Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial)

Prospective, randomized, parallel-controlled, multicenter clinical evaluation of the
MitraClip device for the treatment of clinically significant functional mitral regurgitation
in symptomatic heart failure subjects who are treated per standard of care and who have been
determined by the site's local heart team as not appropriate for mitral valve surgery.
Eligible subjects will be randomized in a 1:1 ratio to the MitraClip device (Device group) or
to no MitraClip device (Control group).

As part of the COAPT trial, a subset of patients (at least 50 up to 100 in total) will be
registered in the CPX Sub-study, which is designed as a prospective, randomized (1:1 ratio to
the MitraClip or no MitraClip device), parallel-controlled, multicenter study registering
approximately 50-100 subjects in up to 50 qualified US sites from the COAPT trial. Subjects
registered and randomized in the CPX Sub-study will contribute to the total enrollment
approximately of 610 subjects in the COAPT trial. Roll-in subjects will not participate in
the CPX Sub-study.

The COAPT CAS study is designed as a prospective, multicenter, single arm, continued access
registry study. A maximum of 800 subjects (anticipated) will be registered from up to 75
sites in the United States. The enrollment will end once pre-market approval (PMA) of the
proposed expanded indication of MitraClip System is obtained. Active follow-up of patients
will be performed through 12 months with scheduled visits at 30 days and 12 months. The
national Trans catheter Valve Therapy Registry (TVT Registry) will be used for data
collection through 12 months. Annual follow-up data from 2 years through year 5 post-implant
will be obtained by linkage to the Centers for Medicare and Medicaid Services (CMS) Claims
database.

COAPT CAS data may be used to support the PMA application of the labeling claims for the
treatment of moderate to severe or severe FMR in symptomatic heart failure subjects. This
single arm registry will provide valuable new information regarding use of the MitraClip® NT
System under more "real world" conditions.

COAPT study completed recruiting subjects in June 2017. COAPT CAS is presently recruiting
subjects.

Inclusion Criteria:

1. Symptomatic functional MR (≥3+) due to cardiomyopathy of either ischemic or
non-ischemic etiology determined by assessment of a qualifying transthoracic
echocardiogram (TTE) obtained within 90 days and transesophageal echocardiogram (TEE)
obtained within 180 days prior to subject registration, with MR severity based
principally on the TTE study, confirmed by the Echocardiography Core Lab (ECL). The
ECL may request a transesophageal echocardiogram (TEE) to confirm MR etiology.

Note: Functional MR requires the presence of global or regional left ventricular wall
motion abnormalities, which are believed to be the primary cause of the MR. If a flail
leaflet or other evidence of degenerative MR is present, the subject is not eligible
even if global or regional left ventricular systolic dysfunction is present.

Note: Qualifying TTE must be obtained after the subject has been stabilized on optimal
therapy including Guideline Directed Medical Therapy (GDMT) and at least 30 days
after:

1. a greater than 100% increase or greater than 50% decrease in dose of GDMT

2. revascularization and/or implant of Cardiac Resynchronization Therapy device (CRT
or CRT-D) or reprogramming of an implanted CRT or CRT-D that results in increased
biventricular pacing (from <92% to ≥92%)

2. In the judgment of the HF specialist investigator at the site, the subject has been
adequately treated per applicable standards, including for coronary artery disease,
left ventricular dysfunction, mitral regurgitation and heart failure (e.g., with
cardiac resynchronization therapy, revascularization, and/or GDMT). The Eligibility
Committee must also concur that the subject has been adequately treated.

3. New York Heart Association (NYHA) Functional Class II, III or ambulatory IV.

4. The Local Site Heart Team (CT surgeon and HF specialist investigators) and the Central
Eligibility Committee concur that surgery will not be offered as a treatment option
and that medical therapy is the intended therapy for the subject, even if the subject
is randomized to the Control group.

5. The subject has had at least one hospitalization for heart failure in the 12 months
prior to subject registration and/or a corrected brain natriuretic peptide (BNP) ≥300
pg/ml or corrected n-Terminal pro- brain natriuretic peptide NT-proBNP ≥1500 pg/ml
measured within 90 days prior to subject registration ("corrected" refers to a 4%
reduction in the BNP or NT-proBNP cutoff for every increase of 1 kg/m2 in BMI above a
reference BMI of 20 kg/m2).

Note: BNP or NT-proBNP must be obtained after the subject has been stabilized on GDMT
and at least 30 days after:

1. a greater than 100% increase or greater than 50% decrease in dose of GDMT

2. revascularization and/or implant of Cardiac Resynchronization Therapy device (CRT
or CRT-D) or reprogramming of an implanted CRT or CRT-D that results in increased
biventricular pacing (from <92% to ≥92%).

6. Left Ventricular Ejection Fraction (LVEF) is ≥20% and ≤50% within 90 days prior to
subject registration, assessed by the site using any one of the following methods:
echocardiography, contrast left ventriculography, gated blood pool scan or cardiac
magnetic resonance imaging (MRI).

Note: The method must provide a quantitative readout (not a visual assessment).

7. The primary regurgitant jet is non-commissural, and in the opinion of the MitraClip
implanting investigator can be successfully be treated by the MitraClip. If a
secondary jet exists, it must be considered clinically insignificant.

