessment required by the protocol.  
• 
Chest X-ray (PA and lateral) or cine fluoroscopy (with device integrity 
assessment for implanted subjects) 
• 
ECG (12-lead)  
• 
Serum chemistries: sodium, potassium, chloride, glucose, BUN, creatinine, and 
NT-BNP 
• 
CBC with differential, includes hemoglobin, hematocrit, platelets, and WBC  
• 
Quality of Life questionnaires:  
– KCCQ 
– SF-12 
• 
NYHA Classification assessment 
• 
Functional assessment: 
– Six minute walk test 
• 
Clinical assessments by the physician and other information to be evaluated and 
recorded as they occur including:   

 
 
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– Concomitant medications 
– Adverse events 
3.8.3 
Follow-Up Schedule – Twelve (12) Months 
Twelve (12) months (365 days  30 days) after the index procedure, the study subject 
will return to the study site for follow-up evaluations.  The evaluations at this visit will 
include: 
• 
Physical examination  
• 
Vital signs 
• 
Echocardiogram (TTE)  
Note: Study sites that have experience and necessary equipment may undertake 
exercise echocardiography in addition to the standard echocardiographic 
assessment required by the protocol.  
• 
Chest X-ray (PA and lateral) or cine fluoroscopy (with device integrity 
assessment for implanted subjects) 
• 
ECG (12-lead) 
• 
Serum chemistries: sodium, potassium, chloride, glucose, BUN, creatinine, and 
NT-BNP 
• 
CBC with differential, includes hemoglobin, hematocrit, platelets, and WBC  
• 
Quality of Life questionnaires: 
– KCCQ 
– SF-12 
• 
NYHA Classification assessment 
• 
Functional assessment: 
– Six minute walk test 
• 
Clinical assessments by the physician and other information to be evaluated and 
recorded as they occur including:   
– Concomitant medications 
– Adverse events 
3.8.4 
Unscheduled Follow-Up Procedures and Data Requirements 
In some circumstances, Investigators may need to see a subject in advance of the normal 
study schedule or a subject may return to the investigational site to report new or 
unresolved signs or symptoms.  Such visits will be documented as unscheduled follow-
up visits.  No specific study evaluations are required to be performed at unscheduled 
visits, but adverse events will be documented and reported. 

 
 
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3.8.5 
Study Exit 
Upon completing the protocol defined follow-up, the subject will be exited from the 
study. Upon study completion, the study investigator should contact the patient’s heart 
failure doctor to discuss their involvement in this study and ongoing medical treatment. 
3.8.6 
Subject Withdrawal 
3.8.6.1 When and How to Withdraw Subjects 
A subject may be withdrawn early from the study prior to study completion for several 
reasons, including but not limited to: 
• 
Loss to follow-up 
• 
Subject consent withdrawal  
• 
Heart transplantation or other confounding intervention 
• 
Physician discretion (for patient health reasons) 
 
If a subject is withdrawn early from the study for any reason, the Cardiac Dimensions 
clinical study monitor must be notified by telephone, facsimile or e-mail.  The 
Investigator or designee must document the reason for the termination of enrollment and 
advise Cardiac Dimension of situations that are not resolved.  
A subject should not be considered lost to follow-up until three or more attempts have 
been made to contact the subject and all attempts have failed.  One of these attempts 
should be a letter sent using certified mail with signature confirmation.   
If a subject is withdrawn from the study early, the study investigator should contact the 
patient’s heart failure doctor to discuss their involvement in this study and the ongoing 
medical treatment plan for the subject. 
3.8.6.2 Procedures for Reporting Subjects Missing Follow-Up 
As soon as it has been determined that a subject has missed a scheduled follow-up 
examination, the Cardiac Dimensions clinical study monitor must be notified by 
telephone, e-mail, or facsimile.  The study coordinator should attempt to contact the 
subject at least three times after each missed visit and one of these attempts should be by 
certified mail with signature confirmation.  The subject should not be considered lost-to-
follow-up until all attempts to contact the subject have failed. 
3.8.6.3 Data Collection and Follow-up for Withdrawn Subjects 
If a subject withdraws consent to participate in the study, attempts should be made to 
obtain permission to record survival data through the 1-year follow-up period.  
3.8.7 
Cross-Over Registry 
Study subjects randomized to the Control group will be offered the option of receiving 
the investigational device after completing their 1-year follow-up if they continue to 
meet all of the study eligibility criteria. 

 
 
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Cross-Over registry subjects will be followed at discharge and for 30-days post the 
CARILLON procedure.  The discharge and 30-day-up assessments will be identical to 
those collected in the randomized portion of the trial (see Sections 3.7.3.1 and 0). On 
completion of the 30-day follow-up the Cross-Over registry subjects will be exited from 
the study. 

 
 
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4 
Blinding 
4.1 
Double-Blind Study 
This will be a double-blind study in order to reduce the effect of bias and potential 
placebo effect on specific primary and/or secondary endpoint assessments.  A double-
blind is a type of masking in which two or more parties involved with the clinical trial 
do not know which participants have been assigned which interventions. All study 
subjects and any study personnel responsible for primary efficacy and/or select 
secondary endpoint assessments (reference section 4.1.1) will be blinded as to whether 
subjects are in the Treatment group or the Control group.  Blinding will be maintained 
through the 12 month follow-up.  All study personnel will be trained to follow study 
blinding procedures to ensure maintenance of the study blind.  Subjects will be 
continually reminded that adhering to the blinding procedures is a critical part of their 
involvement in the study. 
4.1.1 
Blinded Assessments 
The following study-related assessments require the assessor to be blinded to the 
treatment assignment: 
• 
Six minute walk test (6MWT) 
– 6MWT administrator 
• 
All echocardiographic mitral regurgitation and LV hemodynamic parameters 
– Echo corelab assessor  
• 
New York Heart Association (NYHA) classification  
– NYHA assessor  
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
– KCCQ administrator 
• 
SF-12 QoL Questionnaire (SF-12) 
– SF-12 administrator 
4.1.2 
Subject Training 
Study subjects will initially learn about the blinding procedures and the importance of 
maintaining the blind during the informed consent process.  Subjects will be reminded at 
each follow-up visit that blinding is an essential part of their involvement in the study to 
maintain the scientific integrity and value of their participation. 
 
Since subjects may visit non-study related physicians during the course of their 
participation in this study e.g., for emergency or standard care, each subject will be 
given a study participant card with instructions to present the card to healthcare 
providers at any non-study related visit.  The subject participant card will alert non-study 

 
 
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medical personnel that the subject is in a blinded clinical study and request that they 
maintain the study blind whenever possible. 
 
The study subject will be questioned at every follow-up to ask if they have become 
unblinded, and if so, the reason associated with becoming unblinded.  The study site 
personnel will remind the patient that even if they know their group assignment, it is 
imperative that they do not reveal this to any of the study assessors.  
4.1.3 
Site Personnel Training 
Detailed training specific to each study position will be provided to study site personnel 
to ensure that the blinding procedure is fully understood (reference Section 4.2: Blinding 
Procedures).   
4.1.4 
Randomization 
After all pre-randomization assessments have been completed, each subject will be 
assigned sequentially to one of the two study groups (Treatment or Control), by means 
of a computer-generated random number scheme created by the Sponsor (reference 
Section 3.6: Randomization).  The study coordinator and limited study personnel (e.g., 
implanting physician) will also have knowledge of the treatment assignment.  
4.2 
Blinding Procedures 
4.2.1 
Index Procedure through Discharge 
All subjects will experience similar procedures to ensure that they will not be able to 
deduce the treatment assignment based on the type of intervention or time associated 
with the index procedure.  If general anesthesia is not used, subjects will wear earbuds 
while in the catheterization lab to ensure that they cannot hear study personnel 
discussing randomization or the procedure, and their vision masked (either with a 
blindfold or with sterile drapes appropriately positioned) so as to ensure they are unable 
to see any of the catheterization lab monitors. 
 
Catheterization lab personnel will be trained to the importance of maintaining the study 
blind and to ensure that study subjects are treated similarly during and after the 
procedure.  Recovery room and floor nursing staff will receive training on continued 
maintenance of the study blind during the recovery period. 
4.2.2 
Study Follow-Up Visits 
Rigorous efforts on the part of the subjects, implanting physicians, heart failure 
physicians, and supportive personnel will be implemented to ensure that endpoint 
assessors remain blinded through the 12-month follow-up. 
4.2.2.1 Echocardiographic Assessments  
The site echosonographer will conduct intra-procedure echocardiographic assessments 
and cannot be blinded to the subject’s treatment assignment.  In order to ensure that 

 
 
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study subjects remain blinded during scheduled follow-up echocardiograms, 
sonographers at each participating site will be instructed on preserving blinding prior to 
study start.  Specific blinding procedures which will be followed by site sonographers, 
include: 
• 
Keeping the echo screen faced away from the subject during the procedure 
• 
Not discussing any details of the echo results with a study subject 
• 
Not discussing the treatment assignment of a study subject, especially with the 
blinded study personnel or any non-study hospital staff 
 
All baseline and follow-up echocardiographic analysis will be performed by an 
independent echocardiography corelab.  A designated member of the corelab staff will 
remove all subject identifying information (including the date and visit interval) and 
digitally mask the coronary sinus/great cardiac vein (location of device).  This will be 
done for all views required to assess the echocardiographic endpoints related to mitral 
regurgitation and left ventricular hemodynamics. This will ensure that the designated 
corelab assessor will always remain blinded.   
 
For those parameters that are unavoidably affected by digital masking (e.g., mitral 
annular dimensions), an unblinded assessor will be used to gather the most accurate 
information without hindrance of the digital masking.   
 
Echocardiographic analysis will be done in batches, with multiple subjects (Treatment 
and Control) at different visit intervals analyzed within the same batch, at the same time, 
for both consistency and blinding purposes.  (Reference Appendix E: Echocardiogram 
Protocol.) 
4.2.2.2 Functional and QOL Assessments 
The assessors/administrators of the NYHA classification, six minute walk test and QoL 
questionnaires (KCCQ and SF12) will not be aware of the subject’s group assignment.  
Other study personnel will be trained to ensure that these assessors are not included in 
study communications to ensure that they remain blinded. 
 
If a functional assessor/administrator becomes unblinded, a back-up functional assessor 
is to be used for all future assessments for that subject.  Likewise, if a study subject 
becomes unblinded, steps will be taken to ensure the continued blinding of the assessors.   
4.3 
Unblinding 
The treatment assignment for a subject will be unblinded only in the following 
circumstances: 
1) In the event of medical emergency where it is medically necessary to know if 
the subject received an implant. 
2) After a randomized study subject has completed their 12-month visit, the 
treatment assignment for that subject can be unblinded.   

 
 
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The DSMB and/or CEC, upon request, may be provided with the randomization 
assignment of a particular subject(s) or to assess safety trends between study groups. 
This can be provided by the study statistician and does not require unblinding of critical 
site and study personnel. 

 
 
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5 
Adverse Events and Risk Analysis  
5.1 
Adverse Events  
The primary measures of safety are based on reported adverse events.  Adverse events 
shall be assessed and documented from the time of consent and through the last study 
follow-up visit.  An underlying disease that was present at the time of enrollment is not 
reported as an adverse event (AE), but any increase in the severity of the underlying 
disease during the course of the study shall be reported as an AE. The Investigator shall 
provide source documentation as requested by the Sponsor, DSMB, and CEC to 
facilitate adjudication of the adverse event.  
5.1.1 
Adverse Event Definitions 
5.1.1.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory findings) in subjects, 
users or other persons, whether or not related to the investigational medical device.  
Notes: 
1. This definition includes events related to the investigational medical device or the 
comparator. 
2. This definition includes events related to the procedures involved. 
3. For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
5.1.1.2 Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors, and inadequate labeling 
5.1.1.3 Malfunction 
Failure of an investigational medical device to perform in accordance with its intended 
purpose when used in accordance with the instructions for use or CIP.  
5.1.1.4 Use Error 
Act or omission of an act that results in a different medical device response than 
intended by the manufacturer or expected by the user. 
Notes: 
1. Use error includes slips, lapses, and mistakes. 
2. An unexpected physiological response of the subject does not in itself constitute a 
use error. 

 
 
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5.1.1.5 Serious Adverse Event  
An adverse event is considered serious if it: 
a) results in death,  
b) led to serious deterioration in the health of the subject, that either resulted in 
1. 
a life-threatening illness or injury, or 
2. 
a permanent impairment of a body structure or a body function, or 
3. 
in-patient or prolonged hospitalization, or 
4. 
medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by 
the CIP, without serious deterioration in health, is not considered a serious adverse 
event. 
5.1.1.6 Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
Notes:  
1. This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any 
malfunction of the investigational medical device. 
2. This definition includes any event resulting from use error or from intentional 
misuse of the investigational medical device. 
5.1.1.7 Serious Adverse Device Effect (SADE) 
An adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
5.1.1.8 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not 
been identified in the current study documentation. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its 
nature, incidence, severity or outcome has been identified in the risk analysis report.  
5.1.1.9 Anticipated Adverse Events  
Table 5.1 below provides the list of anticipated adverse events for this study.  
Anticipated adverse events are those that are expected to occur in this trial because they 
are associated with: 
• 
The CARILLON Mitral Contour System device or procedure 
• 
Invasive or stress-inducing tests (cardiac catheterization, transesophageal 
echocardiography, exercise) 
• 
A heart failure population over time  
 
Reference Section 9.2: Definitions of Terms for the specific definitions of these adverse 
events. 

