The CARILLON Trial - Assessment of the Carillon® Mitral Contour System® in Treating Functional Mitral Regurgitation Associated With Heart Failure

A total of 450 subjects will be randomized at up to 75 investigational sites in the United
States, Canada, Europe and Australia. Subjects will be randomized into one of two study
groups using a 2:1 (Intervention : Control) ratio.

Study subjects who are eligible for this clinical study will undergo a transthoracic
echocardiographic examination prior to randomization to evaluate the inclusion criteria
associated with the severity of mitral regurgitation. A coronary angiogram will also be
performed to evaluate the coronary artery anatomy as a final eligibility (screening)
assessment. Subjects who meet all eligibility criteria will be randomized into one of two
study groups (Intervention or Control).

Study subjects will undergo a venogram 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 subject will be randomized.

Subjects randomized to the Intervention group will undergo the CARILLON implant procedure.
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
before, during and after device placement to quantitate the degree of functional mitral
regurgitation and to evaluate left ventricular function. After the proximal anchor of the
implant is locked in place, safety 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
Intervention group (without device placement) to ensure that they will not be able to deduce
the group assignment based on the type of intervention or time associated with the procedure.

After the study subjects are discharged, the subjects' primary care specialists
(cardiologist/heart failure physician) and clinical investigation site staff will coordinate
follow-up evaluations. Subjects will be evaluated at one (1), six (6), twelve (12), eighteen
(18) and twenty-four (24) months post-randomization, to assess long-term safety, and
functional and clinical status.

After the 12-month evaluation, all subjects will be unblinded. Control subjects and
Intervention subjects who were not implanted with CARILLON (e.g., due to venous dissection or
other procedural complication - "Non-Implanted"), may be offered the option to receive the
CARILLON device, as part of a Cross-Over Registry, at the discretion of the study physician
and patient.

All Intervention and Control subjects will be followed with an abbreviated annual contact for
an additional three (3) years, for a total of five (5) years.

Inclusion Criteria:

1. Diagnosis of ischemic or non-ischemic cardiomyopathy

2. Symptomatic functional (secondary) mitral regurgitation defined as both: - 2+
(Moderate), 3+ (Moderate/Severe), or 4+ (Severe).

Note: 4+ can only be included if multidisciplinary site assessment (including a
surgeon) determines that surgery is not necessary within the 1-year follow-up period
for this study.

3. NYHA Class II, III, or IV

4. Six Minute Walk distance ≥ 200 meters and ≤ 450 meters

5. Left Ventricular Ejection Fraction ≤ 50%

1. Subjects with LVEF ≤ 40% have no additional restrictions

2. Subjects with LVEF > 40% and ≤ 50%

- MR grade 3+ or 4+ can only be included if the baseline NYHA is class III or
IV

- MR grade 2+ (at rest) can only be included if the baseline NYHA is class III
or IV AND left atrial volume > 48mm/m2 (normalized to body surface area)

6. LVEDD ≤ 70 mm, or LVEDD / BSA ≤ 4.0 cm/m2 Note: As assessed by Imaging Core
Laboratory.

7. Guideline directed heart failure medication regimen. This minimally includes:

- On ACE inhibitor (ACE-I) for three (3) months with stable dosage for one (1)
month (with documentation as to why this is the maximally tolerated medication,
or achieving the mean dose as described in the ACCF/ AHA guidelines

1. This also includes an Angiotensin II Receptor Blocker (ARB) at stable doses
for one (1) month prior to subject registration in the trial, if tolerated,
when ACE-I is not tolerated.

2. The use of an angiotensin receptor-neprilysin inhibitor (ARNI)
(valsartan/sacubitril) is an acceptable Class I acceptable alternative for
use in patients with HFrEF.34

- On a beta-blocker for three (3) months with stable dosage for one (1) month (with
documentation as to why this is the maximally tolerated medication, or achieving
the mean dose as described in the ACCF/ AHA guidelines

- On a diuretic for three (3) months

8. Age ≥ 18 years old and ≤ 85 years old (assessed at the time of consent)

9. CARILLON implant can be sized and placed in accordance with the IFU

10. The subject or the subject's legal representative has been informed of the nature of
the trial and agrees to its provisions, including the possibility of randomization to
the Control group and returning for all required post-procedure follow-up visits, and
has provided written informed consent

Exclusion Criteria:

1. Recipient of intravenous positive-inotrope infusion or intra-aortic balloon pump
support within the past 30 days

2. Heart failure hospitalization within the past 30 days

3. Anticipated need of left ventricular assist device within twelve (12) months

4. Class I indication for cardiac resynchronization therapy (CRT), or anticipated need
for CRT within twelve (12) months

5. Primary renal dysfunction or compromised renal function as reflected by an estimated
Glomerular Filtration Rate (eGFR) < 30 ml/min, as assessed by MDRD formula

6. Status 1 heart transplant or prior orthotopic heart transplantation

7. Presence of a mechanical or bio-prosthetic mitral valve or, mitral valve annuloplasty,
or leaflet repair device.

8. Hypertrophic cardiomyopathy, infiltrative cardiomyopathy, restrictive cardiomyopathy
or constrictive pericarditis

9. Echocardiographic documentation of non-compaction cardiomyopathy as assessed by the
Imaging Core Laboratory

10. Pre-existing device (e.g., pacing lead) in coronary sinus (CS) / great cardiac vein
(GCV)

11. 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), as assessed by the Imaging Core Laboratory

12. Severe tricuspid regurgitation associated with right ventricular dysfunction and
enlargement, as assessed by the Imaging Core Laboratory

13. Severe mitral annular calcification

14. Severe aortic stenosis

15. Not a candidate for right internal jugular venous cannulation

16. Hospitalization in past 30 days due to myocardial infarction, coronary artery bypass
graft surgery or unstable angina

17. Cerebral vascular event within the past 30 days

18. Hospitalization in the past 30 days for coronary angioplasty or stent placement or ICD
implant

19. Pulmonary embolus or deep vein thrombosis within the past six (6) months

20. Expected to require any cardiac surgery, including surgery for coronary artery disease
(CAD) or for pulmonic, aortic, or tricuspid valve disease within one (1) year

21. Expected to require any percutaneous coronary intervention within 30 days of the index
procedure.

22. Hemodynamic instability defined as sustained systolic blood pressure < 90 mmHg with or
without afterload reduction, cardiogenic shock or the need for inotropic support or
intra-aortic balloon pump or other hemodynamic support device

23. Presence of left atrial appendage (LAA) clot or presence of LAA occluder

24. Anemia defined as hemoglobin < 9.0 mg/dL

25. Currently participating in an investigational drug or device study that has not
completed the primary endpoint or that clinically interferes with the current study
endpoints

26. Known hypersensitivity or contraindication to procedural medications which cannot be
adequately managed medically

27. Active infections requiring current antibiotic therapy

28. Chronic, severe, medical conditions or pathology, other than heart failure, that will
prevent likely survival beyond twelve (12) months

29. Female subjects pregnant or planning to become pregnant in the next five (5) years

30. Subjects unable to perform the required study assessments (e.g., 6 minute walk test)

31. Any other medical condition that, in the judgment of the Investigator, makes the
patient a poor candidate for this study

32. Subjects belonging to a vulnerable population per investigator's judgment or subject
has any kind of disorder that compromises his/her ability to give written informed
consent and/or comply with the study procedures