A Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System (ENDURANCE SUPPLEMENTAL TRIAL)

Study Overview
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Brief Summary
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This is a prospective, randomized, controlled, unblinded, multi-center evaluation of safety and efficacy in patients implanted with a HeartWare® HVAD who receive improved blood pressure management. Subjects have chronic Stage D or NYHA Class IIIB/IV left ventricular failure who have received and failed optimal medical therapy, and who are ineligible for cardiac transplantation.

Detailed Description
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The study will evaluate non-inferiority of neurologic injury incidence in a new cohort of subjects receiving improved blood pressure management to a control group (i.e., any FDA-approved LVAD for destination therapy). Secondary endpoints include: a comparison of stroke/TIA incidence to a reference observed in the original IDE clinical trial (HW004) that did not specify improved blood pressure management; and non-inferiority of stroke-free success on the originally implanted device to the control group. Subjects will be randomized to HeartWare® HVAD or control LVAD in a 2:1 ratio. Each subject receiving the HeartWare® HVAD or control LVAD is followed to the primary and secondary endpoints at 12 months, with a subsequent follow-up period extending to 60 months post-implant.

Official Title
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A Prospective, Randomized, Controlled, Unblinded, Multi-Center Clinical Trial to Evaluate the HeartWare™ Ventricular Assist Device System for Destination Therapy of Advanced Heart Failure

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Device: HeartWare® VAS (HVAD)
* Device: Control LVAD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be ≥18 years of age at consent Body Surface Area (BSA) ≥ 1.2 m2 Patients with advanced heart failure symptoms (Class IIIB or IV) who are: (patient must meet one of the following)a. On optimal medical management, including dietary salt restriction and diuretics, for at least 45 out of the last 60 days and are failing to respond; or b. In Class III or Class IV heart failure for at least 14 days, and dependent on intra-aortic balloon pump (IABP) for 7 days and/or inotropes for at least 14 days Left ventricular ejection fraction ≤ 25% LVAD implant is intended as destination therapy Must be able to receive either the HeartWare® HVAD or control LVAD Patient must agree to participate in and comply with an improved blood pressure management program, including maintenance of a patient diary. Female patients of childbearing potential must agree to use adequate contraceptive precautions (defined as oral contraceptives, intrauterine devices, surgical contraceptives or a combination of condom and spermicide) for the duration of the study. The patient or legally authorized representative has signed the informed consent form Exclusion Criteria: Body Mass Index (BMI) > 40 Existence of any ongoing mechanical circulatory support (MCS) other than an intra-aortic balloon pump (IABP) Prior cardiac transplant. History of confirmed, untreated abdominal or thoracic aortic aneurysm > 5 cm. Cardiothoracic surgery within 30 days of randomization. Acute myocardial infarction within 14 days of implant as diagnosed by ST or T wave changes on the ECG, diagnostic biomarkers, ongoing pain and hemodynamic abnormalities as described (Figure 2) in the guidelines published in ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction ;. Patients eligible for cardiac transplantation On ventilator support for > 72 hours within the four days immediately prior to randomization and implant. Pulmonary embolus within three weeks of randomization as documented by computed tomography (CT) scan or nuclear scan. Symptomatic cerebrovascular disease, stroke within 180 days of randomization or > 80% stenosis of carotid or cranial vessels. Uncorrected moderate to severe aortic insufficiency. Correction may include repair or bioprosthesis at the time of implant. Severe right ventricular failure as defined by the anticipated need for right ventricular assist device (RVAD) support or extracorporeal membrane oxygenation (ECMO) at the time of screening/randomization or right atrial pressure > 20 mmHg on multiple inotropes or right ventricular ejection fraction (RVEF) <15% with clinical signs of severe right heart failure (e.g. Lower extremity edema, ascites or pleural effusions refractory to treatment with diuretics and two inotropic drugs). Active, uncontrolled infection diagnosed by a combination of clinical symptoms and laboratory testing, including but not limited to, continued positive cultures, elevated temperature and white blood cell (WBC) count, hypotension, tachycardia, generalized malaise despite appropriate antibiotic, antiviral or antifungal treatment. Uncorrected thrombocytopenia or generalized coagulopathy (e.g., platelet count < 75,000, INR > 2.0 or PTT > 2.5 times control in the absence of anticoagulation therapy). Intolerance to anticoagulant or antiplatelet therapies or any other peri- or postoperative therapy that the investigator may administer based upon the patient's health status. Serum creatinine > 3.0 mg/dL within 72 hours of randomization or requiring dialysis or ultrafiltration. Specific liver enzymes [AST (SGOT) and ALT (SGPT] > 3 times upper limit of normal within 72 hours of randomization. A total bilirubin > 3 mg/dl within 72 hours of randomization, or biopsy proven liver cirrhosis or portal hypertension. Pulmonary vascular resistance is demonstrated to be unresponsive to pharmacological manipulation and the PVR > 6 Wood units. Patients with a mechanical heart valve. Etiology of heart failure is due to, or associated with, uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis, active myocarditis or restrictive cardiomyopathy History of severe COPD or severe restrictive lung disease (e.g. FEV1 <50%) Participation in any other study involving investigational drugs or devices Severe illness, other than heart disease, which would limit survival to < 3 years Peripheral vascular disease with rest pain or ischemic ulcers of the extremities Pregnancy Patient unwilling or unable to comply with study requirements Technical obstacles, which pose an inordinately high surgical risk, in the judgment of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HeartWare® VAS (HVAD)<br>Implant of HeartWare® Ventricular Assist System | Device: HeartWare® VAS (HVAD)<br>* The HeartWare® VAS is an implantable centrifugal pump that was designed to provide flows up to 10 L/min in a small device that is both lightweight and simple to use.<br>|
| Active Comparator: Control LVAD<br>Implant of FDA-approved LVAD approved for destination therapy | Device: Control LVAD<br>* Any FDA-approved LVAD for destination therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Neurologic Injury | The primary endpoint is the percent of participants at 12 months on the originally implanted device with neurologic injury, defined as a stroke with Modified Rankin Scale (MRS) > 0 at 24-weeks post-stroke, or a transient ischemic attack (TIA), or a spinal cord infarction (SCI). The Modified Rankin Scale is scored from 0 to 6, where 0 indicates an absence of symptoms and 6 indicates death. A score of 4 or higher indicates moderately severe or greater disability. | Implant to 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of HeartWare VAS Participants With Stroke/TIA | The first secondary endpoint is the number of HeartWare VAS participants with stroke/TIA at 12 months on the originally implanted device. | Implant to 12 Months | 
| Number of Participants With Stroke-Free Success | Success is defined as alive on the originally implanted device, electively transplanted or explanted due to subject recovery and free from disabling stroke (Modified Rankin Scale >=4). | Implant to 12 Months |