 
 
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Table 5.1  Adverse Event Listing 
Anticipated Adverse Events  
Angina pectoris (stable or unstable) 
Hypotension / Hypertension  
Allergic reaction 
Infection, generalized 
Aneurysm (pseudoaneurysm) 
Infection / Inflammatory response at the 
catheter insertion sites requiring treatment 
Anuria 
Leukopenia 
Aortic Stenosis 
Mitral Stenosis 
Arrhythmias 
Mitral valve injury 
Arterio-venous fistula  
Myocardial Infarction 
Asthenia 
Myocardial Ischemia 
Bleeding  
Nausea / Vomiting 
Cardiac tamponade 
Pain 
Carotid artery trauma 
Perforation (arterial, venous or cardiac)   
Chronic nerve damage 
Pericardial effusion 
Coagulopathy 
Pericarditis 
Deep vein thrombosis 
Peripheral ischemia 
Dental injury 
Pharyngeal and/or laryngeal trauma 
Denudation (arterial or venous) 
Physical injury 
Depression  
Pneumonia 
Device embolization 
Pneumothorax  
Device malfunction or failure  
Radiation dermatitis 
Dissection (arterial or venous) 
Renal failure  
Dyspnea 
Renal insufficiency 
Electromechanical dissociation /  
Pulseless electrical activity 
Respiratory distress 
Embolism (air, tissue, or thrombus)  
Septicemia / Sepsis 
Endocarditis 
Stroke  
Esophageal Injury 
Transient ischemic attack 
Fatigue 
Urinary tract infection 
Headache 
Vasovagal reaction 
Heart failure 
Vessel erosion 
Heart failure hospitalization 
Vessel occlusion (arterial or venous) 
Hematoma  
Vessel spasm or stenosis (arterial or venous)  
Hemolysis 
 
 
5.1.2 
Recording Adverse Events 
All adverse events and device deficiencies occurring during the study, up to and 
including the study subject’s final scheduled visit that are observed by study personnel 
or reported by the subject will be recorded on the appropriate CRFs, whether or not the 
event is considered related to the device and/or the index procedure. Reporting will 
include the event name, onset and resolution date, severity, and assessment of 
relatedness to placement and use of the CARILLON Mitral Contour System or other 
suspected cause.  Adequate documentation must be supplied with all case reports forms 
to determine if the adverse event is related to the device or the index procedure.   

 
 
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5.1.3 
Description of AE Severity 
Mild: awareness of a sign or symptom that does not interfere with the patient’s usual 
activity or is transient, resolved without treatment and with no sequelae. 
Moderate: interferes with the patient’s usual activity and/or requires symptomatic 
treatment 
Severe: symptom(s) causing severe discomfort and significant impact on the patient’s 
usual activity and requires treatment. 
5.1.4 
Description of AE Causal Relationship 
The causal relationship should be rated as follows: 
No = Unrelated: the event is definitely not associated with the investigational device use 
or procedures 
Possible = the temporal sequence between the investigational device use or procedures 
and the event is such that the relationship is likely or patient’s condition or concomitant 
therapy could have caused the AE 
Yes = Definite: the temporal sequence is relevant and the event abates upon 
investigational device use or procedures completion/removal (dechallenge) or 
reappearance of the event on repeated device use or procedure (rechallenge). 
5.1.5 
Reporting SAEs 
All serious adverse events and device deficiencies that could have led to a serious 
adverse device effect (SADE) a) if either suitable action had not been taken, b) if 
intervention had not been made, or c) if circumstances had been less fortunate must be 
reported to the study monitor or Cardiac Dimensions within 24 hours of the 
investigator’s first knowledge of the event.  The Investigator must forward information 
about the event promptly and complete the SAE report form provided by the Sponsor, 
even if the information is incomplete or it is obvious that more data will be needed to 
form any conclusions.  
 
Additional information regarding the event may be recorded on a follow-up SAE report 
form and forwarded to the sponsor/monitor.  Site personnel will submit follow-up 
information and the complete event forms to Cardiac Dimensions as the event continues 
and/or resolves.  
 
It is the responsibility of each Investigator to report all Serious Adverse Events and/or 
Serious Adverse Device Effects to the Ethics Committee. According to national 
regulations and Ethics Committee requirements, this reporting requirement can be under 
the sponsor’s responsibility. Upon review of SAE CRFs, Cardiac Dimensions may 
require the site to provide additional information and source documentation as soon as 
possible, including, physician notes, lab reports, discharge summaries, other appropriate 
hospital/ patient records, etc.  Source documentation must be supplied as requested by 
the Sponsor to allow adequate evaluation of the event and its relationship to the study 
device and procedure.   
 

 
 
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The sponsor will report all reportable Events to the National Competent Authority in 
accordance with Medical Devices directives and all applicable official guidelines and 
national regulations.  
5.1.6 
Vigilance reporting (EU sites) 
At EU sites, vigilance requirements should apply and the site will have to report incidents 
and complaints to the manufacturer as per their institution’s normal procedure.  
5.1.7 
Data Safety Monitoring Board  
In this study, intense and continuous monitoring will occur. A Data Safety Monitoring 
Board (DSMB), independent of the Sponsor and Investigators, will be convened to 
assess the progress of the clinical study, including safety data adverse events 
adjudication and the critical study and subject endpoints at intervals, and to recommend 
to the Sponsor whether to continue, modify or stop the study. 
 
The DSMB will consist of at least three (3) independent medical professionals who are 
experts in the fields of cardiology, interventional cardiology, heart failure, or 
biostatistics, and who are not Investigators.  
5.1.8 
Clinical Events Committee 
A Clinical Events Committee (CEC) will be responsible for adjudicating MAEs, and 
device (incl. USADEs) and procedural adverse events.  The CEC members will be 
independent medical professionals with expertise in the fields of cardiology, 
interventional cardiology (including cardiac surgery), or heart failure and without 
conflict of interest.  The CEC will adjudicate to determine if the event is: 
• 
considered a major adverse event 
• 
related to the device (implant and/or catheter) 
• 
related to the procedure 
• 
an anticipated or unanticipated adverse event. 
 
In addition, the CEC will adjudicate events resulting in death to determine whether the 
death is considered cardiac, non-cardiac, or operative mortality.  Members will be 
provided event data from the clinical study without site or Investigator identification. 
5.2 
Risk Analysis 
Cardiac Dimensions has conducted an analysis of the benefits and risks of the 
CARILLON Mitral Contour System procedure and the study design for the REDUCE 
FMR Trial. 
5.2.1 
Benefits 
The major benefit of percutaneous treatment with the CARILLON Mitral Contour 
System is a potential reduction in mitral regurgitation through a minimally invasive 

 
 
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treatment method, where no current minimally invasive treatment option exists for these 
subjects.  The major potential benefits include: 
• 
Clinical reduction in mitral regurgitation with a non-surgical treatment method 
• 
Improvements in overall function including potential reduction of symptoms 
associated with dilated cardiomyopathy/mitral regurgitation. 
5.2.2 
Risks 
Risks associated with the CARILLON Mitral Contour System include those risks 
associated with routine coronary angiography as well as those risks predominantly 
associated with the delivery and permanent placement of the CARILLON implant.  
These risks are provided in the CARILLON Mitral Contour System Instructions for Use 
(reference Appendix A). 
5.2.3 
Efforts for Risk Minimization 
Efforts to minimize risk include the following: 
• 
Clearly defining the subject inclusion/exclusion criteria 
• 
Selecting only qualified, experienced Investigators who have participated in an 
extensive training program to assure thorough knowledge of the Investigational 
Plan and proper technique for implantation of the CARILLON implant 
• 
Monitoring angiographic, electrocardiographic and hemodynamic parameters 
during placement of the implant to evaluate for compromised coronary flow and 
preclude clinically significant coronary artery compression 
• 
Attending to coronary venous access technique to minimize the trauma to 
vascular structures 
• 
Ensuring that treatment and follow-up of subjects is consistent with standard and 
current medical practice 
• 
Providing proctor and/or field clinical technician to offer device related guidance 
during the implant procedure 
 
If the Investigator and/or the Medical Monitor determine that an adverse event is 
sufficiently severe to remove the subject from the study, a termination assessment will 
be performed. The subject will then be given appropriate treatment under medical 
supervision. 
5.2.4 
Conclusion 
Cardiac Dimensions, its Chief Medical Officer, and the Investigators have determined 
that this research study is justified because the overall potential benefit to the population 
outweighs its attendant risks.  

 
 
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6 
Statistical Plan 
6.1 
Study Populations 
This is a randomized parallel-group, double-blind, multi-center trial to evaluate the 
safety and efficacy of the CARILLON Mitral Contour System in treating functional 
mitral regurgitation (FMR) associated with heart failure.  Following successful 
completion of the cardiac catheterization screening procedures, subjects will be 
randomized in a 3 : 1 allocation to Treatment or Control.  All assessors conducting 
endpoint assessments will be blinded to randomization assignment.   
6.2 
Study Analyses 
The primary analyses will be conducted according to the principles of intent-to-treat.  
All subjects will be analyzed according to randomized group assignment, and subjects 
randomized to the Treatment group but who do not receive a permanent implant will be 
included.  If any subject does not have endpoint data available (12-month data), the 
primary analysis will assume that data as missing and that subject’s data will not be 
included in the primary analysis.   
 
In addition, a series of supportive, sensitivity analyses will be performed to assess the 
robustness of the primary analysis results, including imputing the last value observed 
(last value carried forward) for all missing endpoint evaluations.   
 
Additional subgroup analyses will be conducted for all primary and secondary endpoints 
on as-treated and per-protocol cohorts defined as:   
• 
As-treated: All subjects who left clinic with the randomized therapy 
administered (i.e., randomized to Treatment group and received a permanent 
implant, or randomized to Control group)   
• 
Per-protocol: All subjects who received randomized therapy, assessors 
remained blinded, and who did not receive alternative or confounding therapies 
(e.g., CRT therapy, transplant, stenting, etc.) through the primary endpoint 
timeframe of the study 
 

 
 
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6.3 
Study Objectives 
6.3.1 
Primary Endpoint 
The primary efficacy endpoint is to demonstrate a statistically significant improvement 
in regurgitant volume associated with the CARILLON device at twelve (12) months, 
relative to the Control population. 
6.3.2 
Secondary Endpoints 
The secondary endpoints of the REDUCE FMR Trial are to determine the procedural 
safety of the device and the effect of the CARILLON implant on hemodynamics, subject 
function and long-term safety, further defined as follows. 
6.3.2.1 Safety  
The following secondary safety endpoints will measure the effect of the CARILLON 
Mitral Contour System on clinical safety parameters of interest, relative to the Control 
population  
• 
To document the difference in the rate of major adverse events between 
randomized groups, at 1 and 12-months post randomization.   
Major Adverse Events are defined as a composite of the following: 
– Death 
– Myocardial Infarction  
– Device Embolization 
– Vessel Erosion, requiring percutaneous or surgical intervention 
– Cardiac Perforation, requiring percutaneous or surgical intervention 
– Occurrence of cardiac surgery or percutaneous coronary intervention 
associated with device failure  
• 
To assess the rate of heart failure hospitalizations (number of admissions, and 
total associated days in the hospital), from the time of the index procedure 
through twelve months of follow-up 
6.3.2.2 Efficacy  
The following secondary endpoints will measure the effect of the CARILLON Mitral 
Contour System on clinical parameters of interest, relative to the Control population:  
• 
To assess the change from baseline to twelve months for six-minute walk 
distance  
• 
To assess the change from baseline to twelve months in left ventricular volumes 
(end diastolic and end systolic) 

 
 
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6.3.3 
Observational Data 
The following observational data will provide additional safety, clinical and/or 
mechanistic data: 
• 
Long-term safety will be evaluated as the comparison of the following safety 
events between the Control and Treatment groups: 
– Mortality at six (6) and twelve (12) months  
– Serious adverse events at six (6) and twelve (12) months 
• 
NYHA Classification  
• 
Left ventricular hemodynamicsv: 
– LV end diastolic (LVEDD) and end systolic (LVESD) dimensions  
– Ejection fraction (LVEF) 
– Forward cardiac output (CO) 
• 
Functional Mitral Regurgitation echocardiographic assessmentsv:  
– Vena Contracta (VC)  
– Effective regurgitant orifice area (EROA),  
– MR Jet area / Left atrial area (MRJA/LAA)  
– MR grade 
• 
Left atrial size 
• 
Mitral annular diameter and area 
• 
Diuretic dose change between baseline and 6 / 12 month follow-up 
• 
Pulmonary Artery Systolic Pressure (echo derived at rest & during exercisev) 
• 
NT-BNP 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
Quality-of-Life Assessment (SF-12) 
6.4 
Randomization 
Randomization will occur in a 3:1 allocation to the Treatment or Control group.  
Randomization will be stratified according to investigational center in a randomized 
permuted blocks design.  
 
