Clinical Evaluation of MDT-2111 in Subjects With Small Aortic Annuli and Symptomatic Severe Aortic Stenosis

Study Overview
=================
Brief Summary
-----------------
The primary objective of the present trial is to demonstrate the safety and effectiveness of the MDT-2111 in the treatment of symptomatic severe aortic stenosis in subjects with small aortic annuli and deemed difficult for surgical operation.

Detailed Description
-----------------
The purpose of this trial is to evaluate the effectiveness and safety of the MDT-2111 TAV system in subjects with small annuli and symptomatic severe AS deemed difficult for surgical intervention. The primary endpoint is a composite of functional effectiveness as measured by improvement of at least 1 New York Heart Association (NYHA) class from baseline to 6 months and anatomical effectiveness as measured by Effective Orifice Area (EOA) ≥1.0 cm² at 6 months.

Official Title
-----------------
Medtronic MDT-2111 CoreValve Japan 23mm Study

Conditions
-----------------
Aortic Valve Stenosis

Intervention / Treatment
-----------------
* Device: MDT-2111 TAVI 23 mm


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must have co-morbidities such that one cardiologist and one cardiac surgeon agree that medical factors preclude operation, based on a conclusion that the probability of death or serious morbidity exceeds the probability of meaningful improvement. Subject has senile degenerative aortic valve stenosis with: mean gradient > 40 mmHg or jet velocity greater than 4.0 m/s by either resting or dobutamine stress echocardiogram, or simultaneous pressure recordings at cardiac catheterization (either resting or dobutamine stress), AND an initial aortic valve area of ≤ 0.8 cm² (or aortic valve area index ≤ 0.5 cm²/m²) by resting echocardiogram. Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by NYHA Functional Class Class III or greater. If screening committee agrees the eligibility of a patient with class II , based on medical factors, he/she can be enrolled. Patient has been informed of the nature of the trial and has signed an Informed Consent Form. Patient agrees to comply with specified follow-up evaluations and to return to the same investigational site where the procedure was performed. Exclusion Criteria: Evidence of an acute myocardial infarction ≤ 30 days prior to the intended treatment. Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the procedure. Blood dyscrasias as defined: Leukopenia (WBC count < 1,000 cells/mm³) Thrombocytopenia (platelet count <50,000 cells/mm³) History of bleeding diathesis or coagulopathy Hypercoagulable states Untreated clinically significant coronary artery disease requiring revascularization. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support. Need for emergency surgery for any reason. Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20% as measured by resting echocardiogram. Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack(TIA). End stage renal disease requiring chronic dialysis. GI bleeding within the past 3 months. A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated: Aspirin Ticlopidine Heparin Contrast media Nitinol (titanium and nickel alloy) Ongoing sepsis, including active endocarditis. Subject refuses a blood transfusion. Life expectancy < 12 months due to associated non-cardiac co-morbid conditions. Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the subject from appropriate consent. Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits). Currently participating in an investigational drug or another device trial. Note: Trials requiring extended follow-up for products that were investigational, but have since become commercially available, are not considered investigational trials. Symptomatic carotid or vertebral artery disease. Native aortic annulus size < 18 mm or > 20 mm per the screening diagnostic imaging. Pre-existing prosthetic heart valve in any position. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation). Mitral regurgitation (moderate to severe) or severe tricuspid regurgitation. Moderate to severe mitral stenosis. Hypertrophic obstructive cardiomyopathy. Echocardiographic evidence of intracardiac mass, thrombus or vegetation. Severe basal septal hypertrophy with an outflow gradient. Ascending aorta diameter > 34 mm Congenital bicuspid or unicuspid valve verified by echocardiography. For patients with native coronary artery dependent circulation: Sinus of valsalva width < 25 mm OR Height of the left or right coronary sinus of valsalva (to the tubular aorta) < 15mm. Femoral or iliac artery of the first choice corresponding to any one of the following: Angle at aortic root (the angle between aortic valve annulus plane and horizontal plane/vertebra) exceeds 70°. Vessel diameter of femoral or iliac artery is less than 6 mm. Aorta has severe calcification, excess tortuosity or severe atherosclerosis. Transarterial access not able to accommodate an 18Fr sheath. Subclavian artery of the second choice corresponding to any one of the following: Angle at aortic root (the angle between aortic valve annulus plane and horizontal plane/vertebra) exceeds 70° (in the case of left subclavian artery) and 30° (in the case of right subclavian artery). Vessel diameter of subclavian artery is less than 6 mm. Transarterial access not able to accommodate an 18Fr sheath. Direct Aortic Artery as third line choice of access. Patients are excluded from Direct Aortic access if: Access site is less than 6 cm from the aortic valve basal plane Access site has calcification or porcelain aorta Access site and delivery trajectory contain RIMA or patent RIMA graft
