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The MITRAL II Pivotal Trial (Mitral Implantation of TRAnscatheter vaLves). (MITRAL-II)

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ClinicalTrials.gov Identifier: NCT04408430
Recruitment Status : Recruiting
First Posted : May 29, 2020
Last Update Posted : June 15, 2022
Information provided by (Responsible Party):
Mayra Guerrero, Mayo Clinic

Brief Summary:
A prospective multicenter study enrolling high surgical risk patients with severe mitral annular calcification (MAC) and symptomatic mitral valve disease. There are 2 arms in this study: Transseptal Valve-in-MAC (ViMAC) and a control arm of patients treated with medical treatment only which will include patients who can't be treated due to the presence of anatomical exclusion criteria or other exclusion criteria.

Condition or disease Intervention/treatment Phase
Mitral Annular Calcification Mitral Stenosis Mitral Regurgitation Mitral Valve Disease Device: Transseptal ViMAC Phase 2 Phase 3

Detailed Description:


The purpose of this study is to establish the safety and effectiveness of the Edwards SAPIEN 3 and SAPIEN 3 Ultra valves with Commander delivery system in patients with severe symptomatic calcific mitral valve disease with severe mitral annular calcification who are not candidates for standard mitral valve surgery.


A prospective multicenter study enrolling high surgical risk patients with severe mitral annular calcification (MAC) and symptomatic mitral valve disease. There are 2 arms in this study: Transseptal Valve-in-MAC (ViMAC) and a control arm of patients treated with medical treatment only which will include patients who can't be treated due to the presence of anatomical exclusion criteria or other exclusion criteria.

Enrollment Enrollment will consist of 110 patients in the treatment arm (transseptal ViMAC) and up to 100 in the medically treated arm).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 210 subjects: 110 in treatment arm and 100 in registry of medical treatment for patients who are not eligible for treatment.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Safety and Effectiveness of the SAPIEN 3 and SAPIEN 3 Ultra Valve in Patients With Symptomatic Severe Calcific Mitral Valve Disease With Severe Mitral Annular Calcification Who Are Not Candidates for Standard Mitral Valve Surgery.
Actual Study Start Date : March 8, 2021
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2027

Arm Intervention/treatment
Experimental: Transseptal ViMAC
110 MAC patients treated with transseptal Valve-in-MAC.
Device: Transseptal ViMAC
Transseptal TMVR using balloon-expandable aortic transcatheter valves.
Other Name: ViMAC

No Intervention: Registry of untreated patients
100 MAC patients not eligible for transseptal ViMAC, treated with conservative management including medications.

Primary Outcome Measures :
  1. Primary Safety Endpoint: All Cause Morality and Hospitalization for Heart Failure [ Time Frame: 1 year. ]
    A non-hierarchical composite of all-cause mortality and hospitalization for heart failure.

Secondary Outcome Measures :
  1. Secondary Effectiveness Endpoint [ Time Frame: 1 year ]
    • Stroke at 30 days and 1 year.

  2. Secondary Effectiveness Endpoint [ Time Frame: 1 year. ]
    • Change from baseline in New York Heart Association Class at 1 year.

  3. Secondary Effectiveness Endpoint [ Time Frame: 1 year. ]
    • Change from baseline in distance walked measure by the 6 Minute Walk Test at 1 year.

  4. Secondary Effectiveness Endpoint [ Time Frame: 1 year. ]
    • Change from baseline in quality of life measure by the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 1 year.

  5. Secondary Effectiveness Endpoint [ Time Frame: 1 year. ]
    • Echocardiographic assessment of degree of mitral regurgitation (central and paravalvular) at 1 year.

  6. Secondary Effectiveness Endpoint [ Time Frame: 1 year. ]
    • Significant mitral stenosis defined as mean mitral valve gradient by echo > 10 mmHg at 1 year.

Other Outcome Measures:
  1. Additional Endpoint: Technical Success [ Time Frame: Immediately after the intervention procedure. ]

    • Technical success at exit from the cath lab.

    Defined as:

    • Successful vascular access, delivery and retrieval of the transcatheter valve delivery system.
    • Deployment of a single valve.
    • Correct position of transcatheter valve in the mitral annulus.
    • Adequate performance of the prosthetic heart valve (MVA > 1.5 cm2) without residual mitral regurgitation grade ≥2 (+).
    • No need for additional surgery or re-intervention (includes drainage of pericardial effusion).
    • The patient leaves the cath lab alive.