The study statistician will generate randomization schedules (independent of the 
Sponsor) and the randomization will be identified either through a web-based portal or 
by randomization envelopes provided for each center. 
 
v Left ventricular hemodynamics, FMR assessments and pulmonary artery pressure (echo derived) will also be 
assessed during exercise in randomized patients at a subset of study sites who have supine bicycle ergometry and 
echosonographers experienced in imaging acquisition during exercise. 
 

 
 
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6.5 
Unblinding 
The treatment assignment for a subject will be unblinded only in the following 
circumstances: 
1) In the event of medical emergency where it is medically necessary to know if the 
subject received an implant. 
2) After a randomized study subject has completed their 12-month visit, the treatment 
assignment for that subject can be unblinded. 
 
The DSMB and/or CEC, upon request, may be provided with the randomization 
assignment of a particular subject(s) or to assess safety trends between study groups. 
This can be provided by the study statistician and does not require unblinding of critical 
site and study personnel. 
 
6.6 
Primary Endpoint Evaluation & Sample Size 
Assumptions 
The primary endpoint of the study is to demonstrate a significantly greater improvement 
from baseline in Regurgitant Volume (assessed by echo corelab) associated with the 
CARILLON Mitral Contour System at 12-months, relative to the Control group.  
 
Parameter of Interest 
The parameter of interest for each treatment group is the mean change from baseline in 
regurgitant volume, in milliliters, at 12-months. 
 
Hypotheses 
H0: µCARILLON = µCTL  
Ha: µCARILLON ≠ µCTL, 
where µCARILLON is the mean change in regurgitant volume for those randomized to the 
Treatment group, and µCTL is the mean change in regurgitant volume for those 
randomized to the Control group. 
 
Sample Size Estimation 
Sample size is calculated using a comparison of means (Student’s t test).  The minimum 
required sample size was calculated under the following assumptions: 
• 
Significance level two-sided 0.05 
• 
Statistical power to detect design alternative hypothesis is 80% 
• 
Hypothesized mean regurgitant volume change (baseline to 12-month) in the 
Control group = -2.4 ml 
• 
Hypothesized mean regurgitant volume change (baseline to 12-month) in the 
Treatment group = -12.4 ml 
• 
Hypothesized standard deviation:  

 
 
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▪ Treatment group = 13 ml,  
▪ Control group = 13 ml 
• 
3:1 randomization allocation 
 
Under the assumptions outlined above, the estimated minimum required sample size is 
76 subjects (57 Treatment, 19 Control). 
 
Justification for Sample Size Assumptions  
Assumptions for sample size calculations are derived from a two previous studies of 
subjects implanted with the CARILLON Mitral Contour System in a similar patient 
population – the TITAN and TITAN II studies.  The hypothesized mean change 
(baseline to 12 months) for the Control group is conservatively assumed to be 
approximately -2.4 ml.  The hypothesized mean change for the Treatment group, and the 
standard deviations for both groups, is expected to be similar to that observed in the 
TITAN and TITAN II study cohorts 12 months after implantation.  In these studies, the 
observed change in regurgitant volume at 12 months was -14.1 ml.  The observed mean 
difference between the populations is adjusted to account for as many as 15% of the 
Treatment group subjects not receiving a permanent implant (Non-Implanted Treatment 
group patients) but still counted in the intent to treat analysis, thus yielding regurgitant 
volume results similar to the Control group, without compromising the power of the 
study. This study assumes a -10 ml mean difference in regurgitant volume between the 
study populations. 
 
The clinical relevance of this magnitude of a difference is supported by other trials 
evaluating the clinical impact of functional mitral regurgitation.  For example, Amigoni 
showed in the VALIANT trial database that a 1% increase in FMR was associated with 
an increased risk of heart failure hospitalization, and an increased risk of death or heart 
failure hospitalization.32  Extending the clinical significance to mortality, Grigioni 
showed in a group of patients with Q-wave MI that those patients with a regurgitant 
volume >30 ml demonstrated higher mortality than those regurgitant volume <30 ml 
(RR 1.13 per 10 ml RVol increase).33  In CRT candidate patients with at least mild MR 
and an average LVEF 25 ±7%, Madaric showed that CRT decreased the regurgitant 
volume from 36 ±19 ml to 25 ±11 ml, but he also showed that even an increase in 
regurgitant volume from 25 ±11 ml at rest to 29 ±12 ml with exercise was statistically 
significant to p<0.001.34  Lastly, Bursi noted in their study of heart failure after 
myocardial infarction that patients with MR had worse outcomes, which exhibited a 
graded ‘dose-response’ relationship with the severity of MR, a pattern that supports 
causality.35  These data taken together suggest that a small change in FMR (e.g., 1%) can 
be clinically significant, and the 10 ml difference between populations proposed in this 
study is similar to the magnitude of change seen in other trials, and is clinically relevant. 
 
Data Analysis 
The mean improvement in regurgitant volume for each treatment group, from baseline to 
twelve months, will be compared in a two-sided, two-sample t-test.  The 95% 
confidence interval on the between-group difference will also be calculated and 
presented.  If assumptions of normality are violated, the nonparametric Mann-Whitney 
test will be used to assess statistical significance, and the 95% confidence interval on the 

 
 
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difference between groups will be calculated using the Hodges-Lehmann estimate and 
distribution-free confidence interval based on a Wilcoxon Rank Sum test.  The primary 
analysis will be conducted on the intent-to-treat population, and supportive analyses will 
be performed on the previously defined per-protocol and as-treated populations 
(reference Section 6.2: Study Analyses).  Further supportive analyses will be conducted 
which characterize the longitudinal effect of treatment on regurgitant volume in a 
repeated measures regression model. 
6.7 
Size and Duration of Trial 
An estimated minimum of 76 randomized, evaluable subjects is required to have 80% 
power to detect a reduction in the change in regurgitant volume between CARILLON 
device and Control groups.  A total of 120 subjects at up to 25 centers will be 
randomized, allowing for approximately 30% attrition (mortality, missing data and loss 
to follow-up) in the first 12 months of follow-up.   
6.8 
Secondary Endpoint & Observational Data Assessment  
The secondary endpoints and observational data will be analyzed and the results will be 
reported with descriptive statistics to provide supportive evidence of the safety and 
efficacy of the CARILLON Mitral Contour System. 
6.9 
Supportive Analyses & Missing Data Imputation 
The following supportive analyses will also be undertaken. 
• 
Assessment of treatment efficacy in subjects receiving a permanent implant 
through the primary endpoint – “as-treated” analysis 
• 
Assessment of treatment efficacy in subjects receiving a permanent implant and 
who did not receive alternative or confounding therapies (e.g., CRT therapy, 
transplant, stenting, etc.) through the primary endpoint – “per protocol” analysis 
• 
Assessment of treatment efficacy according to etiology of cardiomyopathy 
(ischemic vs. non-ischemic) through the primary endpoint 
• 
Assessment of treatment efficacy according to baseline LV ejection fraction 
(≤40% vs. 41-50%) through the primary endpoint 
 
Missing data will be imputed using a last observation carried forward (LOCF) 
methodology and be reported separately for: 
• 
the primary and secondary endpoint parameters 
• 
the observational parameters 
• 
the primary (intent to treat) and supportive analyses noted above.  

 
 
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7 
Ethical, Regulatory, and Administrative 
Considerations 
This study will be conducted in accordance with the International Standard ISO 
14155:2011, recommendations guiding physicians in biomedical research involving 
human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 
and later revisions, Good Clinical Practice: Consolidated Guidance (ICH E-6) and any 
regional or national regulations, as appropriate.   
 
Only centers willing and able to comply with these practices will be included in the 
study. 
7.1 
Informed Consent 
To protect the rights and welfare of subjects, this clinical study will be conducted in 
conformance to the International Standard ISO 14155: 2011, Section 4.7: Informed 
Consent.  
 
Informed consent must be obtained from each subject prior to participation in this 
clinical study.  Subjects who elect to enroll in the study must be informed of the risks 
and potential benefits of the CARILLON Mitral Contour System, as well as the risks 
and benefits of the associated medical procedures.  Alternative modes of treatment must 
be explained to the subject as well.  Such information is provided in the Subject 
Informed Consent.  The information that is given shall be in a language that the subject 
understands.  No informed consent, whether oral or written, may include any 
exculpatory language through which the subject is made to waive or appear to waive any 
of their legal rights, or releases or appears to release Cardiac Dimensions, the institution, 
or its agents from liability for negligence. 
 
The subject must be able to comprehend the informed consent and must sign the 
document prior to enrollment in the study.  The subject will receive a copy of the 
respective signed consent form.   
 
The original signed consent, as approved by the respective site Medical Ethics 
Committee (MEC) or Human Research Ethics Committee (HREC), is retained in the 
subject’s study records.  The subject will receive a copy of the signed consent form.  A 
sample of the informed consent is provided in Appendix B. 
 
Alternative consent materials, if used, must be approved by Cardiac Dimensions and the 
study center MEC/HREC prior to use, and must contain the elements of the sample 
informed consent.  Documentation of subject informed consent for each subject must 
be provided to Cardiac Dimensions. 

 
 
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7.2 
Institutional Review 
No clinical studies will begin without documented approval of the clinical investigation 
by the MEC/HREC affiliated with the study center.  The Sponsor or the Principal 
Investigator will obtain approval for the study from the study site’s MEC/HREC.  Prior 
to submission to the MEC/HREC, Cardiac Dimensions must review and approve the 
consent form from the study site.  The Principal Investigator will provide Cardiac 
Dimensions with a copy of the communication from the MEC/HREC indicating 
approval of the Investigational Plan and consent form prior to initiation of the study.   
 
The Principal Investigator will be responsible for obtaining annual MEC/HREC renewal 
through the duration of the study as appropriate, or more frequently if required by the 
MEC/HREC.  Copies of the Principal Investigator’s report and copies of the 
MEC/HREC’s continuance of approval must be maintained in the regulatory binder 
located at the study site.  The Principal Investigator shall report to Cardiac Dimensions 
within five (5) working days, any withdrawal of approval by the reviewing MEC/HREC. 
7.3 
Site Requirements 
The Principal Investigator selected will be responsible for fulfilling the clinical study 
requirements that are outlined in this Investigational Plan.  The investigational site must 
have the necessary resources so that the investigators can adhere to all clinical study 
requirements.  The following criteria will be used to select sites and Principal 
Investigators for participation in this clinical study: 
• 
The Principal Investigator must have expertise in clinical areas relevant to the 
clinical study.  This includes an extensive background in interventional 
cardiology, catheterization procedures, management of subjects with heart failure 
and mitral valve regurgitation, and clinical research. 
• 
Appropriate and sufficient personnel must be available to obtain and report data 
as required by the Investigational Plan.  There will be a team at each center (or 
affiliated with the center) consisting of investigators with expertise in 
interventional cardiology, management of patients with heart failure and 
echocardiography; and a study center coordinator to manage and organize the 
routine activities of the clinical study (i.e., assure that informed consent has been 
obtained, case report forms have been completed, and subject follow-up 
examinations have been scheduled). 
• 
Appropriate and sufficient personnel must be available to meet the implant 
schedule requirements for the CARILLON Mitral Contour System. 
• 
Personnel must be willing to comply with all aspects of the clinical study as 
described in the Investigational Plan.  This includes collection of complete and 
accurate data in a timely manner according to the prescribed subject follow-up 
schedule.  In addition, Principal Investigators must be accessible to their support 
staff and Cardiac Dimensions personnel. 

 
 
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• 
Investigators (Principal and sub-Investigators) must be willing to comply with all 
aspects of the Investigator’s Agreement as described in the Investigational Plan, 
including disclosure of financial information. 
• 
Investigators must have access to a hospital and/or clinic having the equipment 
necessary to perform the clinical study. 
7.3.1 
Individual Responsibilities 
Individuals engaged in the conduct of or responsible for the supervision of this clinical 
study must have the necessary education, training and experience to enable them to 
perform the assigned functions.  The responsibilities of key clinical personnel who will 
be involved in the conduct of this clinical study are described in the following sections. 
7.3.2 
Sponsor Responsibilities 
Sponsor assumes all responsibilities per ISO 14155: 2011, Section 8, including but not 
limited to:  
• 
Selecting qualified Principal Investigators and investigational centers and 
providing them with the information they need to conduct the investigation 
properly 
• 
Ensuring proper monitoring of the investigation 
• 
Ensuring that MEC/HREC review and approval are obtained 
• 
Notifying the applicable National Competent Authority (NCA)  
• 
Ensuring that any reviewing MEC/HREC and NCA are promptly informed of 
significant new information about an investigation 
• 
Obtaining NCA approval for the study 
• 
Ensuring that study specific insurance is contracted where required by 
national/local regulations  
• 
Securing compliance with this Investigational Plan, Investigator agreement, and 
federal, state and local regulations as outlined in Section 7.3.3 
• 
Conducting evaluations of unanticipated serious adverse device effects 
• 
Controlling the device(s) under investigation 
• 
Promptly informing the clinical investigator(s), when a clinical investigation is 
prematurely terminated or suspended, and, where applicable, informing the 
regulatory authority(ies) and ethics committee(s) of the termination or 
suspension and the reason(s) for the termination or suspension 
• 
Maintaining records and reports as outlined in Section 7.9 
• 
Analyzing and reporting data as outlined in Section 7.9 

 
 
