For Investigators

Trial Protocol

Endpoints

Primary Endpoint

  • Composite rate of recurrent HF hospitalizations and CV death

Key Secondary Endpoints

  • Change in 6 Minute Walking Test distance from baseline to 6, 12 and 24 months
  • Change in QoL (KCCQ) from baseline to 12 months
    – All‐cause mortality
    – CV mortality (component of primary EP)
    – Recurrent hospitalisations for HF (component of primary EP)
  • Change in MR severity (by echocardiography) from baseline to 12 months

Key Inclusion Criteria

Subjects must meet ALL of the following inclusion criteria to participate in the trial:

  1. Age between 18 years and 90 years old.
  2. Clinically significant functional mitral regurgitation (moderate-to-severe or severe MR), as defined by European Association of Echocardiography, within 90 days prior to randomization and confirmed by the Echocardiography Core Laboratory.
    Note: The TTE must be obtained after the subject has been stabilized on optimal therapy and has undergone revascularization and/or CRT, as appropriate.
  3. Assessed by the investigator to be on optimal standard of care therapy for heart failure according to current ESC/HFA guidelines with no dose changes of heart failure drugs (with the exception of diuretics) during the last 2 weeks immediately prior to randomization. Comment: Significant dose changes are considered to be present, if a new drug class was started or when the dose of an existing drug class was increase >100%.
  4. Symptomatic with documented New York Heart Association Class II, III or IV heart failure, despite optimal standard of care therapy , within 30 days preceding randomization.
  5. Minimum of one documented hospitalization (acute care admission or emergency room visit) for heart failure within 12 months preceding randomization OR values of at least 300 pg/mL for BNP or at least 1000 pg/mL for NT-proBNP after optimal medical and/or device management within 90 days preceding randomization.
    Note: BNP or NT-proBNP must be obtained after the subject has been stabilized on optimal therapy and has undergone revascularization and/or CRT, as appropriate.
  6. Left ventricular ejection fraction (LVEF) of ≥ 15% to ≤ 35% (if in NYHA Functional Class II) or of ≥ 15% to ≤ 45% (if in NYHA Functional Class III or IV).
    Note: LVEF needs to be determined by one of the following methods: transthoracic echocardiography (TTE), contrast ventriculography, gated blood pool scan, cardiac magnetic resonance) within 90 days prior to randomization.
  7. Patient is ambulatory and able to perform a 6MWT with the only limiting factor(s) being due to cardiovascular fitness, unless in NYHA functional class IV.
  8. Subject agrees to return for all required post-procedure follow-up visits.
  9. The subject has been informed of the nature of the study and agrees to the study’s provisions, including the possibility of randomization to the Control group, and has provided written informed consent as approved by the respective clinical site’s Ethics Committee.

Key Exclusion Criteria

Subjects must NOT meet any of the following exclusion criteria to participate in the trial:

  1. Mitral regurgitation is primarily due to degenerative disease of the mitral valve apparatus (Degenerative MR), as determined by transesophageal echocardiography (TEE) or, if applicable, transthoracic echocardiography (TTE).
  2. Status 1 heart transplant or prior orthotropic heart transplantation
  3. Introduction of a new heart failure drug class within the last 2 weeks prior to randomization
  4. Evidence of acute coronary syndrome, transient ischemic attack or stroke within 90 days prior to randomization.
    Update: An “acute coronary syndrome” (ACS) here means that it is an ACS that requires intervention. An increase in troponin without acute symptoms with “chest pain” is not an ACS in the sense of exclusion criterion 4.
  5. Any percutaneous cardiovascular intervention, carotid surgery, cardiovascular surgery, or atrial fibrillation ablation within 90 days prior to randomization
  6. Implant of any rhythm management device (i.e., pacemaker, Cardiac Resynchronization Therapy with or without cardioverter-defibrillator (CRT or CRT-D), or Implantable Cardioverter Defibrillator (ICD)) within 90 day prior to randomization, or revision of any implanted rhythm management device within 90 days prior to randomization.
  7. Need for any cardiovascular surgery.
  8. Mitral valve surgery is considered the preferred therapeutic option for the subject.
  9. Renal replacement therapy.
  10. Uncontrolled hypertension (i.e. SBP >180 mmHg and/or DBP >105 mmHg) or hypotension (i.e. SBP <90 mmHg)
  11. Unstable angina pectoris as judged by the investigator, other clinically significant uncorrected valvular disease or left ventricular outflow obstruction, obstructive cardiomyopathy, poorly controlled fast atrial fibrillation or flutter, poorly controlled symptomatic brady- or tachyarrhythmia.
  12. 6MWT distance > 475 meters.
  13. Exclusion criteria is a Mitral Valve Area (MVA) by planimetry of <3.0 cm2. If MVA by planimetry is not measurable, pressure half-time measurement is acceptable. MVA estimates of ≥3.0 to <4 cm2 are no automatic exclusion criteria to the study. A MVA of 3.0-4.0 cm2 can be considered acceptable for inclusion in persons with (a) a body surface area (BSA) <2.00 m2 according to either the Du Bois or the Mosteller formula, and (b) a mean valve gradient of ≤3 mmHg not related to regurgitant flow, thus excluding mitral valve stenosis. The MVA estimates must be confirmed by the Echocardiography Core Laboratory to qualify for study inclusion.
  14. Leaflet anatomy which may preclude MitraClip device implantation, proper device positioning on the leaflets, or sufficient reduction in MR as per the investigators opinion.
  15. Presence of an IVC filter in the femoral vein that would interfere with the delivery catheter, or ipsilateral deep vein thrombosis (DVT) is present
  16. Contraindication to transseptal catheterization
  17. Subjects in whom transesophageal echocardiography is contraindicated
  18. Echocardiographic evidence of intracardiac mass, thrombus, or vegetation
  19. Active endocarditis or active rheumatic heart disease or leaflets degenerated from rheumatic disease (i.e., noncompliant, perforated)
  20. Presence of any of the following:
    – Severe aortic stenosis (aortic valve area <1.0 cm2) or severe aortic regurgitation
    – Infiltrative cardiomyopathies (e.g., amyloidosis, hemochromatosis, sarcoidosis)
    – 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
    – Hemodynamic instability requiring inotropic support or mechanical heart circulatory support
  21. Active infections requiring current antibiotic therapy.
  22. Known hypersensitivity or contraindication to procedural medications which cannot be adequately managed medically.
  23. Severe right ventricular failure or severe tricuspid regurgitation.
  24. History of bleeding diathesis or coagulopathy or subject who refuses blood transfusions
  25. Pregnant or planning pregnancy within next 12 months.
    Note: Female patients of childbearing potential need to have a negative pregnancy test performed within 14 days prior to randomization and be adherent to an accepted method of contraception
  26. Concurrent medical condition with a life expectancy of less than 12 months in the judgment of the investigator.
  27. Currently participating in another investigational therapeutic or interventional clinical trial, or in any trial of an unapproved drug, device or procedure.
    Note: Subjects participating in observational studies or registries may be considered as eligible.
  28. 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.

Randomization

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