The Medtronic CoreValve™ Evolut R™ CE Mark Clinical Study

Study Overview
=================
Brief Summary
-----------------
To assess the safety and clinical performance of the CoreValve™ Evolut R™ System.

Detailed Description
-----------------
The study objectives are to assess the safety and clinical performance of the CoreValve™ Evolut R™ System in patients with severe symptomatic aortic stenosis who are considered at high through extreme risk for surgical aortic valve replacement. These objectives will be accomplished by a prospective clinical study involving up to 60 implanted subjects among up to six study centers.

Official Title
-----------------
The Medtronic CoreValve™ Evolut R™ CE Mark Clinical Study

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

Intervention / Treatment
-----------------
* Device: The CoreValve™ Evolut R TAV™ system


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Severe aortic stenosis, defined as aortic valve area of < 1.0 cm2 (or aortic valve area index of < 0.6 cm2/m2) by the continuity equation, AND mean gradient > 40 mmHg or maximal aortic valve velocity > 4.0 m/sec by resting echocardiogram. Estimated 30 day mortality risk of > 15% by study center Heart Team assessment,33 OR at least two cardiovascular surgeons from the study center deny surgery because of prohibitive operative risk, estimated to be a combined >50% risk of irreversible mortality or morbidity. Symptoms of aortic stenosis, and NYHA Functional Class II or greater. The subject meets the legal minimum age to provide informed consent based on local regulatory requirements, and has provided written informed consent as approved by the EC/IRB of the respective clinical site. The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits. Exclusion Criteria: Clinical exclusion criteria: Subject has been offered SAVR but has declined. Any condition considered a contraindication for placement of a bioprosthetic valve (e.g. subject is indicated for mechanical prosthetic valve). Known hypersensitivity or contraindication to Nitinol. Blood dyscrasias as defined: leukopenia (WBC <1000 mm3), thrombocytopenia (platelet count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states. Untreated clinically significant coronary artery disease requiring revascularization. Severe left ventricular dysfunction with left ventricular ejection fraction (LVEF) <20% by echocardiography, contrast ventriculography, or radionuclide ventriculography. End stage renal disease requiring chronic dialysis of creatinine clearance < 20 cc/min. Ongoing sepsis, including active endocarditis. Any condition considered a contraindication to extracorporeal assistance. Any percutaneous coronary or peripheral interventional procedure with a bare metal stent performed within 30 days prior to Heart Team assessment, or within six months prior to Heart Team assessment for procedures with a drug eluting stents. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within eight weeks of Heart Team Assessment . Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support. Recent (within 6 months of Heart Team assessment) cerebrovascular accident (CVA) or transient ischemic attack (TIA). Gastrointestinal (GI) bleeding that would preclude anticoagulation. Subject refuses a blood transfusion. Severe dementia (resulting in either inability to provide informed consent for the study/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits). Estimated life expectancy of less than 12 months due to associated non-cardiac co-morbid conditions. Other medical, social, or psychological conditions that in the opinion of the Investigator precludes the subject from appropriate consent or adherence to the protocol required follow-ups exams. Currently participating in an investigational drug or another device study (excluding registries). Evidence of an acute myocardial infarction ≤30 days before the index procedure. Need for emergency surgery for any reason. Liver failure (Child-C). Subject is pregnant or breast feeding. Anatomical exclusion criteria: Pre-existing prosthetic heart valve in any position. Mixed aortic valve disease (aortic stenosis with moderate or severe aortic regurgitation). Severe mitral regurgitation. Severe tricuspid regurgitation. Moderate or severe mitral stenosis. Hypertrophic obstructive cardiomyopathy. Echocardiographic or Multi-Slice Computed Tomography (MSCT) evidence of intracardiac mass thrombus or vegetation. Congenital bicuspid or unicuspid valve verified by echocardiography.