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7.3.3 
Investigator Responsibilities 
The study investigators are responsible for the management of subjects involved in this 
clinical study as well as for the clinical use of the CARILLON Mitral Contour System at 
the selected site.  The Principal Investigators will assume overall responsibility and 
accountability for the research team and for the clinical data obtained from subjects 
participating in the study.  Principal Investigator assumes all responsibilities per ISO 
14155: 2011, Section 9, including but not limited to:  
• 
Ensure MEC/HREC approval and notifying Competent Authority for this 
Investigational Plan when required by national and/or local regulations 
• 
Ensuring that the clinical study is conducted according to this Investigational 
Plan, federal, state and local regulations, and the signed agreement 
• 
Providing financial disclosure according to federal regulations 
• 
Protecting the rights, safety and welfare of the subjects 
• 
Controlling any study device(s) stored at their site, including supervision and 
disposal of devices 
• 
Obtaining informed consent  
• 
Providing any pertinent new information regarding device safety to study 
subjects 
• 
Inform the Sponsor about all adverse events and adverse device effects in a 
timely manner 
• 
Maintaining records and reports as outlined in Section 7.9 
• 
Reviewing and signing (or assigning to an appropriate designee) all case report 
forms for subjects enrolled in the clinical study under the Principal Investigator’s 
care 
7.3.4 
Study Center Coordinator Responsibilities 
The study (center) coordinator is under the supervision of the Principal Investigator.  
The study center coordinator is responsible for: 
• 
Tracking all subjects involved in the clinical study 
• 
Scheduling required follow-up evaluations 
• 
Maintaining all records defined in the Investigational Plan 
• 
Collecting all clinical data from subjects involved in the clinical study  
• 
Ensuring that complete data obtained in accordance with the Investigational Plan 
are provided to Cardiac Dimensions in a timely manner 
• 
Ensuring that all case report forms are returned to Cardiac Dimensions in their 
entirety 
• 
Maintaining control over any Cardiac Dimensions product (i.e., procedure 
manual and device) received and maintained at the site 

 
 
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• 
Meeting routinely with the Principal Investigator to discuss study progress and 
issues  
• 
Assisting the Sponsor in monitoring the integrity of the site records 
7.4 
Investigational Plan Compliance 
The Principal Investigator is required to conduct the study in accordance with this 
Investigational Plan.  The Principal Investigator will carefully review the procedures 
defined in the Investigational Plan and in the CRFs with his/her staff prior to the time of 
study initiation to ensure appropriate interpretation and implementation.  The Principal 
Investigator must document any deviation to the Investigational Plan on the appropriate 
case report form together with the reason for the deviation.  The Sponsor will classify all 
deviations in accordance with approved procedures. 
 
Deviations from the Investigational Plan to protect the life or physical well-being of a 
subject in an emergency should be reported by the Principal Investigator to the 
MEC/HREC and Sponsor no later than five (5) working days after the emergency.  
Except in such an emergency, prior approval by the Sponsor is required for any change 
in or deviation from the plan, and if the change or deviation could affect the rights, 
safety or welfare of human subjects or the scientific soundness of the plan, MEC/HREC 
approval is also required. 
7.5 
Investigational Plan Amendments 
Investigational Plan amendments will be reviewed by the study’s Executive Committee. 
All changes must be documented in the format of an amendment with justification 
statements.  All amendments must be submitted to the MEC/HREC and regulatory 
authority for review and approval.  Following approval, the protocol amendment will be 
distributed to all protocol recipients at the study site. 
7.6 
Data Completion and Study Monitoring  
Cardiac Dimensions is the Sponsor of the clinical study.  Monitors are selected and 
monitoring will be performed in accordance with the Sponsor’s approved procedures or 
third-party procedures approved by the Sponsor.   
 
Cardiac Dimensions Vice President of Clinical Programs will have overall management 
responsibility for the clinical study.  A Clinical Affairs Manager will have 
administrative management responsibility for the study.  This responsibility may include 
serving as a clinical study monitor.  Additional personnel, as assigned by the Sponsor 
may serve as clinical monitors, study administrators, and/or be responsible for data 
review and data integrity.  Sponsor contact information is provided in Section 8: 
Sponsor Personnel and Contacts.   
 

 
 
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Monitors may change periodically; however Cardiac Dimensions does not consider this 
a significant change to the Investigational Plan.  All monitors will be qualified to 
perform their assigned responsibilities. 
7.6.1 
Study Monitoring 
Monitoring of the clinical study will be a continuous process to ensure that high-quality 
data are obtained through compliance with the Investigational Plan and will be 
conducted in accordance with ISO 14155:2011 Section 8.2.4, and Cardiac Dimensions 
approved procedures or the operating procedures of the Contract Research Organization 
(CRO) designated by Cardiac Dimensions.   
 
Case report forms will be reviewed for completeness, conformity with requirements, and 
safety monitoring of adverse events.  Frequent communication will be maintained with 
each site to keep both the study site and Cardiac Dimensions up-to-date and aware of the 
progress of the clinical study. 
 
On-site monitoring of all study sites will be frequent enough (at least annually) to assure 
continued acceptability of the data by assessing compliance of the center to the 
Investigational Plan, adherence to the data collection procedures, and maintenance of 
study records.  Accuracy of data reported on the case report forms will be verified by 
comparison to the subject’s source documents, when applicable.  If necessary, 
appropriate corrective action will be taken to ensure adherence to the Investigational 
Plan. 
 
The scheduled site visits and/or audits will include, but not be limited to the following. 
7.6.1.1 Pre-Study Qualification 
The Sponsor will assure that the Principal Investigator and their staff understand and 
accept the obligation to conduct the clinical investigation in accordance with the 
Investigational Plan, Cardiac Dimensions approved procedures for conducting clinical 
investigations, applicable federal regulations, and Good Clinical Practices. 
7.6.1.2 Site Initiation Visit 
Site initiation visits will be conducted by Cardiac Dimensions (and/or a designated 
CRO) to train the Principal Investigator and supporting study staff on the objectives, 
study subject timelines, device accountability, and case report form completion 
guidelines specific to the Investigational Plan.   
 
The site initiation visit will occur after the study site has received written MEC/HREC 
approval to conduct the Investigational Plan and all site related requirements (such as 
clinical trial agreements and budget negotiations) have been completed.  The site may 
not enroll study subjects into the clinical trial until the site initiation visit is completed. 

 
 
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7.6.1.3 Interim Site Visits and Audit 
On-site monitoring visits will assess the progress of the clinical study and identify any 
concerns that result from device performance or review of the site’s study records, study 
management documents, and subject informed consent documents.  This includes 
adherence to the Investigational Plan, MEC/HREC review of the clinical study and its 
progress, and maintenance of records and reports. 
 
To assure the integrity of the clinical study data, 100% of individual subject records and 
other supporting documents will be compared to the case report forms and reports 
prepared by the study center coordinator and/or site investigators for submission to 
Cardiac Dimensions.  During monitoring visits or audits, the monitor will compare 
subject records and other supporting documents with reports from the site investigators 
to determine that: 
• 
The facilities used by the investigators continue to be acceptable for the purposes 
of the clinical study 
• 
The Investigational Plan is being followed, and that only eligible subjects are 
being enrolled in the study 
• 
Deviations to the Investigational Plan have been reported to Cardiac Dimensions 
and the MEC/HREC, as applicable 
• 
The Principal Investigator is carrying out the agreed-upon activities and has not 
delegated them to inappropriate personnel 
• 
Adverse events are promptly being reported 
• 
Informed consent has been obtained and documented 
• 
Device accountability is being maintained, if applicable 
• 
The information recorded in the reports and/or case report forms is complete, 
accurate and legible 
• 
There are no omissions in the reports and/or case report forms of specific data 
elements 
• 
Missed follow-up visits are noted in the reports 
• 
Subjects failing to complete the clinical study and the reason for failure are 
recorded 
 
Study investigators not complying with the Investigational Plan and regulations will be 
terminated from the study and shall be required to return all unused devices and/or 
associated study materials and procedure manuals. 
7.6.1.4 Closeout Site Visit 
A closeout site visit to the study center may be made by the monitor, if necessary.  Any 
ongoing responsibilities will be discussed with the Principal Investigator and the study 
center coordinator.  

 
 
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7.6.2 
Completion of Case Report Forms (CRFs) 
The Principal Investigator or his designee will be responsible for completing, in a timely 
manner, a case report form (CRF) for each subject who is registered to participate in this 
study.  An electronic (eCRF) system will be utilized for this study and instructions and 
specific training for their completion will be provided to the study staff.  eCRFs will be 
completed as information becomes available.  If errors or omissions are found in the 
course of a CRF audit, data edit sheets will be generated and the errors, omissions or 
clarifications will be corrected on these sheets.   
 
The Principal Investigator or designate will sign and date the indicated places on the 
eCRF.  This signature will indicate that a thorough inspection of the audited data therein 
has been made and will thereby certify the contents of the form. 
7.6.3 
Central Database 
All study data will be collected and compiled in a central database by the Sponsor or 
delegate. Appropriate quality control measures will be established to ensure secured, 
accurate and complete transfer of information from the study documentation to the 
central database. Procedures used for data review, database cleaning, and issuing and 
resolving data queries and procedures for verification, validation and securing of 
electronic clinical data systems are detailed in the Data Management Plan. 
7.7 
Study Training 
Cardiac Dimensions will provide in-depth training for the Principal Investigators and 
study staff either at the individual sites or at a common location.  Cardiac Dimensions 
clinical research personnel, or their designees, will conduct and document this training 
in accordance with appropriate procedures. 
 
Topics to be covered at this visit include: 
• 
Anatomy 
• 
Disease states 
• 
The CARILLON Mitral Contour System 
• 
Study procedures 
• 
Overview of the study 
• 
Investigational Plan 
• 
Regulatory requirements and compliance 
• 
Issues that might arise in regard to clinical study site management and case 
report forms 
7.7.1 
CARILLON Mitral Contour System Procedure Training 
Cardiac Dimensions will schedule training sessions with the study investigators to 
provide training in the techniques and procedures required for implanting the 

 
 
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CARILLON implant.  The training plan for individual study investigators will be 
tailored to the investigator’s previous experience using the investigational device.  
Cardiac Dimensions staff, including the Chief Medical Officer or consultant 
interventional cardiologists, will conduct the sessions.  
7.8 
Subject Recruitment 
Appropriate recruitment materials, if needed, will be provided by Cardiac Dimensions 
following review and approval by the MEC/HREC.  Recruitment will continue in a 
consecutive manner until enrollment for the study is complete.   
7.9 
Maintenance of Study Records 
It is the responsibility of the Principal Investigator and study staff to maintain a 
comprehensive and centralized filing system of all study-related documentation.  This 
filing system must be suitable for inspection at any time by the Clinical Research 
Associate (CRA) or Quality Assurance (QA) designee of Cardiac Dimensions, the 
MEC/HREC, or other regulatory body.   
 
At all times throughout the clinical investigation confidentiality shall be observed by all 
parties involved. All data shall be secured against unauthorized access. 
 
Privacy and confidentiality of information about each subject shall be preserved in the 
reports and any publication of the clinical investigation data. 
 
Lists of subjects' names and identifying information should, wherever possible, be 
maintained separately from case report forms. 
 
Study record elements should include: 
 
Subject Files 
Contains the completed subject CRFs (as necessary), supporting source 
documentation, and a signed and dated Informed Consent.  Study subject files 
will be maintained on all enrolled subjects.  Documents for subjects who are 
screened but not enrolled will be maintained in the patient’s medical file. 
Regulatory Binder 
Contains the Investigational Plan with all amendments, MEC/HREC approvals 
and communications, current MEC/HREC approved Consent Form, study site 
logs, accountability records and laboratory documents (i.e., certification, 
norms/ranges, etc.). 
Reference Documents 
Contains the resource list; responsibilities of the Principal Investigator, Sponsor, 
and MEC/HREC; regulatory, adverse event, and informed consent guidelines; 
study aids and core/central laboratory instructions. 

 
 
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7.9.1 
Records and Reporting 
7.9.1.1 Investigator Records 
Records may be subject to regulatory inspection and will be retained for a period of two 
years following (1) the date the investigation is completed or terminated, or (2) the 
records are no longer required to support a regulatory submission, whichever is longer.  
The Principal Investigator is responsible for the records cited below: 
• 
All correspondence which pertains to the investigation 
• 
Records of persons authorized to conduct the study 
• 
Records of receipt, use or disposition of the device, if applicable 
• 
Subject medical records and completed case report forms and supporting 
documentation 
• 
Informed consent documentation (including copy of an approved, blank 
informed consent form) 
• 
Adverse events and unanticipated adverse device effects 
• 
Investigational Plan (including certification of approval) and reasons for 
deviations from the Investigational Plan 
• 
Signed Investigator Agreement and curriculum vitae of study investigators 
participating in the study 
 
Investigator records cannot be discarded without written consent from Cardiac 
Dimensions. 
  
Data recorded on the echocardiographic reports and patient questionnaires (Kansas City 
Cardiomyopathy Questionnaire and SF-12 questionnaire) are considered to be source 
data, and are not derived from hospital records.  The data collected on those forms must 
be as accurate, complete and secure as possible to assure data integrity. 
7.9.1.2 Investigator Reports 
The Principal Investigator is responsible for the preparation (review and/or signature) 
and submission of the reports cited in the table below.  These reports are also subject to 
regulatory inspection and record retention requirements described above for Investigator 
Records. 
 
