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

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

Detailed Description
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Non-randomized, prospective, multicenter, single-arm trial.

Official Title
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Clinical Evaluation of MDT-2111 in Subjects With Symptomatic Severe Aortic Stenosis

Conditions
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Aortic Valve Stenosis

Intervention / Treatment
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* Device: MDT-2111 CoreValve for TAVI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must have co-morbidities such that one cardiologist and one cardiac surgeons 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. Subject has been informed of the nature of the trial and has signed an Informed Consent Form. Subject 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 < 20 mm or > 27 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 > 43 mm (in case of the aortic annulus is 23-27 mm) unless the aortic annulus is 20-23 mm in which case the ascending aorta diameter > 40 mm. Congenital bicuspid or unicuspid valve verified by echocardiography. For patients with native coronary artery dependent circulation: Sinus of valsalva width < 29 mm unless the aortic annulus is 20-23 mm, in which case the sinus of valsalva width < 27 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 followings: 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 followings: 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
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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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 CoreValve TAVI<br>Transcatheter Aortic Valve Implantation (TAVI) with MDT-2111 CoreValve system. Access sites for the implant include: Iliofemoral, Subclavian and Direct Aortic. | Device: MDT-2111 CoreValve for TAVI<br>* CoreValve Transcatheter Aortic Valve Implantation (TAVI) using the MDT-2111 system.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Success of Improvement in New York Heart Association (NYHA) Class and a Performance Goal for Effective Orifice Area (EOA). | The primary endpoint was defined as the proportion of implanted subjects with improvement of at least 1 NYHA class from baseline to 6 months and EOA greater than 1.2 cm² at 6 months. | baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NYHA Classification Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I Subject with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 30 days | 
| NYHA Classification Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I Subject with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 6 months | 
| NYHA Classification Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I Subject with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 12 Months | 
| NYHA Classification Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I Subject with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 24 Months | 
| NYHA Classification Over Time | NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I Subject with cardiac disease but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain. Class II Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. Class III Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain. Class IV Subjects with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. | 36 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 | 
| 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 36 months | 
| Device Success as Defined in the Description. | successful vascular access, delivery and deployment of the device, and successful retrieval of the delivery system correct position of the device in the proper anatomical location (placement in the annulus with no impedance on device function) Intended performance of the prosthetic valve (aortic valve area >1.2 cm² (by echocardiography using the continuity equation) and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve AR) Only one valve implanted in the proper anatomical location | after procedure or discharge | 
| Procedural Success, Defined as Device Success and Absence of In-hospital MACCE. |  | after procedure or 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 - Mean Gradient |  | 36 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- Effective Orifice Area (EOA) |  | 36 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 - Left Ventricular Ejection Fraction (LVEF) |  | 36 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Valve Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 30 days | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Valve Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 6 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Valve Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 12 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Valve Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 24 months | 
| Echocardiographic Assessment of Prosthetic Valve Performance - Total Aortic Valve Regurgitation (Transvalvular & Paravalvular) (Total AR) |  | 36 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 | 
| Repeat Hospitalization |  | 0 day to 36 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 | 
| Valve-related Deaths |  | 0 day to 36 months | 
| Quality of Life Assessment Using SF-36 Questionnaire - Physical Component Summary (Paired Change From Baseline) (Q of L) | 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 v2TM Scoring Program2,3 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. 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) (Q of L) | 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 v2TM Scoring Program2,3 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. 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) (Q of L) | 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 v2TM Scoring Program2,3 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. 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) (Q of L) | 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 v2TM Scoring Program2,3 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. 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 | 
| Quality of Life Assessment Using SF-36 Questionnaire - Physical Component Summary (Paired Change From Baseline) (Q of L) | 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 v2TM Scoring Program2,3 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. 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 36 Months | 

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