J-Valve Transfemoral Pivotal Study

This is a prospective, single arm, multi-center, interventional pivotal study that will enroll up to 194 subjects in up to 35 investigational sites, predominantly in the United States and up to 7 in Canada, Europe, and Japan. Of the 194 subjects, the CMR imaging sub-study will include up to 75 subjects with severe AR already confirmed by TTE. Additionally, up to 40 roll-in subjects may be treated to enable clinical experience and exposure to the device while allowing a reasonable learning curve. The subjects will then be followed 5-years post-procedure of the J-Valve TF System.

• J-Valve Transfemoral (TF) System (Device): Treatment includes using the J-Valve Transfemoral (TF) System, a transcatheter aortic valve replacement system that consists of the J-Valve TF Bioprosthesis and the J-Valve TF Delivery Device and Loading Accessories, during transcatheter aortic valve replacement (TAVR). The Edwards 16Fr eSheath+ Introducer Set may be used for the introduction and removal of the J-Valve TF System.

Primary outcomes

• All-cause mortality at 1 year [1-year post-procedure]
• The composite rate of early-safety outcomes at 30 days as defined by the Valve Academic Research Consortium 3 (VARC-3) [30-days post-procedure]: Includes: * All-cause death * All stroke * VARC-3 type 2-4 bleeding * Major vascular, access-related, or cardiac structural complication * Acute kidney injury (AKI) stage 3 or 4 * New permanent pacemaker due to procedure-related conduction abnormalities * Surgery or intervention related to the device

Secondary outcomes

• Rate of improvement in cardiovascular-specific health status [Baseline to 1-year follow-up]: As measured by the Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS)
• Improvement in left ventricular end diastolic diameter index (LVEDDi) [Baseline to 1-year follow-up]: To measure LV remodeling
• Improvement in left ventricular end diastolic volume index (LVEDVi) [Baseline to 1-year follow-up]: To measure LV remodeling
• Improvement in effective stroke volume index (ESVi) [Baseline to 1-year follow-up]: To measure LV remodeling
• Improvement in effective cardiac output index (ECOi) [Baseline to 1-year follow-up]: To measure LV remodeling

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Symptomatic according to New York Heart Association (NYHA) functional class (FC) II or higher
2. Severe AR, defined as follows, as assessed by Imaging Core Laboratory:

   A. Severe AR by Transthoracic Echocardiography (TTE) (grade 3 or 4)

   B. OR, if indeterminate AR, by TTE, ANY ONE of the following:

   i. Cardiac magnetic resonance imaging (CMR)-derived aortic regurgitant fraction (RF) ≥43% ii. CMR-derived RF ≥33% + left ventricular dilation (left ventricular end diastolic volume index \[LVEDVi\]) >105 mL/m\^2 for men or LVEDVi >96 mL/m\^2 for women) iii. CMR-derived RF ≥33% + LV ejection fraction (LVEF) ≤55% or left ventricular end systolic volume index (LVESVi) ≥43mL/m\^2; iv. Severe AR by Transesophageal Echocardiography (TEE) (grade 3 or 4)
3. High risk for surgery as judged by a multi-disciplinary heart team
4. Suitable anatomy to accommodate the insertion, delivery, and deployment of the study devices (see anatomic exclusions below)
5. Written informed consent and agreement to comply with all required post-procedure follow-up visits at investigational site.