 

 
 
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Table 7.1  Principal Investigator Reporting Requirements 
Report Title 
Submit to  
Requirements 
All serious adverse 
events  (SAE) and 
device deficiencies that 
could have led to a 
serious adverse device 
effect (SADE)  
a) if either suitable 
action had not been 
taken,  
b) if intervention had 
not been made, or  
c) if circumstances had 
been less fortunate  
(see section 5 - 
Adverse Events and 
Risk Analysis) 
Sponsor, MEC/HREC (if 
required by national/local 
regulations) 
Report of event must be submitted within 
24 hours after the investigator first learns 
of the event (see section 5). 
Withdrawal of 
MEC/HREC Approval 
Sponsor 
Report must be submitted without delay 
after the investigator learns of the 
withdrawal. 
Progress Report/ 
Continuing Review 
Sponsor/Monitor and 
MEC/HREC 
Report must be submitted annually, or as 
required per individual MEC/HREC 
policies, for the duration of the clinical 
investigation.  Alternatively, the Sponsor 
may prepare the report. 
Deviations from the 
Investigational Plan 
Sponsor and MEC/HREC 
 
• Anticipated 
If the deviation may affect the 
scientific soundness of the plan 
or the rights, safety and welfare 
of the subjects, the deviation 
must be approved by the 
Sponsor, NCA (if applicable), 
and the MEC/HREC.  If the 
deviation does not affect these 
issues then only the Sponsor 
must approve it. 
Changes must be approved before 
implementation. 
• Without Prior  
Notification 
 
Notification must be made no later than 5 
working days after the event if the 
deviation was to protect the life or 
physical well-being of a subject, and 
there was inadequate time to obtain prior 
approval from the Sponsor. 
Failure to Obtain 
Informed Consent 
Sponsor and MEC/HREC 
Notification must be made within 5 
working days of the device use.  The 
report will include a brief description of 
the circumstances justifying failure. 
Final Report 
Submission 
Sponsor and MEC/HREC 
Report must be submitted per the 
national/local regulations. 
Subject Case Report 
Forms 
Sponsor 
Forms must be completed and ready for 
submission in a timely manner.  

 
 
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7.9.1.3 Sponsor Records 
Cardiac Dimensions will maintain records for each investigational site for a period of at 
least two (2) years following (1) the date the investigation is completed or terminated, or 
(2) the records are no longer required to support a regulatory submission, whichever is 
longer.  Cardiac Dimensions will maintain the following records: 
• 
All correspondence which pertains to the investigation 
• 
Records of device shipment, receipt and disposition 
• 
Study Site qualification records, including: 
– Curriculum vitae (and as applicable statements of relevant experience) of the 
investigators 
– A signed Investigator Agreement and related clinical study agreements 
(including financial disclosure) 
– Documentation of NCA and MEC/HREC approval 
– Informed consent form (if different than Sponsor draft) 
• 
Copies of completed case report forms and specific source documents (e.g., X-
rays, echo reports) 
• 
Adverse device effects and adverse events 
7.9.1.4 Sponsor Reports 
Cardiac Dimensions (or an authorized designate) is responsible for the reports cited in 
the table below.  These reports are also subject to record retention and inspection 
regulations.  Records will be maintained in accordance with Cardiac Dimensions 
approved procedures. 
 

 
 
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Table 7.2  Cardiac Dimensions Reporting Requirements 
Report Title 
Submit to  
Requirements 
All serious adverse 
events  (SAE) and 
device deficiencies 
that could have led to 
a serious adverse 
device effect 
(SADE)  
a) if either suitable 
action had not been 
taken,  
b) if intervention had 
not been made, or  
c) if circumstances 
had been less 
fortunate  
(see section 5 - 
Adverse Events 
and Risk 
Analysis) 
Principal Investigator  
NCA (per national/local 
regulations) 
Report of event must be submitted 
immediately, but not later than 7 calendar 
days after initial notification of the event.   
Report must be submitted immediately, but 
not later than 2 calendar days after initial 
notification if an event indicates an imminent 
risk of death, serious injury, or serious illness 
and that requires prompt remedial action for 
other patients, or a new finding to it. 
Withdrawal of 
MEC/HREC 
Approval 
NCA (if necessary) 
Report must be submitted within 5 working 
days receipt of withdrawal. 
Withdrawal of NCA 
Approval 
Principal Investigator/ 
MEC/HREC 
Report must be submitted without delay after 
receipt of notice.  
Progress Reports 
All MEC/HREC 
NCA (if necessary) 
Reports must be submitted per NCA and 
MEC/HREC requirements. 
Recall and Device 
Disposition 
MEC/HREC 
NCA (if necessary) 
Notification must be made within 30 working 
days. 
Final Report 
NCA (notification and 
report, if necessary) 
Principal Investigators/ 
MEC/HREC (report only) 
Per NCA and MEC/HREC requirements. 
Failure to Obtain 
Informed Consent 
NCA (if necessary) 
Reports will be submitted within 10 working 
days of receipt of notice of use. 
7.10 Product Handling & Accountability 
The Principal Investigator should take adequate precautions, including storage of the 
products, to prevent theft or diversion of the products into unauthorized channels of 
distribution.  Should a product not be used, the Principal Investigator or appropriate 
designee will return or dispose of the device as per the Sponsor’s instructions. 

 
 
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7.10.1 Investigational Product Accountability and Supply 
The Principal Investigator or responsible designee will record the receipt and 
dispensation of the CARILLON Mitral Contour System in the Device Accountability 
Log.  Cardiac Dimensions will monitor these forms on an ongoing basis.  At the end of 
the study, the originals will be returned to the Sponsor and a copy kept in the regulatory 
records binder at the study site. 
Principal Investigators will be provided with the material necessary to prepare the 
application for MEC/HREC review, including the Investigational Plan (with informed 
consent materials, case report forms, etc.).  The materials will include a summary of the 
results of prior pre-clinical and clinical studies. 
 
At site initiation, study center coordinators will be provided with an Investigator file 
containing the Investigational Plan, and supporting study management materials.  
Sufficient subject files containing the case report forms will be provided to initiate the 
study.  Additional subject files will be supplied as Cardiac Dimensions is notified of 
CARILLON implant procedures. 
7.10.2 Device Accountability 
Only institutions participating in the clinical study will be eligible to receive the 
CARILLON Mitral Contour System and accessories. Devices may be sent to the study 
site upon receipt by Cardiac Dimensions of the following: 
• 
Curriculum vitae of the Investigator(s) 
• 
A signed Investigator’s Agreement 
• 
Documented NCA and MEC/HREC approvals 
• 
An MEC/HREC approved informed consent form 
 
The Sponsor will supply devices to the sites as described in the clinical study procedures 
for this study.  Sites may be allowed to store controlled inventory when qualified.  
 
Study sites are responsible for maintaining control over any associated product received 
and maintained at the investigational site.  These devices must be segregated, and 
provided only to investigators participating in the study.   
7.11 Confidentiality and Data Protection 
Information about study subjects will be kept confidential and managed according to the 
requirements of ISO 14155: 2011, Section 6.7. 
 
At all times throughout the clinical investigation confidentiality shall be observed by all 
parties involved. All data shall be secured against unauthorized access. 
 
Privacy and confidentiality of information about each subject shall be preserved in the 
reports and any publication of the clinical investigation data. 

 
 
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Lists of subjects' names and identifying information should, wherever possible, be 
maintained separately from case report forms. 
7.12 Study Termination For Cause 
Cardiac Dimensions retains the right to terminate a Principal Investigator or an 
investigational site’s participation in this study for any cause, suspending subject 
enrollment and removing all investigational products and related study materials from 
the study site at any time.  Specific instances that may precipitate such termination are: 
• 
Consistent deviation from Investigational Plan requirements 
• 
Inaccurate and/or incomplete data recording on a recurrent basis 
• 
Unauthorized use of investigational products in any laboratory study or 
administration to any subject not enrolled as part of this Investigational Plan 
• 
Delinquent fulfillment of obligation on the part of the Principal Investigator with 
regard to adverse event reporting, unacceptable subject enrollment, or other 
responsibilities as outlined in this Investigational Plan 
 
Disclosure of study termination by the Sponsor will be made immediately to the 
MEC/HREC. 
 
If a study site is terminated, the treatment assignment for the patients enrolled and 
randomized at that site will be divulged to the Principal Investigator so that study 
subjects can be appropriately followed up. 
7.13 Authority to Execute 
The Principal Investigator warrants that he/she is permitted to conduct this study and 
that the terms of the Investigational Plan are not in conflict with any employment 
agreement the Principal Investigator may hold with another party or any other 
contractual arrangement to which the Principal Investigator or institution is a party.  
7.14 Publication Plan 
As specified in the Clinical Trial Agreement, neither the complete nor any part of the 
results of the study carried out under this Investigational Plan, nor any of the 
information provided by the Sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study Sponsor.  Any 
Investigator involved with this study is obligated to provide the Sponsor with complete 
test results and all data derived from the study.  The first publication of the results of the 
study will be made by the Principal Investigator, in conjunction with the presentation of 
the results of the multi-center study with the Investigators and institutions from all sites 
contributing data, analyses and comments. 

 
 
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8 
Sponsor Personnel and Contacts 
STUDY SPONSOR: 
Cardiac Dimensions Pty Ltd 
5540 Lake Washington Blvd. NE 
Kirkland, WA 98033 
 
Sponsor Contact: 
 
 
 
Vice President, Operations, Regulatory & Quality (or designee) 
 
 
Clinical Study Administration: 
 
Vice President, Clinical Programs (or designee) 
 
 
Medical Monitor: 
Chief Medical Officer (or designee) 
 
 
CLINICAL RESEARCH ORGANIZATION: MedPass International  
 
  
 
 
 
95 bis boulevard Pereire 
 
  
 
 
 
75017 Paris - France 
 
CLINICAL RESEARCH ORGANIZATION: Mobius Medical Pty Ltd 
Level 32, 1 Market Street 
Sydney, NSW 2000, Australia 
 
ECHOCARDIOGRAPHY CORE LAB:  
Menzies Institute of Medical Research 
 
  
 
 
 
University of Tasmania  
 
  
 
 
 
17 Liverpool Street 
 
  
 
 
 
Hobart TAS 7000 
 
  
 
 
 
Australia 
DATA MANAGEMENT:  
 
 
MedPass International  
 
  
 
 
 
95 bis boulevard Pereire 
 
  
 
 
 
75017 Paris - France 
 
AUTHORIZED EU REPRESENTATIVE:  
MedPass International Limited 
Windsor House 
Bretforton, Evesham  
Worcestershire WR11 7JJ 
United Kingdom 
 
 
LEGAL REPRESENTATIVE (Europe): 
MedPass Limited 
Windsor House 
Bretforton, Evesham  
Worcestershire WR11 7JJ  
United Kingdom 
 

 
 
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9 
Definitions of Terms, Abbreviations and 
Acronyms 
 
This section provides definitions for terms and abbreviations used in this Investigational 
Plan. 
9.1 
Definitions of Abbreviations and Acronyms 
6MWT / 6MWD 
Six minute walk test / Six minute walk distance 
21 CFR 
Title 21, Code of Federal Regulations (various applicable parts and subparts 
referenced) 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event  
AHA 
American Heart Association 
AIV 
Anterior interventricular vein 
ARB 
Angiotensin receptor blocker 
AV 
AtrioVentricular 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CBC 
Complete blood count 
CEC 
Clinical Events Committee 

 
 
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CHF 
Congestive heart failure 
Cr 
Creatinine 
CRA 
Clinical research associate 
CRO 
Contract research organization 
CRF 
Case report form 
CS 
Coronary Sinus 
cTn 
Cardiac Troponin 
CXR 
Chest x-ray (PA and lateral) or cinefluoroscopy 
DSMB 
Data Safety Monitoring Board 
ECG/EKG 
Electrocardiogram, usually 12-lead 
ECHO 
Echocardiogram 
EF 
Ejection fraction 
ETT 
Exercise treadmill test (modified Naughton) 
FMR 
Functional mitral regurgitation 
GCV 
Great Cardiac Vein 
HREC 
Human Research Ethics Committee 
ICD 
Implantable cardioverter defibrillator 

 
 
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IFU 
Instructions for Use 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
Left atrium 
LAA 
Left atrial appendage 
LV 
Left ventricle  
LVAD 
Left ventricular assist device 
LVEDd 
Left ventricular end diastolic dimension 
LVESd 
Left ventricular end systolic dimension 
LVEF 
Left ventricular ejection fraction 
MAE 
Major adverse event 
MEC 
Medical Ethics Committee 
MI 
Myocardial infarction (heart attack) 
MR 
Mitral regurgitation 
MRJA/LAA 
Mean regurgitant jet area to left atrial area 
MV 
Mitral valve 
NT-BNP 
N-terminal B-type natriuretic peptide 
NYHA 
New York Heart Association 

 
 
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PISA 
Proximal iso-velocity surface area 
QOL 
Quality of life 
QRS 
Complex of cardiac rhythm representing ventricular depolarization 
SAE 
Serious adverse event 
SAM 
Systolic anterior motion of the mitral valve leaflet 
TEE 
 
Transesophageal echocardiogram 
TIA 
Transient ischemic attack 
TIMI  
Thrombolysis in Myocardial Infarction 
TTE 
Transthoracic echocardiogram 
URL 
Upper reference limit 
USADE 
Unanticipated serious adverse device effect 
WBC 
White blood count 
9.2 
Definitions of Terms  
ANTERIOR INTERVENTRICULAR VEIN 
The coronary vein located in the anterior interventricular groove. 
 