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MDT-2111 TAVI 23 mm<br>Subjects with small annuli and symptomatic severe AS deemed difficult for surgical intervention. | Device: MDT-2111 TAVI 23 mm<br>* Device: 23 mm MDT-2111 System for Transcatheter Aortic Valve Implantation (TAVI) Transcatheter Aortic Valve Implantation (TAVI) using the 23 mm MDT-2111 system.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Score of Change in New York Heart Association (NYHA) Class and Effective Orifice Area (EOA). | The primary endpoint is a composite of functional effectiveness as measured by improvement of at least 1 NYHA class from baseline to 6 months and anatomical effectiveness as measured by Effective Orifice Area (EOA) ≥1.0 cm² at 6 months. | baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New York Heart Classification (NYHA) Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I: Subject with cardiac disease but without resulting limitations of physical activity. Class II: Subjects with cardiac disease resulting in slight limitation of physical activity. Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. | 30 days | 
| New York Heart Classification (NYHA) Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I: Subject with cardiac disease but without resulting limitations of physical activity. Class II: Subjects with cardiac disease resulting in slight limitation of physical activity. Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. | 6 months | 
| New York Heart Classification (NYHA) Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I: Subject with cardiac disease but without resulting limitations of physical activity. Class II: Subjects with cardiac disease resulting in slight limitation of physical activity. Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. | 12 months | 
| New York Heart Classification (NYHA) Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I: Subject with cardiac disease but without resulting limitations of physical activity. Class II: Subjects with cardiac disease resulting in slight limitation of physical activity. Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. | 24 months | 
| Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) | MACCE is defined as a composite of: all-cause death myocardial infarction (MI) all stroke, and reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 0 day to 30 days | 
| Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) | MACCE is defined as a composite of: all-cause death myocardial infarction (MI) all stroke, and reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 0 day to 6 months | 
| Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) | MACCE is defined as a composite of: all-cause death myocardial infarction (MI) all stroke, and reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 0 day to 12 months | 
| Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) | MACCE is defined as a composite of: all-cause death myocardial infarction (MI) all stroke, and reintervention (defined as any cardiac surgery or percutaneous reintervention catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted valve) | 0 day to 24 months | 
| Device Success as Defined in the Description. | The following components must be satisfied for device success: successful vascular access, delivery and deployment of device and successful retrieval of delivery system correct position of device in the proper anatomical location EOA≥1.0 cm² AND mean gradient <20 mmHg or peak velocity <3 m/s, without moderate or severe AR only one valve implanted. | after procedure or discharge | 
