Medtronic CoreValve Evolut R U.S. Clinical Study

Study Overview
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Brief Summary
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The study objectives are to assess the safety and efficacy of the CoreValve Evolut R transcatheter aortic valve replacement (TAVR) system in patients with severe symptomatic aortic stenosis are considered at high or extreme risk for surgical aortic valve replacement.

Detailed Description
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This objective will be accomplished by a prospective, single arm, historical controlled, multi-site study involving a minimum of 150 implanted subjects with no more than 250 implanted subjects at up to 25 study sites in the United States. Procedural and 30 day safety and efficacy results from this study will be compared to appropriate historical control data for the Medtronic CoreValve System. Subjects will be followed up to 5 years following implantation. The enrollment phase of the study is estimated to take approximately 6-9 months. As each implanted subject is to be followed up to 5 years, the estimated study duration is approximately 66-69 months, excluding the time required for preparing the final report.

Official Title
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Medtronic CoreValve Evolut R United States IDE Clinical Study

Conditions
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Aortic Stenosis

Intervention / Treatment
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* Device: CoreValve Evolut R TAVR system


Participation Criteria
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Eligibility Criteria
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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. Subjects with low-flow/low gradient severe aortic stenosis can be included, provided low-dose dobutamine or exercise stress echocardiography demonstrates a mean gradient of >40 mmHg or a maximal aortic valve velocity of >4.0 m/sec, AND aortic valve area of <1.0cm2 (or aortic valve area index of <0.6 cm2/m2). STS score of ≥ 8 OR documented heart team agreement of ≥ high risk for AVR due to frailty or co-morbidities. Symptoms of aortic stenosis, AND NYHA Functional Class II or greater The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits. Exclusion Criteria Any condition considered a contraindication for placement of a bioprosthetic valve (e.g. subject is indicated for mechanical prosthetic valve). A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated: aspirin or heparin (HIT/HITTS) and bivalirudin, ticlopidine and clopidogrel, Nitinol (titanium or nickel), contrast media 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 or creatinine clearance < 20 cc/min. Ongoing sepsis, including active endocarditis. Any percutaneous coronary or peripheral interventional procedure with a bare metal or drug eluting stent performed within 30 days prior to the study procedure. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 10 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 study procedure. Need for emergency surgery for any reason. Liver failure (Child-Pugh class 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 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. For transfemoral or transaxillary (subclavian) acess: - Access vessel diameter <5.0mm or <6.0mm for patent LIMA
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: CoreValve Evolut R TAVR system<br>The CoreValve Evolut R System is a transcatheter aortic valve implantation system comprised of the following three components: Evolut R Transcatheter Aortic Valve (TAV) EnVeo R Delivery Catheter System (DCS) with EnVeo R InLine Sheath EnVeo R Loading System (LS) | Device: CoreValve Evolut R TAVR system<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause Mortality at 30 Days by Percent | Percentage of patients that died by any cause at 30 days | Assessed at 30 days post-implantation | 
| Percentage of Patients With Disabling Stroke at 30 Days | Stroke Diagnostic Criteria: > Acute episode of focal or global neurological deficit with at least 2 of the following: change in level of consciousness > hemiplegia, hemiparesis numbness or sensory loss affecting 1 side > dysphasia or aphasia hemianopia amaurosis fugax > other neurological signs or symptoms consistent with stroke 2.) No other readily identifiable non-stroke cause or the clinical presentation, to be determined by or in conjunctions with the designated neurologist 3.) Confirmation of the diagnosis by at least 1 of the following: Neurological specialist > Neuroimaging procedure, or on clincial grounds alone > Stroke: durations of neural deficit > 24 h if available neuroimaging documents a new hemofrrhage or infarct; or the neurological deficit results in death Defined by VARC II: > An mRS (Modified Rankin Score) of 2 or more at 90 days and an increase in at least 1 mRS category from pre-stroke baseline | Assessed at 30 days post-implantation | 
| Percent Device Success Rate Between 24 and 7 Day | Percentage of patients with Device Success defined as: Absence of procedural mortality, AND Correct positioning of a single Evolut R valve into the proper anatomical location, AND Absence of patient-prosthesis mismatch, and mean gradient , 20 mm Hg (or peak velocity < 3m/sec, AND Absence of moderate or severe prosthetic valve regurgitation | Assessed at 24 hours to seven days post implantation | 