ADVERSE EVENT 
An adverse event is defined as any untoward medical occurrence, unintended disease 
or injury, or untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the investigational medical 
device.  
Notes: 

 
 
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1. This definition includes events related to the investigational medical device or 
the comparator. 
2. This definition includes events related to the procedures involved. 
3. For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
 
ALLERGIC REACTION 
 
Hypersensitivity to a particular contrast agent, device, medication, or transfusion 
product given to the subject for completion of a study related procedure (e.g., cardiac 
catheterization, CARILLON implant) that may or may not require treatment. 
ANCHORING 
The proprietary mechanism by which the CARILLON implant is fixed in position 
within the coronary sinus/great cardiac vein. 
ANEURYSM (pseudoaneurysm) 
Any abnormal dilation of a vessel, including pseudoaneurysm or dissection, 
requiring medical or surgical intervention, or resulting in death, that occurs as a 
result of the subject’s index procedure at any of the catheter insertion sites. 
 
ANGINA PECTORIS (stable or unstable) 
A deep, poorly localized chest, arm, or jaw discomfort caused by inadequate flow to 
the heart muscle.  These events may occur at any time throughout a subject’s 
participation in the study. 
 
 
Stable angina 
Angina without change in frequency or pattern associated with physical exertion or 
emotional stress and relieved promptly (e.g., less than 5 minutes) by rest or 
sublingual nitroglycerin.  
 
 
Unstable angina 
A more frequent or severe form of angina, which can occur at rest.  This is an acute 
process of myocardial ischemia that is not of sufficient severity and duration to 
result in permanent myocardial damage.  This episode does not present with ST-
segment elevation on the ECG and does not release biomarkers indicative of 
myocardial necrosis into the blood. 
ANGIOGRAM/ANGIOGRAPHY 
A radiographic record of the size, shape and location of the heart and blood vessels, 
after introduction of a radiopaque contrast medium. 
ANNULOPLASTY 
Plication ("tightening”) of tissue around the heart valve annulus. 
ANURIA 
Absence of urine formation, which requires treatment. 
 

 
 
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AORTIC STENOSIS 
A narrowing of the aorta or its orifice, obstructing free flow of blood from the left 
ventricle to the aorta, which requires treatment.  This may occur at any time 
throughout a subject’s participation in the study. 
ARRHYTHMIA 
Documented dysrhythmia by ECG or other rhythm monitoring device (e.g., portable 
heart monitor, pacemaker) that results in the signs and symptoms of vital organ 
hypoperfusion (e.g., dizziness, lightheadedness, or syncope) and requires treatment.  
This may occur at any time throughout a subject’s participation in the study.  
ARTERIOGRAM 
Angiography of an artery. 
ARTERIO VENOUS FISTULA 
An abnormal channel or passage between the artery and vein that disrupts the normal 
blood flow pattern and requires surgical intervention. 
ARTIFICIAL HEART 
A mechanical pump used to replace the function of a damaged heart, either 
temporarily or as a permanent internal prosthesis. 
ASTHENIA 
General weakness or loss of strength, which requires treatment.  Asthenia may occur 
at any time throughout a subject’s participation in the study. 
 
BLEEDING COMPLICATIONS 
Major Bleeding 
Major bleeding events involve episodes of intra-cranial, pericardial, or 
retroperitoneal bleeding or a procedure-related hemorrhagic event that requires 
transfusion (two units or greater) or surgical intervention, or results in a greater than 
five (5) gram decrease in hemoglobin. 
 
Minor Bleeding 
Minor bleeding events involve all other episodes of blood loss that do not meet the 
definition of Major Bleeding. 
CARDIAC ARREST 
Defined as the absence of pulse and respirations occurring in the post-operative 
period and resulting from ventricular tachycardia, ventricular fibrillation, 
electromechanical dissociation, or asystole. 
CARDIAC SURGERY OR PERCUTANEOUS CORONARY INTERVENTION 
FOR NON-CARILLON IMPLANT FAILURE 
Defined as surgery or percutaneous coronary intervention performed for the 
treatment of cardiovascular disease, including coronary artery bypass surgery, 
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procedures not related to cardiac surgery performed for failure of the CARILLON 
implant.  The priority of surgery is defined as: 
1. Elective:  Surgery not requiring immediate attention and performed at the 
subject’s convenience. 
2. Urgent:  Subject must have surgery within 24 hours. 
3. Emergency:  Immediate need for surgery to preserve life. 
 
CARDIAC SURGERY OR PERCUTANEOUS CORONARY INTERVENTION 
FOR CARILLON IMPLANT FAILURE  
Defined as cardiac surgery or percutaneous coronary intervention performed for 
failure of the CARILLON implant, including implant detachment, migration, or 
other CARILLON implant malfunction that may result in cardiac injury to the 
annulus.  The priority of surgery is defined as: 
  
1. Elective:  Surgery not requiring immediate attention and performed at the 
subject’s convenience. 
2. Urgent:  Subject must have surgery within 24 hours. 
3. Emergency:  Immediate need for surgery to preserve life. 
 
CARDIAC TAMPONADE 
Fluid in the pericardial space, documented by echocardiography or other methods, 
that results in systemic hypotension requiring percutaneous or open surgical 
intervention.  This may occur at any time throughout a subject’s participation in the 
study. 
CARILLON MITRAL CONTOUR SYSTEM 
The CARILLON Mitral Contour System is the investigational device that is the 
subject of this clinical study.  It is composed of a proprietary implant intended for 
permanent implantation in the Coronary Sinus (CS)/Great Cardiac Vein (GCV) and 
a proprietary, catheter-based delivery system through which the implant is deployed, 
anchored, and locked in the CS/GCV.  The delivery system can also be used to 
recapture and remove the implant, if necessary, prior to decoupling. 
CAROTID ARTERY TRAUMA 
Trauma to a subject’s carotid artery during the index procedure that prolongs the 
hospitalization and/or requires percutaneous or surgical intervention. 
CHRONIC NERVE DAMAGE 
Damage to a nerve during the index procedure or other study related procedure 
causing permanent nerve impairment. 
COAGULOPATHY 
A defect in the blood-clotting mechanisms that occurs at any time throughout a 
subject’s participation in the study. 

 
 
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CORONARY SINUS 
A vessel or passage that receives the blood flow from the cardiac veins and opens 
into the right atrium. 
DEATH 
Death is divided into two categories and will be reported at any time in a subject’s 
participation in the study: 
 
Cardiac death is defined as death due to any of the following: 
• 
Acute Myocardial Infraction 
• 
Cardiac perforation/pericardial tamponade 
• 
Arrhythmia or conduction abnormality 
• 
Stroke within 30 days of the procedure or stroke suspected of being related to 
the procedure 
• 
Death due to complication of the index procedure, including bleeding, vascular 
repair, transfusion reaction, or bypass surgery 
• 
Any death for which a cardiac cause cannot be excluded 
 
Non-cardiac death is defined as death not due to cardiac causes (as defined above). 
Operative mortality is defined as death from any cause that occurs during the 
hospitalization in which the operation was performed or through 30 days 
postoperatively if the subject was discharged. 
All deaths will be adjudicated by the Clinical Events Committee. 
DEEP VEIN THROMBOSIS 
A condition where there is a blood clot in a deep vein, occurring at any time 
throughout a subject’s study participation, that may or may not require treatment. 
DELIVERY CATHETER 
The CARILLON Mitral Contour System delivery catheter facilitates percutaneous 
entry of the marker catheter, attachment of the cartridge which houses the 
CARILLON implant, and enables placement and recapture of the implant. 
DENTAL INJURY 
Injury to the teeth or oral cavity related to a transesophageal echocardiogram 
performed during the subject’s participation in the study, which requires treatment.   
 
DENUDATION (ARTERIAL OR VENOUS) 
Removal of layer(s) of a blood vessel wall. 
DEPLOYMENT 
Deployment is the procedure of delivering and locking the CARILLON implant 
anchors within the CS/GCV. 

 
 
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DEPRESSION 
Psychological distress, depression, or anxiety, which requires treatment. 
 
DEVICE EMBOLIZATION 
The movement of the CARILLON implant (distal anchor, proximal anchor and/or 
ribbon connector) to a location out of the coronary sinus/great cardiac vein that 
creates an obstruction to a cardiac chamber or a blood vessel and requires 
percutaneous or surgical intervention.  
DEVICE MALFUNCTION OR FAILURE 
Device malfunction  
The failure of a device to meet any of its performance specifications or otherwise 
perform as intended. Performance specifications are claims made in the labeling of 
the device. 
 
Device failure 
A device that is used in accordance with the Instructions for Use, but does not 
perform according to the Instructions for Use and negatively impacts the treatment. 
A device malfunction or failure may occur at any time throughout a subject’s 
participation in the study.  A device malfunction or failure is an adverse event only if 
it causes an untoward event in the subject. 
 
DEVICE MIGRATION 
The physical movement of the complete CARILLON implant (the distal anchor, 
proximal anchor and ribbon connector), from its deployed location (after decoupling 
of the CARILLON implant from the delivery system has occurred). 
DISSECTION (ARTERIAL OR VENOUS) 
A tear of the layers in the blood vessel that causes blood to flow between the layers 
of the wall of the blood vessel and that results in residual contrast staining of the 
vessel wall after contrast has cleared the vessel lumen.   
DILATED CARDIOMYOPATHY 
Left ventricular end diastolic dimensions (LVEDd) > 55 millimeters (mm) or 
LVEDd/BSA > 3.0 cm / m2. 
DOUBLE BLIND 
A type of masking in which two or more parties involved with the clinical trial do 
not know which participants have been assigned which interventions.  
DYSPNEA 
Shortness of breath, resulting in labored or difficult breathing, which requires 
treatment. 
 
ECHOCARDIOGRAM 
Cardiac ultrasound including color flow Doppler. 

 
 
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ELECTROCARDIOGRAM 
Twelve (12) lead electrocardiogram and monitoring electrocardiogram used in a 
cardiac catheterization laboratory. 
ELECTROMECHANICAL DISSOCIATION / PULSELESS ELECTRICAL 
ACTIVITY 
Persistence of electrical activity in the heart without an associated mechanical 
contraction or pulse. 
 
EMBOLISM (AIR, TISSUE, OR THROMBUS) 
Sudden obstruction of a blood vessel (arterial or venous, including the coronary 
sinus) or cardiac chamber by foreign or biological substances brought to its site of 
lodgment by the cardiovascular system, which may cause symptoms such as 
dyspnea, hypotension, sharp chest pains and decreased level of consciousness, and 
which requires treatment.  This may occur at any time throughout a subject’s 
participation in the study. 
EMERGENCY CARDIAC SURGERY 
The requirement for a subject to have non-planned, emergent interventional 
procedure or surgery for the treatment of a new or worsening cardiovascular 
condition (e.g., coronary artery stenosis, mitral valve dysfunction), occurring at any 
time throughout a subject’s participation in the study. 
ENDOCARDITIS 
Any infective endocarditis associated with the CARILLON implant or implant 
procedure as defined by the Duke Scale36 and assessed by echocardiographic 
findings, clinical criteria including positive cultures, clinical signs (fever, new or 
altered cardiac murmurs, splenomegaly, systemic emboli, or immunopathological 
lesions) and/or histologic confirmation of endocarditis at biopsy or autopsy.  This 
may occur at any time during a subject participation in the study.  A full course of 
antibiotic therapy is defined as seven (7) days or longer. 
 
ESOPHAGEAL INJURY 
Esophageal perforation 
An opening or hole through the esophagus, requiring treatment.  This may be related 
to the transesophageal echocardiogram (TEE) performed during the index procedure 
or anytime during the trial should this test become necessary.  
Esophageal stricture 
An abnormal narrowing of the esophagus acquired from trauma (e.g., TEE) or 
infection that may result in mechanical or chemical irritation, muscular spasm, or 
pressure from adjacent structure or tumors, and which requires treatment.  This event 
may occur at any time throughout a subject’s participation in the study and may be 
temporary or permanent. 
FATIGUE 
A feeling of tiredness or weariness resulting from continued activity or as a side 
effect of prolonged radiation exposure or psychotropic drug.  

 
 
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FEVER 
A fever above 101 degrees Fahrenheit that results in medical intervention. This may 
occur at any time throughout a subject’s participation in the study. 
GREAT CARDIAC VEIN 
The vein in the transverse groove between the left cardiac atrium and ventricle that 
drains into the coronary sinus. 
HEADACHE 
An acute or chronic, diffuse pain in different portions of the head, not confined to 
any nerve distribution area.  It may be frontal, temporal, or occipital, and may be 
confined either to one side of the head or to the region immediately over one eye.  
Headaches requiring treatment will be documented as adverse events. 
 
