Mitral Implantation of TRAnscatheter vaLves

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 two arms in this study evaluating two 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.

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.

The primary safety endpoint is technical success at exit from the cath lab and procedural
success at 30 days.

- 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 (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

- 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 (valve area > 1.5 cm2, MV gradient < 10 mmHg)

- Replacement valve regurgitation < 2 + (including central and paravalvular leak) and
without associated hemolysis

- No increase in AI from baseline and LVOT gradient < 20 mmHg increase from baseline

The primary effectiveness endpoint is individual patient success at one year.

• Individual patient success at one year is defined as:

Device success AND all of the following:

- The patient returns to the pre-procedural setting

- No re-hospitalizations or re-interventions for HF or the underlying MV condition
(including HF hospitalization or HF hospitalization equivalents, drainage pleural
effusions, new listing for heart transplant, VAD or other MCS)

- NYHA improvement of at least 1 class vs. baseline

- KCCQ improvement > 10 vs. Baseline

- 6MWT improvement > 50 meters vs. baseline

The secondary safety and effectiveness endpoint is a non-hierarchical composite of various
adverse events, as well as each individual event listed below. The secondary endpoint 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.

The specific components of the composite are:

- all stroke and TIA

- myocardial infarction

- major vascular complication (MVARC)

- life-threatening bleeding (MVARC)

- 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)

- permanent pacemaker insertion

- new aortic valve dysfunction

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

- acute kidney injury (MVARC)

Additional Safety Endpoints:

1. Freedom from major vascular complications (MVARC)

2. Freedom from all neurological events all stroke and TIA (MVARC)

3. Freedom from myocardial infarction

4. Freedom from acute kidney injury (MVARC)

5. Freedom from access site infections

6. Freedom from new permanent pacemaker

7. Freedom from atrial fibrillation at each visit

8. Procedure related complications composites: two endpoints based on MVARC definitions

9. A non-hierarchical composite of all stroke, major vascular complications and
reintervention. The endpoint will be evaluated at 30 days and 1 year.

10. Freedom from transfusion

Additional Effectiveness Endpoints:

1. 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: effective orifice area

3. Improvement in hemodynamic function: mean gradient

4. Freedom from structural valve deterioration

5. 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 >
680 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 > 680 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.