Mitral Implantation of TRAnscatheter vaLves
Mitral Implantation of TRAnscatheter vaLves
The purpose of this trial is to establish the safety and feasibility of the Edwards SAPIEN
 XT™and SAPIEN 3™ device and delivery systems in patients with severe symptomatic calcific
 mitral valve disease with severe mitral annular calcification who are not candidates for
 standard mitral valve surgery.
Design:

 A prospective pilot study enrolling extremely high surgical risk patients with symptomatic
 severe calcific mitral valve disease undergoing implantation of an Edwards Sapien XT or
 SAPIEN 3 valve in the mitral position.

 There are three arms in this study evaluating three separate patient populations described
 below:

 -  Native Mitral Valve with severe Mitral Annular Calcification (MAC): Patients with
 symptomatic severe disease of a native mitral valve due to severe mitral annular
 calcification.

 -  Valve-in-Ring: Patients with symptomatic failing surgical rings resulting in severe
 mitral regurgitation or stenosis.

 -  Valve-in-Valve: Patients with failing bioprosthetic surgical valves with severe
 regurgitation or stenosis

 The delivery approaches include: standard transeptal, modified transeptal approach with a
 guidewire externalized through a sheath percutaneously placed in the left ventricle, surgical
 trasnapical and surgical transatrial delivery approach with or without surgical resection of
 the anterior MV leaflet (in the native mitral valve arm).

 The MITRAL Trial site investigative team (heart team) consists of dedicated representatives
 from cardiac surgery, interventional cardiology, echocardiology, neurology, study
 coordination and other multi-disciplinary team members consistent with a transcatheter aortic
 valve replacement (TAVR) model.

 Endpoints

 Most endpoints were defined following the Mitral Valve Academic Research Consortium (MVARC)
 recommendations with minor modifications.73

 The primary safety endpoint is: technical success at exit from the cath lab

 • Technical success (at exit from the cath lab) is defined as:

 -  Successful vascular and/or TA 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 (mean MVG <10 mmHg) 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

 The primary performance endpoint is: absence of MR grade 2 (+) or greater or mean MVG ≥10
 mmHg at 30 days and 1 year.

 Secondary safety endpoints include: Procedural success and all -cause mortality at 30 days
 and 1 year.

 -  Procedural Success (30 days) in 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.

 -  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

 Additional secondary safety and effectiveness endpoints will be evaluated at two time points:
 (1) acute, covering events occurring out to 30 days or hospital discharge, whichever is
 longer; and (2) longer-term, covering events from 31 days to 1 year, and include the
 following:

 Additional Safety Endpoints:

 Freedom from

 -  all stroke and TIA (MVARC)

 -  myocardial infarction

 -  major vascular complication (MVARC)

 -  life-threatening bleeding (MVARC)

 -  mitral valve reoperation or catheter-based intervention for: valve thrombosis, valve
 displacement, or other valve placed procedure-related complication

 -  hemolysis

 -  endocarditis

 -  moderate or severe central mitral insufficiency ≥ 2 (+), and/or moderate or severe
 perivalvular leak causing ≥ 2 (+) mitral insufficiency

 -  significant mitral stenosis (mean MVG >10 mmHg)

 -  new permanent pacemaker insertion

 -  new aortic valve dysfunction (difference greater than 1(+) severity compared with
 baseline)

 -  new LVOT gradient ≥ 20 mmHg, or ≥ 20 mmHg increase from baseline LVOT gradient.

 -  acute kidney injury (MVARC)

 -  new onset atrial fibrillation

 -  blood transfusion

 -  access site infection

 -  need for iatrogenic ASD closure after index procedure

 Additional Effectiveness Endpoints:

 1. Rehospitalization at 1 year and Total days alive and out of hospital (from date of index
 procedure)

 2. Clinical improvement per NYHA Class (from baseline) by at least 1 class.

 3. Clinical improvement per Quality of Life instruments (>10 points from baseline): (KCCQ
 12) (Appendix N)

 4. Clinical improvement per 6 Minute Walk Test (> 50 meters from baseline) and 5 meter walk
 test. (Appendix H)

 5. Mean ICU and total index procedure hospital length of stay

 Additional Valve Performance Endpoints:

 1. Freedom from major mitral paravalvular leak

 2. Improvement in hemodynamic function: mean gradient

 3. Freedom from structural valve deterioration

 4. Total mitral regurgitation
Inclusion Criteria in Native Mitral Valve arm

 All Candidates must meet the following criteria:

 1. Patient has severe calcific native mitral valve stenosis with mitral annular
 calcification with echocardiographically derived mitral valve area (MVA) of ≤1.5 cm2,
 or severe mitral regurgitation with severe mitral annular calcification and at least
 moderate mitral valve stenosis. Qualifying echo must be within 60 days of the date of
 the procedure.