HEART FAILURE 
A chronic syndrome resulting from failure of the heart to maintain adequate 
circulation of blood.  Symptoms resulting from decompensation of the heart or 
exacerbation of heart failure symptoms, which occur during the study and require 
treatment, will be documented as adverse events. 
HEART FAILURE HOSPITALIZATION 
A diagnosis of acute decompensated heart failure hospitalization (ADHF) requires 
an in-hospital stay that includes at least one calendar date change and requires 
intravenous or mechanical heart failure treatment. The length of hospital stay will be 
calculated from admission to discharge to home or other disposition. 
The diagnosis of ADHF will be based on: 
▪ Symptoms of worsening heart failure such as increased shortness of breath, 
orthopnea, paroxysmal nocturnal dyspnea, fatigue, decreased exercise 
tolerance or history of weight gain; 
▪ Physical examination evidence such as neck vein distention, the presence 
of a third heart sound, bilateral pulmonary rales, worsening ascites or pedal 
edema, hypotension or signs of worsening end-organ perfusion; and/or 
▪ Laboratory evidence, which may include pulmonary congestion on chest x-
ray, elevated natriuretic peptide level, worsening oxygenation or 
respiratory acidosis. 
 
Examples of intravenous heart failure therapy would include: 
▪ IV bolus or infusion of loop diuretics, vasodilators such as nitrates, 
nitroprusside, nesiritide, vasopressors including dobutamine or dopamine, 
and inotropic agents such as milrinone. 
▪ Also included would be other invasive or mechanical heart failure 
treatments such as ultrafiltration, or hemodynamic assist devices such as 
intra-aortic balloon pumps or LVADs. 
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1. Treatment with IV antiarrhythmic medication, electrical cardioversion and/or 
ablation in the absence of other intravenous or invasive heart failure treatments 
would not per se constitute an ADHF event. 
2. Heart failure exacerbation that can be managed solely by augmentation of oral 
heart failure therapies does not meet criteria for heart failure hospitalization. 
3. ADHF that develops secondary to another diagnosis such as a non-cardiac 
diagnosis (e.g., pneumonia/bronchitis, limb fracture, renal failure), an acute MI 
complicated by ADHF, acute onset of atrial fibrillation with rapid ventricular 
response or a rupture chordae would not be counted as ADHF events. 
HEART TRANSPLANT 
Replacement of a native heart with a donor heart. 
HEMATOMA 
A swelling or mass of blood (usually clot), six (6) centimeters or longer, that causes 
bruising or bleeding of the body tissue at the catheter insertion site.  This event may 
occur after the index procedure and may or may not require treatment. 
HEMOLYSIS 
A new onset of anemia associated with laboratory evidence of red cell destruction.  
This is diagnosed as plasma free hemoglobin that is greater than 40 mg/dL on two 
(2) measures within 24 hours or on one measure if the intervention is initiated based 
upon other clinical symptoms. 
HYPOTENSION/HYPERTENSION 
Hypotension 
A decrease of the systolic and diastolic blood pressure to below normal for the 
subject, which requires treatment.  This may occur as a result of infection, fever, 
hemorrhage, shock, or anemia.  It may occur anytime throughout a subject’s 
participation in the study.  
Hypertension 
A higher than normal blood pressure that requires treatment.  This may occur at any 
time throughout a subject’s participation in the study. 
INDEX PROCEDURE 
The index procedure takes place immediately following randomization and is the 
starting point for timing of all follow-up evaluations and data analyses. 
INFECTION, GENERALIZED 
The presence and growth of microorganisms that produces tissue damage, usually 
accompanied by inflammation.  Infection requiring treatment will be documented as 
an adverse event.  
INFECTION AT THE CATHETER INSERTION SITES 
An infection or inflammatory response that occurs at one or more catheter insertion 
sites in relationship to the index procedure and that requires treatment. 

 
 
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INFORMED CONSENT 
Informed consent is a process by which a subject voluntarily confirms his or her 
willingness to participate in a particular study, after having been informed of all 
aspects of the investigation that are relevant to the subject’s decision to participate.  
Informed consent is documented by means of a written, signed, and dated informed 
consent form. 
INVESTIGATOR 
A person responsible for the conduct of the clinical investigation at an investigation 
site.  If an investigation is conducted by a team of individuals at an investigation site, 
the Investigator is the responsible leader of the team and may be called the Principal 
Investigator.  The Investigator is responsible for assuring the investigation is 
conducted in accordance with all applicable regulations including those protecting 
human subjects. 
INVESTIGATIONAL PRODUCT 
Investigational product is defined as the investigational device, its accessories, and 
accompanying labeling. 
LEFT VENTRICULAR EJECTION FRACTION 
The percentage of the blood emptied from the ventricle during systole. 
LEUKOPENIA 
Decrease in white blood count to below the lower limit of normal.  Leukopenia may 
be caused by prolonged radiation exposure. 
 
MAJOR ADVERSE EVENT (MAE) 
Defined as one of the following:  (1) Death; (2) Myocardial Infarction;  
(3) Device embolization; (4) Vessel erosion requiring percutaneous or surgical 
intervention; (5) Cardiac perforation requiring percutaneous or surgical intervention; or 
(6) Occurrence of cardiac surgery or percutaneous coronary intervention associated with 
device failure.  
MARKER CATHETER 
An angiographic catheter used to measure the coronary sinus/great cardiac vein. 
MEDICAL ETHICS COMMITTEE 
The medical ethics committee, according to Directive 2001/20/EC, is an independent 
body in a member state of the European Union, consisting of healthcare 
professionals and non-medical members, whose responsibility it is to protect the 
rights, safety and well being of human subjects involved in a clinical trial and to 
provide public assurance of that protection, by, among other things, expressing an 
opinion on the clinical trial protocol, the suitability of the investigators involved in 
the trial and the adequacy of facilities, and on the methods and documents to be used 
to inform trial subjects and obtain their informed consent.  
MITRAL ANNULOPLASTY RING 
A prosthetic ring sutured into the mitral valve annulus during open heart surgery.  

 
 
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MITRAL REGURGITATION 
The backward flow of blood across the mitral valve from the left ventricle to the left 
atrium that results from imperfect closure of the mitral valve.  Mitral valve 
regurgitation may be classified in several ways including echocardiographically, 
fluoroscopically, and clinically.   
 
Primary cardiomyopathy with secondary mitral regurgitation will be distinguished 
by the presence of left ventricular dilation, left ventricular dysfunction, and 2+ - 4+ 
mitral regurgitation and the absence of significant mitral valve pathology where 
mitral valve pathology includes mitral valve prolapse, flail leaflet, or evidence of 
degenerative or rheumatic mitral valve disease.  Primary mitral regurgitation with 
secondary dysfunction implies that structural valve pathology exists (e.g., prolapse, 
flail leaflet, degenerative or rheumatic mitral valve disease) and has caused the left 
ventricular dilation and dysfunction.  Thus, subjects with significant organic mitral 
valve pathology and left ventricular dysfunction will be considered to have primary 
mitral regurgitation and secondary dysfunction. 
Mitral regurgitation may occur at any time throughout a subject’s participation in the 
study.  An acute, hemodynamically significant increase in MR will be documented 
as an adverse event. 
MITRAL STENOSIS 
A narrowing of the mitral orifice, obstructing free flow of blood from the left atrium 
to the left ventricle. This may occur at any time throughout a subject’s participation 
in the study. 
This study will define mitral stenosis as being present if both of the following 
criteria are met: 
1. Either peak E wave velocity > 1.5 m/s (corresponding to a peak gradient  10 
mmHg), or mean pressure gradient > 5 mmHg, and 
2. Either, one of the following: 
a. Mitral valve area calculated by PHT is < 2.0 cm2 (i.e., PHT > 110 msec), or  
b. 2D mitral valve planimetry (or alternatively a mitral inflow color PISA, if 
present) reveals a mitral valve area of < 2.0 cm2.  
MITRAL VALVE 
The cardiac valve between the left atrium and left ventricle. 
MITRAL VALVE INJURY  
Injury or trauma to the mitral valve that requires observation or intervention 
throughout a subject’s participation in the study. 
MYOCARDIAL INFARCTION 
Myocardial infarction (MI) is defined for events that occur  24 hours and for events 
that occur > 24 hours after the index procedure or any percutaneous cardiac 
intervention that may be required during the subject’s participation in the study. 
 
Less than or equal to 24 hours post-intervention 

 
 
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In patients undergoing PCI with normal (≤99th percentile URL) baseline cTn 
concentrations, elevations of cTn >5 x 99th percentile URL occurring within 48 
hours of the procedure—plus either:  
(i) evidence of prolonged ischemia (≥20 min) as demonstrated by prolonged chest 
pain, or  
(ii) ischemic ST changes or new pathological Q waves, or  
(iii) angiographic evidence of a flow limiting complication, such as of loss of 
patency of a side branch, persistent slow-flow or no-reflow, embolization, or  
(iv) imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality 
is defined as PCI-related MI (type 4a). 
Note: When a cTn value is ≤5 x 99th percentile URL after PCI and the cTn value was 
normal before the PCI—or when the cTn value is >5 x 99th percentile URL in the 
absence of ischemic, angiographic or imaging findings—the term ‘myocardial 
injury’ should be used. 
 
More than 24 hours post-intervention 
Myocardial infarctions more than 24 hours after percutaneous cardiac intervention 
will be defined according to the ESC/ACCF/AHA/WHF Expert Consensus 
Universal Definition of MI37 and will be adjudicated by an independent Clinical 
Events Committee. 
 
MYOCARDIAL ISCHEMIA 
Inadequate circulation of blood to the heart muscle due to obstructions of coronary 
arteries as documented by electrocardiography and/or imaging modalities. This may 
occur at any time throughout a subject’s participation in the study. 
NAUSEA/VOMITING 
Nausea is an uneasiness of the stomach that often accompanies the urge to vomit, but 
doesn’t always lead to vomiting.  Vomiting is the forcible voluntary or involuntary 
emptying (“throwing up”) of stomach contents through the mouth.  Nausea or 
vomiting requiring treatment will be documented as adverse events. 
   
NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) 
Classification system for defining cardiac disease and related functional limitations into 
four broad categorizations.  NYHA Classification assessment will be made by 
independent examiner at all study time-points.  Refer to Appendix D for specific 
definitions. 
NITINOL 
A super-elastic shape-memory Nickel-Titanium alloy used commonly in cardiac, 
dental, and orthopedic implants as well as in other non-implant medical devices. 
NON-PYROGENIC 
The term applies to a biocompatibility test of the device materials to assure that no 
foreign proteins are produced by the interaction of the device with the myocardial 
tissue that would cause a fever. 

 
 
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PAIN 
An unpleasant sensory and emotional experience arising from actual or potential 
tissue damage, which requires treatment. 
 
PERFORATION (arterial, venous or cardiac) 
Perforation associated with puncture and/or rupture of a cardiac structure, or of a 
arterial or venous access vessel.   
 
A perforation during the index procedure will be classified as a major adverse event 
only if it is associated with puncture or rupture of a cardiac structure (heart, coronary 
artery, and/or coronary vein) leading to hemopericardium and requiring 
percutaneous or surgical intervention. 
PERFUSION 
Passage of blood into the surrounding tissue 
PERICARDIAL EFFUSION 
Fluid in the pericardial space documented by echocardiography or other methods. 
PERICARDITIS 
Inflammation of the pericardium or development of an unexplained pericardial 
effusion.  Pericarditis will be diagnosed by the presence of at least two of the 
following clinical features: 1) chest pain, 2) pericardial friction rub on exam, 3) 
characteristic ECG changes (new widespread ST elevation or PR depression), and 4) 
pericardial effusion.   
PERIPHERAL ISCHEMIA 
Inadequate flow of blood to the arteries or veins of the extremities that may result in 
pain or injury to the blood vessel. This event may or may not require intervention 
and can occur at any time throughout a subject’s participation in the study. 
PHARYNGEAL / LARYNGEAL TRAUMA 
Injury to the pharynx or larynx (e.g., dysphagia, vocal cord disorder, throat pain), 
which requires treatment and is related to a transesophageal echocardiogram 
performed during the subject’s participation in the study. 
 
PHYSICAL INJURY 
Trauma or damage to a part of the body, which requires treatment and is related to 
functional tests (e.g., exercise treadmill) performed during the subject’s participation 
in the study. 
 
PLICATION 
The creation of folds or tucks in tissue (e.g., vein) to shorten its length. 
PNEUMONIA 
An inflammation of the alveoli, interstitial tissue, and bronchioles of the lungs due to 
infection by bacteria, virus, or other pathogenic organisms, or to irritation by 
chemical or other agents. 

 
 
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PNEUMOTHORAX 
A collection of air in the pleural cavity that requires intervention. This may be a 
result of injury, bleb, or superficial lung abscess and may occur at any time 
throughout a subject’s participation in the study. 
RADIATION DERMATITIS 
Skin burns ranging from erythema to blistering/ulceration, and caused by prolonged 
radiation exposure. 
 
RECAPTURE 
The mechanism of retrieving the CARILLON implant from its anchored position 
within the coronary sinus/great cardiac vein.  This is achieved by using the delivery 
catheter to collapse the device into the catheter for removal from the subject.  The 
CARILLON Mitral Contour System is designed to enable acute recapturing (i.e., 
prior to decoupling from the delivery system) if the implant cannot be placed safely 
in its intended location. 
REINTERVENTION 
Any unscheduled visit to the operating room or catheterization laboratory for 
reintervention related to the CARILLON investigational procedure or study device. 
RENAL FAILURE  
Renal insufficiency resulting in an increase in serum creatinine that requires dialysis.  
This event may occur as a result of any study procedures that require the use of 
contrast media. 
RENAL INSUFFICIENCY  
Any clinically significant increase in creatinine above baseline requiring treatment 
(excluding dialysis). 
RESPIRATORY DISTRESS 
Severe and sustained impairment of respiratory function, which is related to study 
procedures and requires treatment. 
 