| Percentage of Patients With Less Than Moderate Prosthetic Regurgitation at Early Post Procedure Echocardiogram (24 Hours to 7 Days) | Percentage of patience with none, trace or mild total prosthetic regurgitation at early post procedure echo cardiogram (24 hours to 7 days) as evaluated by echo core lab. | Assessed at 24 hours to 7 days post implantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual Component of VARC II Safety Endpoint: Percentage of People Requiring Valve-related Dysfunction Requiring Repeat Procedure (BAV, TAVI, or SAVR) | Percentage of patients with any valve dysfunction that requires repeat procedure (e.g. balloon valvuloplasty, TAVI, or surgical AVR), per VARC II definition. | Assessed at 30 days post-implantation | 
| Coronary Artery Obstruction Requiring Intervention. | Angiographic or echocardiographic evidence of a new, partial or complete, obstruction of a coronary ostium, either by the Evolut R prosthesis itself, the native leaflets, calcifications, or dissection, occurring during or after the TAVI procedure. | Assessed at 30 days post-implantation | 
| Percent VARC II Combined Safety Endpoint at 30 Days | VARC II composite safety endpoint rate includes percent freedom from the following components: All-cause mortality All stroke (disabling and non-disabling) Life-threatening bleeding Acute kidney injury: stage 2 or 3 (including renal replacement therapy). Coronary artery obstruction requiring intervention. Major vascular complication. Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) | Assessed at 30 days post-implantation | 
| Percent of Patients With Acute Kidney Injury: Stage 2 or 3 (Including Renal Replacement Therapy). | Stage 2 Increase in serum creatinine to 200%-299% (2.0%-2.99% increase compared with baseline) OR > Urine output <0.5 mL/kg/h for >12 but <24 h > Stage 3 > 1) Increase in serum creatinine to ≥300% (>3 x increase compared with baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute increase of at least 0.5 mg/dL (44 mmol/L) OR Urine output <0.3 ml/kg/h for ≥24 h OR > Anuria for ≥12 h | Assessed at 30 days post-implantation | 
| Percentage of Patients With Life-threatening or Disabling Bleeding Event Rate | Fatal bleeding (BARC type 5) OR > Bleeding in a critical organs, such as intracranial, intraspinal, > intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b and 3c) OR > Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) OR > Overt source of bleeding with drop in hemoglobin ≥5 g/dL or whole blood or packed red blood cells (RBCs) transfusion ≥4 units* > (BARC type 3b) | Assessed at 30 days post-implantation | 
| Percent Rate of Patients Who Received New Permanent Pacemaker Implant at 30 Days | Percent of patients who underwent implantation of new permanent pacemaker or ICD during or after index procedure | Assessed at 30 days | 
| Percent Resheath and Recapture Success Rate | Resheath or recapture success rate (where attempted) where a successful resheath is defined as the intended portion of the Evolut R is resheathed into the capsule of the delivery catheter to the intended amount, as verified by flouroscopy; and a successful recapture is defined as the entire Evolut R TAV (including the frame) is full resheathed into the capsule of the delivery catheter until there is no gap between the capsule and the tip , as verified by flouroscopy. Resheath or recapture wa attempted in a subset of patients. Success rate is calculated as successful resheath or recaputure events in the number of total events. Resheath anad recapture is only possible during the index procedure. | Assessed intra-procedurally | 
| Hemodynamic Performance -Mean Gradient | Mean gradient by Doppler echocardiography. | Assessed at baseline, 30 days, 6 months, and 1 year | 
| Major Vascular Complication | Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical aneurysm/pseudoaneurysm OR > Access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, compartment syndrome, percutaneous closure device failure) leading to death, life-threatening or major bleeding, visceral ischemia, or neurological impairment OR > Distal embolization (noncerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage OR > The use of unplanned endovascular or surgery associated with death, major bleeding, visceral ischemia or neurological impairment OR > Any new ipsilateral lower extremity ischemia documented by patient symptoms, physical exam, and/or decreased or absent blood flow on lower extremity angiogram OR > Surgery for access site nerve injury OR > Permanent access related nerve injury | Assessed at 30 days post-implantation | 
| Hemodynamic Performance - Aortic Valve Area | Hemodynamic performance by Doppler echocardiography - Aortic Valve Area cm2 | Assessed at baseline, 30 days, 6 months, and 1 year | 
| Hemodynamic Performance: Total Prosthetic Valve Regurgitation Graded as Moderate or Severe | Hemodynamic performance: the percent of patients who have a degree of total prosthetic valve regurgitation that is moderate or severe. | Assessed at 30 days, 6 months, and 1 year |