8. Creatine Kinase-MB (CK-MB) obtained within prior 14 days < local laboratory Upper
Limit of Normal (ULN).

9. Transseptal catheterization and femoral vein access is determined to be feasible by
the MitraClip implanting investigator.

10. Age 18 years or older.

11. The subject or the subject's legal representative understands and agrees that should
he/she be assigned to the Control group, he/she will be treated with medical therapy
and conservative management without surgery and without the MitraClip, either
domestically or abroad. If the subject would actively contemplate surgery and/or
MitraClip if randomized to Control, he/she should not be registered in this trial.

12. 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.

13. Left Ventricular End Systolic Dimension (LVESD) is ≤ 70 mm assessed by site based on a
transthoracic echocardiographic (TTE) obtained within 90 days prior to subject
registration.

For the CPX Sub-study: Subjects have to meet the COAPT study eligibility criteria to be
registered in the CPX Sub-study.

COAPT CAS study Inclusion Criteria:

1. Subjects must meet all of the above COAPT RCT inclusion criteria, and must have national
Medicare coverage by the Centers for Medicare and Medicaid Services (CMS).

Exclusion Criteria:

1. Chronic Obstructive Pulmonary Disease (COPD) requiring continuous home oxygen therapy
or chronic outpatient oral steroid use.

2. Untreated clinically significant coronary artery disease requiring revascularization.

3. Coronary artery bypass grafting (CABG) within 30 days prior to subject registration.

4. Percutaneous coronary intervention within 30 days prior to subject registration.

5. Transcatheter aortic valve replacement (TAVR) within 30 days prior to subject
registration.

6. Tricuspid valve disease requiring surgery or transcatheter intervention.

7. Aortic valve disease requiring surgery.

8. Cerebrovascular accident within 30 days prior to subject registration.

9. Severe symptomatic carotid stenosis (> 70% by ultrasound).

10. Carotid surgery or stenting within 30 days prior to subject registration.

11. American College of Cardiology /American Heart Association (ACC/AHA) Stage D heart
failure.

12. Presence of any of the following:

- Estimated pulmonary artery systolic pressure (PASP) > 70 mm Hg assessed by site
based on echocardiography or right heart catheterization, unless active
vasodilator therapy in the cath lab is able to reduce the pulmonary vascular
resistance (PVR) to < 3 Wood Units or between 3 and 4.5 Wood Units with v wave
less than twice the mean of the pulmonary capillary wedge pressure

- Hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive
pericarditis, or any other structural heart disease causing heart failure other
than dilated cardiomyopathy of either ischemic or non ischemic etiology

- Infiltrative cardiomyopathies (e.g., amyloidosis, hemochromatosis, sarcoidosis)

- Hemodynamic instability requiring inotropic support or mechanical heart
assistance.

13. Physical evidence of right-sided congestive heart failure with echocardiographic
evidence of moderate or severe right ventricular dysfunction as assessed by site.

14. Implant of any Cardiac Resynchronization Therapy (CRT) or Cardiac Resynchronization
Therapy with cardioverter-defibrillator (CRT-D) within the last 30days prior to
subject registration.

15. Mitral valve orifice area < 4.0 cm2 assessed by site based on a transthoracic
echocardiogram (TTE) within 90 days prior to subject registration.

16. Leaflet anatomy which may preclude MitraClip implantation, proper MitraClip
positioning on the leaflets or sufficient reduction in MR by the MitraClip. This
evaluation is based on transesophageal echocardiogram (TEE) evaluation of the mitral
valve within 180 days prior to subject registration and includes:

- Insufficient mobile leaflet available for grasping with the MitraClip device

- Evidence of calcification in the grasping area

- Presence of a significant cleft in the grasping area

- Lack of both primary and secondary chordal support in the grasping area

- Leaflet mobility length < 1 cm

17. Hemodynamic instability defined as systolic 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.

18. Need for emergent or urgent surgery for any reason or any planned cardiac surgery
within the next 12 months.

19. Life expectancy < 12 months due to non-cardiac conditions.

20. Modified Rankin Scale ≥ 4 disability.

21. Status 1 heart transplant or prior orthotopic heart transplantation.

22. Prior mitral valve leaflet surgery or any currently implanted prosthetic mitral valve,
or any prior transcatheter mitral valve procedure.

23. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.

24. Active endocarditis or active rheumatic heart disease or leaflets degenerated from
rheumatic disease (i.e., noncompliant, perforated).

25. Active infections requiring current antibiotic therapy.

26. Subjects in whom transesophageal echocardiography (TEE) is contraindicated or high
risk.

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

28. Pregnant or planning pregnancy within next 12 months.

Note: Female patients of childbearing age should be instructed to use safe
contraception (e.g. intrauterine devices, hormonal contraceptives: contraceptive
pills, implants, transdermal patches hormonal vaginal devices, injections with
prolonged release.

29. Currently participating in an investigational drug or another device study that has
not reached its primary endpoint. Note: Trials requiring extended follow-up for
products that were investigational, but have since become commercially available, are
not considered investigational trials.

30. Subject belongs 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 to comply with study procedures.

For the CPX Sub-study: Subjects who have any contraindications to CPX and are not capable
of performing CPX per investigator's assessment should not be registered in the CPX
Sub-study.

COAPT CAS study Exclusion Criteria:

1. Subjects must not meet any of the above COAPT RCT exclusion criteria.