INcrease Of VAgal TonE in CHF

Study Overview
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Brief Summary
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The purpose of the INOVATE-HF study is to demonstrate the long-term safety and efficacy of vagus nerve stimulation with the CardioFit® system for the treatment of subjects with Heart Failure.

Detailed Description
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Prospective, Randomized (3:2 active:control), Open Label, Event-driven Interventional Study. All subjects undergo the following: Baseline, Randomization, (Implantation & Optimization for subjects randomized to the active therapy), and Follow-up Period, followed by an Extension period, which lasts until the end of the study. The Clinical Events Committee (CEC) and Data Monitoring and Safety Board (DSMB) will conduct scheduled independent reviews of the data at the following time-points in order to ensure that an ongoing acceptable safety profile is being achieved.

Official Title
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INcrease Of VAgal TonE in CHF (INOVATE-HF) - A Randomized Study to Establish the Safety and Efficacy of CardioFit® for the Treatment of Subjects With Heart Failure and Left Ventricular Dysfunction

Conditions
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Left Ventricular Dysfunction, Heart Failure

Intervention / Treatment
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* Device: CardioFit® System
* Other: Standard of Care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic symptomatic heart failure in New York Heart Association functional class III. Age of at least 18 years. Subjects should be predominately in sinus rhythm at the time of enrollment. On stable optimally uptitrated medical therapy recommended according to current guidelines as standard of care for heart failure therapy. LVEF ≤ 40% per site measurement within three months before enrollment. The left ventricular end diastolic diameter, per site measurement, should be between 50 and 80 mm. The subject is a male or postmenopausal female. Females of childbearing age may be included if an acceptable contraception measure is used. Subject must sign an approved informed consent form. Subject agrees to attend all followup evaluations. Subjects with CRT devices may be included in the trial provided they have had CRT for at least 12 months. Exclusion Criteria: Presence of a life threatening condition or disease other than heart failure, that is likely to lead to death within 6 months. Acute myocardial infarction (MI), variant angina pectoris, unstable angina or acute coronary syndrome in the previous one month. History of stroke or TIA within the previous 3 months or significant neurological damage that would impair the ability to respond to or detect improvement with the vagal nerve stimulation. Coronary Artery Bypass Surgery (CABG), valve replacement or repair, aortic surgery or PCI) in the prior 3 months or planned/anticipated within 6 months. Heart failure due to acute myocarditis, restrictive cardiomyopathy, constrictive pericarditis or hemodynamically significant aortic valve insufficiency, aortic stenosis, or mitral valve stenosis. Severe renal failure (creatinine level > 3 mg/dL (265 micromole/liter). Severe hepatic failure (transaminase level four times ULN, or total bilirubin level > 1.8 mmol/dL). Uncontrolled Diabetes Mellitus, which in the opinion of the investigator, would compromise the safety of the implant procedure and/or the ability to respond or detect improvement with vagal nerve stimulation. Previous right neck surgery, including for cerebrovascular disease (CVD), malignancy, and previous irradiation therapy of the neck, which in the opinion of the implanting surgeon, would preclude safe implantation of the vagal nerve cuff. Subjects with more than 70% right carotid artery stenosis assessed on carotid ultrasound are excluded. Current hypotension (systolic blood pressure below 80 mmHg). Active peptic ulcer disease or history of upper GI bleeding, or ulcer within 6 months. History of lung disease such as severe asthma, COPD (e.g., FEV1<1.5 liter) or continuous oxygen dependence. 2nd or 3rd degree AV block or other pacemaker indication that is not treated with a pacemaker. Chronic atrial fibrillation or flutter in the previous 3 months, or hospitalization for AF due to clinical manifestations of such in the last 6 months. Use of unipolar sensing Congenital or acquired long QT syndrome. Documented recorded or suspected vaso-vagal syncope or vaso depressor syncope. Treatment by investigational drug or device within the past 3 months. The subject must not have received inotropic therapy within 2 months or be considered a possible candidate for inotropic therapy within the next 1 month. Inability to understand the informed consent and/or prior diagnosis of major affective disorder e.g., major depression or bipolar disorder or schizophrenia that requires ongoing treatment and is not adequately controlled by medication. Subjects transplanted with heart or other tissues or organs, or on a heart transplant waiting list and anticipated to receive a transplant within 6 months of randomization. Immunosuppressed subjects; subjects under systemic steroid treatment. Anemia with Hgb ≤ 9.5 g/L. Treatment with erythropoietin or other similar agents is allowed if used to keep Hgb > 9.5 g/L. Untreated obstructive sleep apnea (OSA) with apnea-hypopnea index of 15 or more; or OSA that is treated for less than 3-months.

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: CardioFit® System<br>Vagal nerve stimulation with the CardioFit® system | Device: CardioFit® System<br>* Vagal nerve stimulation with the CardioFit® system<br>|
| Active Comparator: Standard of Care<br>Usual care (no CardioFit System implant) | Other: Standard of Care<br>* Usual care for LV dysfunction and heart failure (no CardioFit System implant)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants reaching all-cause mortality or unplanned heart failure hospitalization or equivalent. | The primary efficacy end-point of the study is the composite of all-cause mortality or unplanned heart failure hospitalization equivalent using a time to first event analysis, as compared between the two study arms after a pre-specified number of such events have been accumulated. | Until the end of the study | 
| Co-Primary Safety Endpoints: a) Freedom from procedure and system related complication events and b) Number of all-cause death cases or complications resulting in hospitalization | The co-primary safety endpoints of the study are the following: Freedom from procedure and system related complication events through 90 days Demonstrate time to first event equivalence in all-cause mortality and complications resulting in prolonged hospitalization between the Control and CardioFit | a) 90 days and b) Until the end of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The rate of unplanned heart failure hospitalization equivalents | The rate of unplanned heart failure hospitalization equivalents | Until the end of the study | 
| Mean improvement in LVESVi from baseline to 12-months | Mean improvement in LVESVi from baseline to 12-months | 12 Months | 
| Mean improvement in the summary score of the KCCQ from baseline to 12-months | Mean improvement in the summary score of the KCCQ from baseline to 12-months | 12 Months | 
| Mean improvement in 6 minute walk test from baseline to 12-months | Mean improvement in 6 minute walk test from baseline to 12-months | 12 Months | 
| All cause mortality and the number of unplanned heart failure hospitalization equivalents | All cause mortality and the number of unplanned heart failure hospitalization equivalents | Until the end of the study | 
| Rate of hospitalization-free days | Rate of hospitalization-free days | Until the end of the study | 
| Secondary Safety Endpoints: Mortality and Complications | The following additional (secondary) safety endpoint data will also be evaluated comparatively at 6- and 12-months: All-cause mortality Cardiovascular mortality Serious adverse events Complications System- or procedure-related complications | Until the end of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LV Dysfunction, Heart Failure