 2. Patient is symptomatic from mitral valve disease, as demonstrated by reported NYHA
 Functional Class II or greater, or symptoms during stress test.

 3. The patient is at least 22 years old.

 4. The heart team agrees (and verified in the case review process) that valve
 implantation will likely benefit the patient.

 5. The heart team agrees that medical factors preclude operation, based on a conclusion
 that the probability of death or serious, irreversible morbidity exceeds the
 probability of meaningful improvement. Specifically, the STS score is ≥15% or the
 probability of death or serious, irreversible morbidity is ≥ 50%. The surgeons'
 consult notes shall specify the medical or anatomic factors leading to that conclusion
 and include a printout of the calculation of the STS score to additionally identify
 the risks in the patient (some medical factors and definitions are provided below). At
 least one of the cardiac surgeon assessors must have physically evaluated the patient.
 All patients must be approved by the Patient Selection and Procedure Management
 Steering Committee (at least 2 member votes, one must be a cardiac surgeon).

 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.

 Inclusion Criteria in Valve-in-Ring arm

 All Candidates must meet the following criteria:

 1. Patient has a failing surgical ring in the mitral position with severe mitral
 regurgitation or stenosis (echocardiographically derived mitral valve area [MVA] of
 ≤1.5 cm2. Qualifying echo must be within 60 days of the date of the procedure.

 2. Patient is symptomatic from mitral valve disease, as demonstrated by reported NYHA
 Functional Class II or greater, or symptoms during stress test, or severe hemolytic
 anemia requiring blood transfusions and no other cause of hemolytic anemia is found
 after extensive work up.

 Inclusion Criteria items #3 to 7 will be the same as in Native MV arm described above

 Inclusion Criteria in Valve-in-Valve arm

 All Candidates must meet the following criteria:

 1. Patient has a failing surgical bioprosthesis in the mitral position with severe mitral
 regurgitation or stenosis with echocardiographically derived mitral valve area (MVA)
 of ≤1.5 cm2. Qualifying echo must be within 60 days of the date of the procedure.

 2. Patient is symptomatic from mitral valve disease, as demonstrated by reported NYHA
 Functional Class II or greater, or symptoms during stress test.

 Inclusion Criteria items #3 to 7 will be the same as in Native MV arm described above

 Exclusion Criteria:

 Candidates will be excluded from the study if any of the following conditions are present:

 1. Heart Team assessment of operability (the heart team considers the patient is a
 surgical candidate).

 2. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before the intended
 treatment [defined as: Q wave MI, or non-Q wave MI with total CK elevation of CK-MB ≥
 twice normal in the presence of MB elevation and/or troponin level elevation (WHO
 definition)].

 3. Mitral annulus is not calcified (only applies to patients included in Native MV arm).

 4. Complex untreated coronary artery disease:

 1. Unprotected left main coronary artery

 2. Syntax score > 32 (in the absence of prior 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. Patients with planned concomitant surgical or transcatheter ablation for Atrial
 Fibrillation.

 8. Leukopenia (WBC < 3000 cell/mL), acute anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt <
 50,000 cell/mL).

 9. Hypertrophic obstructive cardiomyopathy (HOCM).

 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 ventricular dysfunction with LVEF < 20%.

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

 14. Active upper GI bleeding within 3 months (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. For patients enrolled in the Native MV arm: Native mitral annulus size < 275 mm2 or >
 740 mm2 as measured by CT scan.

 For patients in Valve-in-Ring arm: surgical ring with a true mean internal diameter
 ≤18 mm or ≥ 29 mm or an area < 275 mm2 or > 740 mm2 as measured by CT scan. Caution
 recommended in:

 -  Incomplete bands due to risk of paravalvular leak and risk of LVOT obstruction.
 Careful measurements by CT and CT-guided procedural planning is recommended.

 -  Non-circular rigid or semi-flexible rings (e.g., D-shaped, saddle shaped, etc)
 due to risk of para-valvular leak and/or out of round or incomplete valve
 expansion.

 For patients in Valve-in-Valve arm: surgical bioprosthesis with a true internal
 diameter ≤18 mm or ≥ 29 mm

 17. Clinically (by neurologist) or neuroimaging confirmed stroke or transient ischemic
 attack (TIA) within 6 months (180 days) of the procedure.

 18. Estimated life expectancy < 24 months (730 days) due to carcinomas, chronic liver
 disease, chronic renal disease or chronic end stage pulmonary disease.

 19. Expectation that patient will not improve despite treatment of mitral stenosis

 20. Active bacterial endocarditis within 6 months (180 days) of procedure.