Exclusion Criteria:

1. Previous prosthetic aortic valve (bioprosthesis or mechanical) implant
2. Aortic valve stenosis > moderate*
3. Severe mitral valve or tricuspid valve regurgitation*
4. Severe mitral valve or tricuspid valve stenosis*
5. Active infection, including infective endocarditis
6. Cardiac imaging evidence of cardiac mass, thrombus or vegetation
7. Inability to tolerate or a condition precluding treatment with antithrombotic (antiplatelet, anticoagulant) therapy
8. Renal insufficiency (eGFR <30 mL/min/1.73m\^2) or end stage renal disease requiring chronic dialysis
9. Liver disease (cirrhosis of the liver \[Child-Pugh Class B or C\])
10. Blood dyscrasias as defined: leukopenia (WBC <3000 cells/mcL), thrombocytopenia (platelet count <50,000 cells/mcL), anemia (hemoglobin <9 g/dL), history of bleeding diathesis coagulopathy, or hypercoagulable state (unless therapeutically stable)
11. Known hypersensitivity or contraindication to aspirin, heparin, bivalirudin, clopidogrel, Nitinol (Nickel, Titanium) or sensitivity to contrast media, which cannot be adequately premedicated
12. Left ventricular dysfunction with left ventricular ejection fraction (LVEF) <25% as measured by resting echocardiogram (or by CMR, when performed)*
13. Clinically significant untreated coronary artery disease requiring revascularization or anticipated coronary revascularization procedure within 12-months post index procedure
14. Acute myocardial infarction within 30 days prior to index procedure
15. PCI within 30 days prior to index procedure
16. Carotid intervention within 6 weeks prior to index procedure or carotid artery disease requiring intervention
17. Previous, or planned, other surgical or interventional procedures within 30 days before, during, or within 30 days after the index procedure
18. Uncontrolled atrial fibrillation
19. Severe right ventricular (RV) dysfunction*
20. Pulmonary hypertension (systolic PA pressure >70mmHg or systolic PA pressure ≥2/3 of systemic systolic BP)
21. Severe chronic obstructive pulmonary disease (COPD) requiring chronic oral steroids or requiring continuous home O2
22. Stroke (CVA), transient ischemic attack (TIA) or neurological signs and symptoms attributed to carotid or vertebrobasilar disease within 90 days prior to index procedure
23. Cardiogenic shock defined as systolic blood pressure <90 mmHg in addition to signs of tissue hypoperfusion or the need for vasopressors and/or mechanical hemodynamic support to maintain systolic blood pressure ≥90mmHg
24. Patient requires mechanical circulatory support within 30 days prior to index procedure
25. Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid conditions
26. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up requirements
27. Participation in another investigational study that has not reached its primary endpoint
28. Considered to be part of a vulnerable population

    * As assessed by Imaging Core Laboratory

Anatomic Exclusions:

1. Ascending Aortic diameter >5 cm*
2. Aortic Annulus Perimeter <57 mm or >104 mm*
3. Inappropriate anatomy for femoral introduction and delivery of the study system
4. Left ventricular end-diastolic diameter (LVEDD) >75 mm*
5. Congenital aortic valve disease including Unicuspid, Bicuspid, or Quadricuspid aortic valve anatomy*
6. Congenital univentricle or other condition that, in the opinion of the investigator and/or consulting physician, may constitute an unwarranted surgical risk
7. Excessive aortic valve prolapse that would preclude proper seating of the implant in the aortic annulus
8. Abdominal/thoracic aortic aneurysm ≥5.0 cm*
9. Aorto-iliac disease requiring intervention to facilitate delivery of access sheath
10. Excessive tortuosity of delivery system pathway, defined as severe tortuosity of multiple vessels including iliofemoral, thoracoabdominal aorta, aortic arch, or LV-aortic root angle >80⁰
11. Non-native anatomy in aortic zones 0A \& 0B (aortic valve annulus to the distal margin of the right pulmonary artery); 0C (to innominate) only if deemed unfavorable by the Study Screening Committee

    * As assessed by Imaging Core Laboratory

• Dean J Kereiakes, MD, Study chair, The Christ Hospital Heart & Vascular Institute
• Michael Reardon, MD, Study chair, The Methodist Hospital Research Institute
• Santiago Garcia, MD, Principal investigator, The Christ Hospital and The Carl and Edyth Lindner Center for Research and Education
• Tsuyoshi Kaneko, MD, Principal investigator, Washington University School of Medicine