  2. Additional Endpoint: Procedural Success [ Time Frame: 30 days ]

    • Procedural Success at 30 days.

    Defined as:

    • Device success at 30 days.
    • No device/procedure related SAE's including: death, stroke, MI or coronary ischemia requiring PCI or CABG, stage 2 or 3 AKI including dialysis, life threatening bleeding, major vascular or access complications (arterial, venous, or TA - any event requiring additional unplanned surgical or transcatheter intervention), pericardial effusion or tamponade requiring drainage, severe hypotension, heart failure or respiratory failure requiring intravenous pressors or invasive or mechanical treatments such as ultrafiltration or hemodynamic assist devices including intra-aortic balloon pump or left ventricular assist device, or prolonged intubation for ≥48 hrs, or any valve-related dysfunction, migration, thrombosis, or other complication requiring surgery or repeat intervention.

  3. Additional Endpoint: Device Success [ Time Frame: 30 days. ]

    Device success is defined as:

    • Stroke free survival with original valve in place.
    • No need for additional surgery or re-intervention related to the procedure, access or to the replacement valve.
    • Proper placement and intended function of the replacement valve, including
    • No migration, fracture, thrombosis, hemolysis or endocarditis.
    • No replacement valve stenosis (MV gradient < 10 mmHg).
    • Replacement valve regurgitation < 2 + (including central and paravalvular leak) and without associated hemolysis.
    • No increase in AI from baseline (more than 1 grade) and LVOT gradient < 20 mmHg increase from baseline.

  4. Additional Efficacy Endpoint - NYHA Class at 30 days. [ Time Frame: 30 days. ]
    • Change from baseline in NYHA Class at 30 days.

  5. Additional Efficacy Endpoint - Distance walked in 6 MWT at 30 days [ Time Frame: 30 days. ]
    • Change from baseline in distance walked measure by the 6 MWT at 30 days.

  6. Additional Efficacy Endpoint - KCCQ at 30 days [ Time Frame: 30 days. ]
    • Change from baseline in KCCQ at 30 days.

  7. Additional Efficacy Endpoint - MR severity at 30 days [ Time Frame: 30 days ]
    • Degree of mitral regurgitation (central and paravalvular) at 30 days.

  8. Additional Safety Endpoint - Stroke at 30 days and 1 year. [ Time Frame: 30 days and 1 year. ]
    • Stroke at 30 days and 1 year.

  9. Additional Safety Endpoint - Need for ASD Closure [ Time Frame: 30 days. ]
    • Iatrogenic ASD causing RV failure or hypoxemia or need for ASD closure at discharge and 30 days.

  10. Additional Safety Endpoint - New LVOT Gradient [ Time Frame: 30 days and 1 year. ]
    • New mean LVOT gradient ≥ 20 mmHg, or ≥ 20 mmHg increase from baseline LVOT gradient at 30 days and 1 year.

  11. Additional Efficacy Endpoint - Mitral Valve Reintervention [ Time Frame: 30 days and 1 year. ]
    • Mitral Valve reintervention at 30 days and 1 year.

  12. Additional Safety Endpoint - Hospitalizations at 1 year [ Time Frame: 1 year. ]
    • Number of hospitalizations at 1 year.

  13. Additional Efficacy Endpoint - Days Alive Out of the Hospital [ Time Frame: 1 year. ]
    • Days alive out of hospital at 1 year from index procedure (ViMAC arm) or from enrollment day (medical treatment arm).

  14. Additional Safety Endpoint - Hemolysis [ Time Frame: 30 days and 1 year. ]
    • Hemolysis at 30 days and 1 year.

  15. Additional Safety Endpoint - Endocarditis [ Time Frame: 30 days and 1 year. ]
    • Endocarditis at 30 days and 1 year.

  16. Additional Safety Endpoint - Blood Transfusion [ Time Frame: 30 days and 1 year. ]
    • Blood transfusion at 30 days and 1 year.

  17. Additional Safety Endpoint - New Pacemaker Requirement [ Time Frame: 30 days and 1 year. ]
    • New pacemaker requirement at 30 days and 1 year.

  18. Additional Safety Endpoint - New Aortic Valve Insufficiency [ Time Frame: 30 days and 1 year. ]
    • New aortic valve insufficiency at 30 days and 1 year.