| Procedural Success, Defined as Device Success and Absence of In-hospital MACCE | Procedural success is defined as device success and absence of in-hospital MACCE. | from admission for procedure to discharge | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Mean Gradient |  | 30 days | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Mean Gradient |  | 6 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Mean Gradient |  | 12 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Mean Gradient |  | 24 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Effective Orifice Area (EOA) |  | 30 days | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Effective Orifice Area (EOA) |  | 6 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Effective Orifice Area (EOA) |  | 12 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Effective Orifice Area (EOA) |  | 24 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Left Ventricular Ejection Fraction (LVEF) |  | 30 days | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Left Ventricular Ejection Fraction (LVEF) |  | 6 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Left Ventricular Ejection Fraction (LVEF) |  | 12 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Left Ventricular Ejection Fraction (LVEF) |  | 24 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 30 days | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 6 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 12 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 24 months | 
| Repeat Hospitalization |  | 0 day to 30 days | 
| Repeat Hospitalization |  | 0 day to 6 months | 
| Repeat Hospitalization |  | 0 day to 12 months | 
| Repeat Hospitalization |  | 0 day to 24 months | 
| Valve-related Deaths |  | 0 day to 30 days | 
| Valve-related Deaths |  | 0 day to 6 months | 
| Valve-related Deaths |  | 0 day to 12 months | 
| Valve-related Deaths |  | 0 day to 24 months | 
| Quality of Life Assessment Using SF-36 Questionnaire - Physical Component Summary (Paired Change From Baseline) | The SF-36 assessment was used to evaluate subject Quality of life (QoL) by assessing change in physical function and general health status. The SF-36 v2 ͭ ͫ Scoring Program was used to convert raw scores ranging from 0 to 100 into norm-based scores, allowing direct comparison to the reference values for the Japanese population. The Z-score of each subdomain is calculated as the numbers of standard deviation away from the Japanese population mean of the corresponding raw score. Norm-based score is then derived as fifty plus 10 times of the z-score. A norm-based score of less than 50 was interpreted as below average when compared to the Japanese population whereas norm-based scores greater than 50 were interpreted as above average. | Baseline to 30 days | 
| Quality of Life Assessment Using SF-36 Questionnaire - Physical Component Summary (Paired Change From Baseline) | The SF-36 assessment was used to evaluate subject Quality of life (QoL) by assessing change in physical function and general health status. The SF-36 v2 ͭ ͫ Scoring Program was used to convert raw scores ranging from 0 to 100 into norm-based scores, allowing direct comparison to the reference values for the Japanese population. The Z-score of each subdomain is calculated as the numbers of standard deviation away from the Japanese population mean of the corresponding raw score. Norm-based score is then derived as fifty plus 10 times of the z-score. A norm-based score of less than 50 was interpreted as below average when compared to the Japanese population whereas norm-based scores greater than 50 were interpreted as above average. | Baseline to 6 months | 
| Quality of Life Assessment Using SF-36 Questionnaire - Physical Component Summary (Paired Change From Baseline) | The SF-36 assessment was used to evaluate subject Quality of life (QoL) by assessing change in physical function and general health status. The SF-36 v2 ͭ ͫ Scoring Program was used to convert raw scores ranging from 0 to 100 into norm-based scores, allowing direct comparison to the reference values for the Japanese population. The Z-score of each subdomain is calculated as the numbers of standard deviation away from the Japanese population mean of the corresponding raw score. Norm-based score is then derived as fifty plus 10 times of the z-score. A norm-based score of less than 50 was interpreted as below average when compared to the Japanese population whereas norm-based scores greater than 50 were interpreted as above average. | Baseline to 12 months | 
| Quality of Life Assessment Using SF-36 Questionnaire - Physical Component Summary (Paired Change From Baseline) | The SF-36 assessment was used to evaluate subject Quality of life (QoL) by assessing change in physical function and general health status. The SF-36 v2 ͭ ͫ Scoring Program was used to convert raw scores ranging from 0 to 100 into norm-based scores, allowing direct comparison to the reference values for the Japanese population. The Z-score of each subdomain is calculated as the numbers of standard deviation away from the Japanese population mean of the corresponding raw score. Norm-based score is then derived as fifty plus 10 times of the z-score. A norm-based score of less than 50 was interpreted as below average when compared to the Japanese population whereas norm-based scores greater than 50 were interpreted as above average. | Baseline to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Valvular Heart Disease, Severe Aortic Stenosis, Aortic Valve Replacement