SEPTICEMIA/SEPSIS 
A serious, systemic, rapidly progressive, life-threatening infection caused by 
pathogenic organisms or their toxins, that may or may not be associated with a 
positive blood culture, and requiring hospitalization and treatment with antibiotics.  
A full course of antibiotic therapy is defined as seven (7) days or longer. 
SERIOUS ADVERSE EVENT 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in 
 1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
 3) in-patient or prolonged hospitalization, or 

 
 
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4) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect 
 
NOTE Planned hospitalization for a pre-existing condition, or a procedure required 
by the CIP, without serious deterioration in health, is not considered a serious 
adverse event. 
 
SIGNIFICANT ORGANIC MITRAL VALVE PATHOLOGY 
Moderate or severe myxomatous degeneration, with or without mitral leaflet 
prolapse, rheumatic disease, full or partial chordal rupture. 
STROKE 
A neurological deficit lasting 24 hours or longer, or lasting less than 24 hours with a 
brain imaging study showing infarction.  This may occur at any time throughout a 
subject’s participation in the study and may or may not require treatment. 
 
SYSTOLIC ANTERIOR MOTION 
Anterior displacement of the anterior mitral valve leaflet during systole causing left 
ventricular outflow tract obstruction. 
 
TENSIONING 
With the CARILLON implant deployed, tensioning is the process of applying 
translational movement (by pulling) of the delivery system to cause the coronary 
sinus/great cardiac vein tissue to plicate. 
 
TIMI CLASSIFICATION 
Thrombolysis in Myocardial Infarction has four classifications: 
 
TIMI 0:  No perfusion. 
 
TIMI 1:  Penetration with minimal perfusion.  Contrast fails to opacify the entire 
bed distal to the stenosis for the duration of the cine run. 
 
TIMI 2:  Partial perfusion.  Contrast opacifies the entire coronary bed distal to the 
stenosis.  However, the rate of entry and/or clearance is slower in the coronary bed 
distal to the obstruction than in comparable areas not perfused by the dilated vessel. 
 
TIMI 3:  Complete perfusion.  Filling and clearance of contrast equally rapid in the 
coronary bed distal to stenosis as in other coronary beds. 
 
TISSUE NECROSIS 
Tissue death within the external or internal layers of the blood vessel(s) (arterial or 
venous), heart structures, or myocardium caused by the CARILLON implant, which 
requires treatment.  This may occur at any time throughout a subject’s participation 
in the study. 
 
TISSUE PENETRATION 
Outward radial movement of the CARILLON implant (e.g., the anchor wireforms) 
from the lumen of the vein into the adjacent tissue, with no compromise to the 

 
 
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integrity of the tissue.  The relative position of the device with respect to its intended 
position within the vein is unchanged.   
 
TRANSIENT ISCHEMIC ATTACK (TIA) 
A neurological deficit lasting less than 24 hours and, if an imaging study is 
performed, shows no evidence of infarction.  This may occur at any time throughout 
a subject’s participation in the study and may or may not require treatment. 
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has 
not been identified in the current version of the study documentation.   
URINARY TRACT INFECTION 
Infection of the urinary tract with microorganisms, which requires treatment. 
 
VASOVAGAL REACTION 
Hypotension, pallor, sweating, hyperventilation, bradycardia, and/or syncope 
produced by stimulation of the vagus nerve during study-related procedures.  A 
vasovagal reaction requiring treatment will be documented as an adverse event. 
 
VENOGRAM 
Angiography of the vein. 
VENTRICULAR ASSIST DEVICE 
A mechanical pump that assists the heart by pumping blood through the body. 
VESSEL EROSION 
A physical or inflammatory process adjacent to the CARILLON implant causing 
loss of tissue integrity of the blood vessels (arterial or venous), heart structures, or 
myocardium.  Vessel erosion will be classified as a major adverse event only if 
percutaneous or surgical intervention is required. 
VESSEL OCCLUSION (arterial or venous) 
Complete blockage of a blood vessel preventing the flow of blood and resulting in 
cardiac symptoms and requiring treatment. 
VESSEL SPASM OR STENOSIS (ARTERIAL OR VENOUS) 
Vessel Spasm 
Temporary abrupt contraction of the muscles in the wall of a blood vessel resulting 
in reduced blood flow.  A spasm that results in myocardial ischemia or requiring 
treatment will be considered an adverse event. 
Vessel Stenosis 
Narrowing of a blood vessel that requires treatment. 

 
 
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Appendix A – Instructions for Use 
This appendix provides a copy of the Instructions for Use for the CARILLON Mitral 
Contour System. 
 
 

 
 
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Appendix B – Sample of Informed Consent 
This appendix provides a copy of the sample informed consent for the REDUCE FMR 
Trial. 
 

 
 
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Appendix C – Subject Study Calendar 
Schedule of assessments: 
PRIMARY STUDY 
 
CROSS-OVER REGISTRY  
(Treatment & Control pts)  
(Control pts upon primary study completion) 
Study Task 
Screening / 
Baseline 
Index 
Procedure 
Discharge 
1 Month  
(±7 Days) 
6 month 
(±14 Days)  
12 month 
(±30 Days) 
 
Screening / 
Baseline 
CARILLON 
Procedure 
Discharge 
1 month 
(±7 Days) 
Informed Consent 
X 
Randomization
 
 
 
 
 
 
 X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
X 
 
 
 
Past Medical History & 
Physical Exam 
X 
 
 
 
 
 
 
X11,12 
 
 
 
Serum Pregnancy Test 
X 
 
 
 
 
 
 
X 
 
 
 
TEE1 
X 
 
 
 
 
 
 
X 
 
 
 
Coronary Angiography 
X2 
X2 
 
 
 
 
 
X 
X 
 
 
Coronary Sinus Venogram 
X 
 
 
 
 
 
 
X 
 
 
 
Intraprocedure Echo 
(TTE or TEE) 
 
X 
 
 
 
 
 
 
X 
 
 
Physical Exam 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
Vital Signs3 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Coagulation Tests4 
X 
 
 
 
 
 
 
X 
 
 
 
Cardiac Enzymes5 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
Chemistries6 
X 
 
X 
X 
X 
X 
 
X12 
 
X 
X 
CBC7 
X 
 
X 
X 
X 
X 
 
X12 
 
X 
X 
12-Lead ECG 
X 
 
X 
X 
X 
X 
 
X12 
 
X 
X 
Complete TTE 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
Exercise TTE8 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
Abbreviated TTE9 (safety) 
 
 
X 
 
 
 
 
 
 
X 
 
CXR or cine fluoroscopy 
 
 
X 
 
X 
X 
 
 
 
X 
 
Six Minute Walk Test 
X10 
 
 
X 
X 
X 
 
X12 
 
 
X 
NYHA Classification  
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
KCCQ 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
SF-12 QoL 
X 
 
 
X 
X 
X 
 
X12 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
1. To rule out LAA clot - only required for subjects with a prior history of atrial fibrillation 
2. The eligibility angiography may occur immediately prior to randomization, unless a recent angiogram (see section 3.4.3.2) indicating no CAD requiring 
intervention is available. All Treatment group subjects undergo coronary angiography as part of the CARILLON Mitral Contour System procedure.  
3. Vital signs include: Blood pressure, heart rate, respiratory rate, oxygen saturation, temperature (degrees Celsius), weight, height (baseline only).  
4. Coagulation Tests include: PTT and Prothrombin time. 
5. Cardiac enzymes: cardiac troponin (cTn).  
6. Serum chemistries: sodium, potassium, chloride, BUN, creatinine and NT-BNP.  
7. CBC with differential: hemoglobin, hematocrit, platelets, and WBC.  
8. Exercise TTE will be done only at pre-identified qualified sites with supine bicycle ergometry. 
9. Abbreviated TTE safety assessment to rule out pericardial effusion.  
10. Six-minute walk test will be undertaken for screening and baseline (reference Appendix F: Six Minute Walk Test Protocol).  
11. No past medical history needed, physical exam only. 
12. Data from 12-mo follow-up of the primary study may be used if assessments were performed within 45 days to scheduled Cross-Over CARILLON   procedure. 

 
 
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Appendix D – NYHA Classification of Patients 
with Diseases of the Heart  
 
Functional Classification 
Class I 
Patient with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
Class II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results 
in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased. 
 
(New York Heart Association Criteria Committee: Diseases of the Heart and Blood Vessels: Nomenclature and 
Criteria for Diagnosis, 6th ed. Boston, Little, Brown, & Co. 1964) 
 
 
 

 
 
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Appendix E – Echocardiogram Protocol 
This appendix provides a copy of the Echocardiogram Protocol for the baseline, 
procedure, discharge, and follow-up echocardiograms for the REDUCE FMR Trial. 

 
 
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Appendix F – Six Minute Walk Test Protocol 
All study subjects will perform a Six Minute Walk Test (6MWT) at screening, baseline 
and at each scheduled follow-up visit.  To minimize any training effect, the screening 
and baseline tests should be two distinct assessments. Site personnel who administer the 
6MWT will be blinded to the study subject’s randomization assignment. 
The test will be supervised by the Investigator or designee who will be responsible for 
the quality of patient preparation, reports and data collection.  
• 
Prior to the start of each exercise test, make sure that the subject has not had any 
unstable cardiac symptoms and that there is no contraindication for proceeding 
with a stress test. 
• 
Select a low-traffic corridor that is at least 25 meters in length.  This corridor must 
not have any doors or obstructions that would open into the course and interfere 
with the subject’s ability to walk.  Mark off sections that are five (5) meters apart. 
• 
Have a chair available for the study subject to rest in if needed. 
Six Minute Walk Test Procedure 
1 
Study Subject Instructions 
Instruct the study subject to walk as far as they can for six minutes.  If they need to 
stop for fatigue or other medical reasons, they may do so, but should start walking as 
soon as they are able or are instructed to stop.  Inform the subject to turn around 
when they reach the 25 meter mark and walk back to the starting point.  They are to 
repeat this process as many times as they are able until they are instructed to stop.  
Answer any questions the subject has regarding the 6MWT prior to starting the test. 
2 
Exercise 
As soon as the study subject starts walking, start the stop watch and monitor the 
distance covered.  During the test, DO NOT speak with the subject unless there is an 
emergent reason. 
3 
Immediate Post Exercise 
At six minutes, instruct the subject to stop and stand in that spot.  Bring the chair to 
the subject and ask him or her to rest.  Calculate the total distance walked during the 
six minutes to the nearest meter. 
 
 

 
 
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Appendix G – Definition of Stable Heart Failure 
Regimen 
All study subjects must be on a stable heart failure medical regimen. A stable regimen is 
defined as the following: 
• On an adjustable diuretic dose for three (3) months 
• On ACE inhibitor or angiotensin receptor blocker for three (3) months with stable 
dosage for two (2) months (or documented intolerance to the medication) 
• On a beta-blocker for three (3) months with stable dosage for two (2) months (or 
documented intolerance to the medication) 
Patients must meet all three of the medication criteria unless intolerance to the 
medications is documented. 

 
 
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Appendix H – Exercise Echocardiography 
Protocol Synopsis 
Only study centers with the necessary exercise equipment and echosonographers 
experienced in obtaining echo imaging during exercise will be allowed to undertake 
exercise TTE assessments.  
Study subjects who are physically capable of exercising on a supine bicycle ergometer 
and who consent to undergoing exercise echocardiography will undertake these 
assessments at baseline and at each scheduled follow-up visit.  
The assessment will be supervised by the Investigator or qualified designee who will be 
responsible for the safety of the subject during the exercise protocol, quality of patient 
preparation, reports and data collection.  
• 
Prior to the start of each exercise test, make sure that the subject has not had any 
unstable cardiac symptoms and that there is no contraindication for proceeding 
with the exercise test. 
Exercise Methodology 
Resting echo measurements will be obtained as part of the complete TTE assessment 
undertaken in the primary study protocol. Subjects will then undergo a graded exercise 
test on a supine bicycle ergometer with workloads being increased by 25W every 3 
minutes until patient/symptom limitation.  
Single-lead electrocardiograms and blood pressure will be recorded every minute. 
Subjects will be asked to declare their perceived exertion according to a Borg scale 
during the test.   
Criteria to halt the test will be chest pain, severe dyspnea, severe fatigue, sustained 
hypotension, sustained ventricular tachycardia, short runs of three or more ventricular 
premature contractions, pallor, or dizziness.  
Echocardiographic Acquisition Methodology 
All echocardiographic images will be obtained in the last 90 seconds of each 3-minute 
workload level.  Imaging should be acquired during a breath hold at the end of 
expiration. The averages of three consecutive beats during exercise will be used for each 
parameter.  
Imaging views to assess the following parameters will be acquired: 
• Effective Regurgitant Orifice Area 
• Mitral Annular diameter/area measurements 
• Pulmonary artery systolic pressure (from TR velocity) 

 
 
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