  19. Additional Safety Endpoint - Acute Kidney Injury [ Time Frame: 30 days and 1 year. ]
    • Acute kidney injury (MVARC) at 30 days and 1 year.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

All Candidates must meet the following criteria:

  1. - 18 years of age or older
  2. -Severe mitral annular calcification with severe mitral stenosis defined as mitral valve area (MVA) of ≤1.5 cm2, or moderate to severe or severe mitral regurgitation.
  3. - NYHA Functional Class ≥II.
  4. The heart team agrees that valve implantation will likely benefit the patient.
  5. High or prohibitive risk for standard mitral valve surgery as determined by the heart team (at least one site cardiac surgeon must personally examine the subject to determine operative risk).
  6. The study patient has been informed of the nature of the study, agrees to its provisions and has provided written informed consent as approved by the Institutional Review Board (IRB) of the respective clinical site.
  7. The study patient agrees to comply with all required post-procedure follow-up visits including annual visits through 5 years and analysis close date visits, which will be conducted as a phone follow-up.

Exclusion Criteria:

  1. - The heart team considers the patient is a surgical candidate.
  2. - Mitral annulus is not calcified.
  3. - Myocardial infarction requiring revascularization within 30 days from procedure.
  4. - Clinically significant untreated coronary artery disease requiring revascularization.
  5. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is performed within 30 days of the index procedure (unless part of planned strategy for treatment of concomitant coronary artery disease). Implantation of a permanent pacemaker is not excluded.
  6. Any patient with a balloon valvuloplasty (BMV) within 30 days of the procedure (unless BMV is a bridge to procedure after a qualifying Echo).
  7. Severe symptomatic tricuspid regurgitation (hepatic dysfunction, ascites, edema not controlled with diuretics) requiring surgery.
  8. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Platelets < 50,000 cell/mL), history of coagulopathy or hypercoagulable state.
  9. Hypertrophic obstructive cardiomyopathy (HOCM) with mean LVOT gradient of ≥20 mm Hg at rest or ≥50 mmHg with Valsalva.
  10. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or mechanical heart assistance within 30 days of screening evaluation.
  11. Need for emergency surgery for any reason.
  12. Severe left ventricular dysfunction with LVEF < 20%.
  13. Echocardiographic evidence of intracardiac mass, thrombus or vegetation.
  14. Active upper GI bleeding within 90 days prior to procedure.
  15. A known contraindication or hypersensitivity to all anticoagulation regimens, or inability to be anticoagulated for the study procedure.
  16. Cardiac anatomy that would preclude appropriate delivery and deployment of a SAPIEN 3 or SAPIEN 3 Ultra valve in MAC via transseptal access, including but not limited to:

    • Native neo mitral annulus size < 275 mm2 or > 810 mm2 as measured by CT scan.
    • Significant risk of LVOT obstruction or valve embolization as assessed by CT core lab
  17. Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic attack (TIA) within 90 days of the procedure.
  18. Estimated life expectancy <12 months due to non-cardiac conditions.
  19. Expectation that patient will not improve despite treatment of mitral valve dysfunction.
  20. Active bacterial endocarditis within 180 days of procedure.
  21. - Severe right ventricular dysfunction as assessed by Echo core lab
  22. - Active infection requiring antibiotic therapy (subject may be a candidate after 2 weeks of antibiotic discontinuation.
  23. - Female who is pregnant or lactating.
  24. - Participating in another investigational device study.
  25. - Aortic valve disease requiring intervention.
  26. - Severe fixed pulmonary hypertension (PASP ≥70 mmHg).
  27. - Severe chronic obstructive pulmonary disease requiring continuous home oxygen.
  28. - The patient refuses mitral valve intervention
  29. - Recent symptomatic COVID-19 infection with residual symptoms that may affect the outcomes of this trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04408430

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Contact: Tatiana Kaptzan, Ph. D. 507-284-1610 kaptzan.tatiana@mayo.edu

Show Show 21 study locations
Sponsors and Collaborators
Mayra Guerrero
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Principal Investigator: Mayra Guerrero, MD Mayo Clinic
Additional Information:
Publications of Results:
Other Publications:

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Responsible Party: Mayra Guerrero, Principal Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT04408430    
Other Study ID Numbers: 20-002438
First Posted: May 29, 2020    Key Record Dates
Last Update Posted: June 15, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Keywords provided by Mayra Guerrero, Mayo Clinic:
Transcatheter Mitral Valve Replacement
Additional relevant MeSH terms:
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Mitral Valve Insufficiency
Heart Valve Diseases
Mitral Valve Stenosis
Calcium Metabolism Disorders
Metabolic Diseases
Heart Diseases
Cardiovascular Diseases