The HeartWare™ Ventricular Assist System as Destination Therapy of Advanced Heart Failure: the ENDURANCE Trial

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and effectiveness of the HeartWare Ventricular Assist System in patients with chronic Stage D/ New York Heart Association (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 HeartWare Ventricular Assist System (VAS) is intended for use in patients with chronic Stage D/NYHA Class IIIB/IV left ventricular failure who have received and failed optimal medical therapy and who are ineligible for cardiac transplantation. The ENDURANCE clinical study is a prospective, randomized, unblinded, multi-center, non-inferiority evaluation of the HeartWare® VAS versus a control group consisting of any FDA-approved Left Ventricular Assist Device (LVAD) approved for destination therapy. Patients are randomized to HeartWare® VAS or control LVAD in a 2:1 ratio. Each patient receiving the HeartWare® VAS or control LVAD is followed to the primary endpoint at 2 years, with a subsequent follow-up period extending to 5 years post implant.

Official Title
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A Prospective, Randomized, Controlled, Un-blinded, Multi-Center Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System (VAS) for Destination Therapy of Advanced Heart Failure

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Device: HeartWare® VAS
* 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 (New York Heart Association (NYHA) Class IIIB or IV) who are: (patient must meet one of the following) 3a. 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 3b. In NYHA Class III or NYHA 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® VAS or control LVAD Female patients of childbearing potential must agree to use adequate contraceptive precautions 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 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 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) or right atrial pressure > 20 mmHg on multiple inotropes, right ventricular ejection fraction (RVEF) <15% or clinical signs Active, uncontrolled infection diagnosed by a combination of clinical symptoms and laboratory testing. 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 (does not include use of ultra-filtration for fluid removal). 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 (PVR) 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 Chronic Obstructive Pulmonary Disease (COPD) or severe restrictive lung disease 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<br>Implant of HeartWare® Ventricular Assist System | Device: HeartWare® VAS<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 LVADs 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 |
| --- | --- | --- |
| Stroke-Free Survival Probability for 2 Years Post Implant | The primary endpoint of the trial is stroke-free survival at two years, defined as alive on the originally implanted device, electively transplanted or explanted due to patient recovery and free from disabling stroke (Modified Rankin Scale >=4). 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. Weibull model estimates of survival probability (shown as a percent of 100) are used. | Implant to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Bleeding | Number of participants with bleeding, per Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definition. The event of bleeding is defined as: An episode of suspected internal or external bleeding that results in one or more of the following: Death, Re-operation, Hospitalization, Transfusion of red blood cells as follows: During first 7 days post implant Adults (≥ 50 kg): ≥ 4U packed red blood cells (PRBC) within any 24 hour period during first 7 days post implant. After 7 days post implant Any transfusion of packed red blood cells (PRBC) after 7 days following implant. | Implant to two years | 
| Number of Participants With Major Infections | Number of participants with major infections, per INTERMACS definition. A major infection is defined as: A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by anti-microbial agents (non-prophylactic). A positive culture from the infected site or organ should be present unless strong clinical evidence indicates the need for treatment despite negative cultures. The general categories of infection include Localized non-device infection Percutaneous site and/or pocket infection Internal pump component, inflow or outflow tract infection Sepsis | Implant to two years | 
| Overall Survival at 2 Years | Overall survival is the probability (expressed as a percent of 100) did not died within 2 years post implant via the Kaplan-Meier method. Participants that did not died were censored at the time of last follow-up or 2 years post implant, whichever occurred first. | Implant to two years | 
| Number of Participants With Device Malfunctions | Number of Participants with device malfunctions per INTERMACS definition. Device malfunction denotes a failure of one or more of the components of the Mechanical Circulatory Support Device (MCSD) system which either directly causes or could potentially induce a state of inadequate circulatory support (low cardiac output state) or death. The manufacturer must confirm device failure. A failure that was iatrogenic or recipient-induced will be classified as an Iatrogenic/Recipient-Induced Failure. Device failure should be classified according to which components fails as follows: Pump failure (blood contacting components of pump and any motor or other pump actuating mechanism that is housed with the blood contacting components). Non-pump failure (e.g., external pneumatic drive unit, electric power supply unit, batteries, controller, interconnect cable, compliance chamber) | Implant to two years | 
| Health Status Change Measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) | Health Status change as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score. The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (e.g., better functioning, fewer symptoms, better quality of life). The Overall Summary Score is calculated as the mean of the Physical Limitation, Total Symptom, Quality of Life and Social Limitation scores. A positive change in score from baseline indicates an improvement. | Change from baseline to 2 years | 
| Health Status Change Measured by EuroQol EQ-5D (Version 3L) | The EuroQol-5D (version 3L) is a brief self-administered, validated instrument consisting of 2 parts. The second part consists of the EQ-5D general health status as measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state). An adjustment was done on the response where the scores were normalized based on this paper: Johnson JA, Coons SJ. Comparison of the EQ-5D and SF-12 in an adult US sample. Qual Life Res. 1998 Feb;7(2):155-66. | Change from baseline to 2 years | 
| Change in Functional Status Measured by New York Heart Association (NYHA) Class | Change in Functional status, as measured by New York Heart Association (NYHA) class. There are 4 levels of NYHA: I (Mild): No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea. II (Mild): Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea. III (Moderate): Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. IV (Severe): Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased. Improvement is defined as moving from a higher numerical NYHA level to a lower numerical NYHA level (e.g., IV to III). | Change from baseline to 2 years | 
| Change in Functional Status as Measured by 6-minute Walk | Change in functional status, as measured by 6-minute walk test. | Change from baseline to 2 years | 
| Length of Initial Hospitalization | Length of Initial Hospitalization post implant | Implant to the end of the initial hospitalization | 
| Number of Participants Who Had a Re-hospitalization | Number of participants who had a re-hospitalization while on the device | Implant to two years | 
| Duration of Re-hospitalization | Duration of Re-hospitalization while on device | Implant to two years | 
| Cause of Re-hospitalization | Cause of Re-hospitalization while on device. The reason a participant may have been re-hospitalized was due to an adverse event, the need for an explant, or for various Other reasons. | Implant to two years |