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: The CoreValve™ Evolut R TAV™ system<br>CoreValve™ Evolut R™ System which consists of the Evolut R™ Transcatheter Aortic Valve (26 & 29 mm sizes), EnVeo R™ Delivery Catheter System with Enveo InLine™ Sheath, and EnVeo R™ Loading System | Device: The CoreValve™ Evolut R TAV™ system<br>* CoreValve™ Evolut R™ System which consists of the Evolut R™ Transcatheter Aortic Valve (26 & 29 mm sizes), EnVeo R™ Delivery Catheter System with Enveo InLine™ Sheath, and EnVeo R™ Loading System<br>* Other names: EnVeoR™ Loding System;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality Rate at 30 Days | The All-cause mortality rate at 30 days per the VARC II recommendation of clinical endpoints for TAVI. More specifically: Cardiovascular mortality (Any of the following criteria) Death due to proximate cardiac cause (e.g. myocardial infarction, cardiac tamponade, worsening heart failure) Death caused by non-coronary vascular conditions such as neurological events, pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular disease All procedure-related deaths, including those related to a complication of the procedure or treatment for a complication of the procedure All valve-related deaths including structural or non-structural valve dysfunction or other valve-related adverse events Sudden or unwitnessed death Death of unknown cause Non-cardiovascular mortality Any death in which the primary cause of death is clearly related to another condition (e.g. trauma, cancer, suicide) | 30 days | 
| Stroke Rate (Disabling and Non-disabling) at 30 Days | The Stroke rate (disabling and non-disabling) at 30 days per the VARC II definitions. Stroke is defined as an acute episode of focal or global neurological dysfunction caused by the brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction. Stroke may be classified as ischaemic or haemorrhagic with appropriate subdefinitions. Ischaemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of central nervous system tissue. Haemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid haemorrhage. A stroke may be classified as 'undetermined' if there is insufficient information to allow the categorization as ischaemic or haemorrhagic. | 30 days | 
| Device Success Rate at 24 Hours to Seven Days | Device success rate at 24 hours to seven days, defined as: Absence of procedural mortality, AND Correct positioning of a single prosthetic heart valve into the proper anatomical location, AND Intended performance of the prosthetic heart valve, defined as the absence of patient-prosthesis-mismatch and mean aortic valve gradient less than 20 mmHg (or peak velocity < 3 m/sec), AND absence of moderate or severe prosthetic valve regurgitation. The percentage of subjects with no more than mild aortic regurgitation at early post procedure echocardiogram (24 hours through seven days). | 24 hours to seven days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VARC II Combined Safety Endpoint at 30 Days | The VARC II Combined Safety Endpoint at 30 days includes the following components: All-Cause Mortality, All Stroke, Life Threatening or Disabling Bleeding, Acute Kidney Injury: Stage 2 or 3, Coronary Artery Obstruction, Major Vascular Complication, and Valve-Related Dysfunction Requiring Repeat Procedure. | 30 days | 
| Event Rates of the Individual Components of the VARC II Composite Safety Endpoint at 30 Days | The Individual components of the VARC II composite safety endpoint at 30 days per the Kaplan Meier Event Rate (%). | 30 days | 
| Hemodynamic Performance Metrics at 30 Days by Doppler Echocardiography - Mean Gradient | The hemodynamic performance will be measured by the Mean Prosthetic Valve Gradient for 59 subjects, measured with the Doppler echocardiography. | 30 days | 
| Hemodynamic Performance Metrics at 30 Days by Doppler Echocardiography - • Effective Orifice Area (EOA) | Effective orifice area | 30 days | 
| Hemodynamic Performance Metrics at 30 Days by Doppler Echocardiography - Total Aortic Regurgitation (Transvalvular & Paravalvular) | Degree of Total prosthetic valve regurgitation (transvalvular & paravalvular) | 30 days | 
| Resheath or Recapture Success Rate (When Attempted), Where Successful Recapture is Defined as Evolut R™ TAV (Including the Frame) is Fully Resheathed Into the Capsule of the Delivery Catheter, as Verified by Fluoroscopy. | Resheath or Recapture success rate (when attempted), where successful recapture is defined as Evolut R™ TAV (including the frame) is fully resheathed into the capsule of the delivery catheter, as verified by fluoroscopy. Resheathing or recapturing of the TAV was attempted on 15 subjects. | Day 1 |