Neural Cardiac Therapy for Heart Failure Study (NECTAR-HF)

Study Overview
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Brief Summary
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The NECTAR-HF feasibility trial is designed to evaluate the application of right vagal nerve stimulation in heart failure patients with a New York Heart Association Class III, an ejection fraction equal to or less than 35 %, and a narrow QRS duration equal to or less than 130 ms.

Detailed Description
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The objectives of this study are to assess the impact of right vagal nerve stimulation on left ventricular remodeling, functional capacity, quality of life, and other measures in heart failure patients over a 6-month period. In addition, the study will assess the safety of the NECTAR-HF study system over an 18-month period.

Official Title
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Neural Cardiac Therapy for Heart Failure Study

Conditions
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Heart Failure, Congestive Heart Failure

Intervention / Treatment
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* Device: Implant of investigational device system
* Procedure: Titration during the randomization phase
* Procedure: Titration after the randomization phase
* Diagnostic Test: Blood Draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or above, and of legal age to give informed consent specific to national laws Willing and capable of providing informed consent Capable of participating in all testing associated with this clinical investigation Stable symptomatic heart failure NYHA class II-III Left ventricular (LV) ejection fraction equal or smaller than 35 % Left ventricular end diastolic diameter (LVEDD) of 5.5 cm or greater Prescribed to optimal pharmacologic therapy Exclusion Criteria: QRS larger than 130 ms Patients who have been hospitalized for heart failure and who required the use of HF IV therapy within 30 days before enrollment Patients unable to tolerate anesthesia required for implant Patients with unstable angina, myocardial infarction, PTCA, coronary artery bypass graft, cerebral vascular accident, or transient ischemic attack within previous 90 days before enrollment Patients whose primary cause of heart failure is mitral or aortic valve disease, with a severe classification Patients with persistent or permanent atrial fibrillation within 90 days prior to enrollment Pacemaker indicated patients Patients whose heart failure is due to congenital heart disease Patients who have started treatment for sleep apnea or sleep disordered breathing with therapies to maintain airway patency (e.g., CPAP, Bi-PAP,APAP) with or without oxygen supplementation within the previous 6 months prior to enrollment Patients with hypertrophic obstructive cardiomyopathy or infiltrative cardiomyopathy (e.g. amyloidosis, sarcoidosis) Patients with documented chronic obstructive lung disease Patients on or indicated for renal dialysis Type 1 diabetic patients Type 2 diabetic patients that have been treated with insulin for more than 5 years prior to enrollment Patients with a life expectancy of less than 12 months per physician judgment Patients involved in any concurrent clinical investigation Women of childbearing potential who are or might be pregnant at the time of the study or breastfeeding Patients with a prior cardiac transplant or expecting a heart transplant operation within the next 12 months Patients with a prior vagotomy Patients with prior or existing vagal nerve stimulation treatment Patients implanted with any active implantable medical device other than a left sided single or dual chamber implantable cardioverter defibrillator (ICD) with bipolar sensing, or a left sided CRT device with each sensing channel programmed to either bipolar sensing or no sensing. All CRT patients must have had CRT for at least 1 year prior to enrollment. The total number of CRT patients will not exceed 30 Patients with locally implanted semi-/permanent devices such as vascular catheters, etc. that would interfere with the NECTAR-HF study system Patients with previously implanted devices on the right side that became infected before removal Patients with previous neck surgery and resultant scar formation that interferes with the ability to implant the study system on the right side of the neck (Thyroid/parathyroid, carotid artery etc) Patients with known recurrent nerve paralysis Patients who have undergone radiotherapy for thyroid disease/cancer Patients who have existing or prior tracheotomy Patients with severe vertebral cervical disease and limited mobility in the neck; includes those that frequently wear a brace Patients with carotid murmur/vascular bruit/carotid artery lesion Patients with known/suspected vascular malformation in carotid/vertebral circulatory bed Patients who are likely to need an MRI of the neck area because of previous medical conditions

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: Crossover Assignment
Interventional Model Description: Patients were randomized in a 2:1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LVend systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapy<br>Implant of investigational device system for vagus nerve stimulation. Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The experimental arm was receiving vagus nerve stimulation during the first 6 months after implant. Titration during the randomization phase with delivery of highest tolerable by patient stimulation current. Blood Draw before implant and 6 months after implant. Titration after the randomization phase with adjustments of the chronically highest tolearble by patient current. | Device: Implant of investigational device system<br>* Vagus nerve stimulation lead was wrapped around the right cervical vagus nerve and then connected to a stimulator permanently implanted in the right pectoral region.<br>Procedure: Titration during the randomization phase<br>* Amplitude of the chronically delivered vagus nerve stimulation in the experimental arm was adjusted to the highest tolerable by patient value. No chronically delivered vagus nerve stimulation in the control arm during the randomization phase.<br>Procedure: Titration after the randomization phase<br>* Amplitude of the chronically delivered vagus nerve stimulation was adjusted to the highest tolerable by patient value in all patients in both arms of the study.<br>Diagnostic Test: Blood Draw<br>* Blood draw before implant and 6 months after implant at the end of the randomization phase.<br>|
| Sham Comparator: Control<br>Implant of investigational device system for vagus nerve stimulation. Control group was implanted with study system like the experimental arm, but was not receiving experimental vagus nerve stimulation therapy during the first 6 months after implant. 6-month after implant a cross-over took place and the control arm also started to receive experimental vagus nerve stimulation. Blood Draw before implant and 6 months after implant. Titration after the randomization phase with adjustments of the chronically highest tolearble by patient current. | Device: Implant of investigational device system<br>* Vagus nerve stimulation lead was wrapped around the right cervical vagus nerve and then connected to a stimulator permanently implanted in the right pectoral region.<br>Procedure: Titration after the randomization phase<br>* Amplitude of the chronically delivered vagus nerve stimulation was adjusted to the highest tolerable by patient value in all patients in both arms of the study.<br>Diagnostic Test: Blood Draw<br>* Blood draw before implant and 6 months after implant at the end of the randomization phase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Left Ventricular End-systolic Dimension (LVESD) | Change in the Left ventricular end-systolic dimension (LVESD) between Baseline and the value at the end of the randomization phase (6 months after Baseline) i.e. 6 months after vagus nerve stimulation in the THERAPY Arm. No Vagus nerve stimulation during that time window in the CONTROL Arm. The sign (- ) indicates a reduction in the LVESD. Minus means a reduction in LVESD. The change was calculated from two time points as the value at the later time point minus the value at the earlier time point (e.g., value at 6 months minus value at baseline). | LVESD at Baseline and at 6-months post Baseline | 
| Percentage of Surviving Participants | As pre-specified in the study protocol, the All-cause Survival endpoint combined both groups into one analysis population. Subjects contributed data according to the follow-up period during they received VNS therapy (Implant through 18 months for Therapy subjects, 6 through 18 months for Control subjects). Control patients who exited the study in the first 6 months, or who did not have a 6 month visit, were excluded. | 18-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LVEF, Left Ventricular Ejection Fraction | LVEF, left ventricular ejection fraction. | LVEF at Baseline and at 6-months after Baseline | 
| Exercise Capacity, Peak VO2 | Assessment of functional capacity (e.g., peak VO2) as measures related to patient heart failure status. | Measurements at Baseline and at 6-months after Baseline | 
| LVESV, Left Ventricular End Systolic Volume | Measurements of LVESV, left ventricular end systolic volume at Baseline and 6 months after Baseline in the Control Arm and in the Therapy Arm | At Baseline and at 6-months after Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Congestive heart failure, New York Heart Association Class II-III, Vagal therapy, Vagal nerve stimulation