Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial)
Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial)
The purpose of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy
 for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) Trial is to confirm
 the safety and effectiveness of the MitraClip System for the treatment of moderate-to-severe
 or severe functional mitral regurgitation (FMR) 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. This randomized controlled trial will provide the
 opportunity to strengthen or add labeling claims regarding safety and clinical benefits of
 the MitraClip System for symptomatic heart failure patients with moderate-to-severe or severe
 functional mitral regurgitation.

 Approximately 610 subjects will be randomized at up to 100 investigational sites with
 approximately 305 subjects targeted to receive the study device. COAPT study completed
 recruiting subjects in June 2017.

 As part of the COAPT trial, a subset of patients will be registered in the cardiopulmonary
 exercise (CPX) sub-study. The objective of this sub-study is to evaluate the exercise
 responses in a sub-cohort of COAPT subjects who receive MitraClip device (Device group)
 compared to the Control group who do not receive MitraClip device. (Note: the CPX Sub-study
 subjects will contribute to the analyses of the COAPT primary and secondary endpoints)

 As an extension of the COAPT RCT trial, COAPT CAS study will be conducted after COAPT
 enrollment is complete under the same investigational device exemption (IDE(G120024)). The
 objective of this study is to evaluate the MitraClip® NT System for the treatment of
 clinically significant functional mitral regurgitation (FMR) 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. The anticipated Study
 Completion Date is July 2024. COAPT CAS completed recruiting subjects in March 2019.
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 completed recruiting
 subjects in March 2019.
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.

 .