Neural Cardiac Therapy for Heart Failure Study (NECTAR-HF) | NCT01385176

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Therapy	Experimental	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 Procedure: Titration during the randomization phase Procedure: Titration after the randomization phase Diagnostic Test: Blood Draw
Control	Sham Comparator	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 Procedure: Titration after the randomization phase Diagnostic Test: Blood Draw

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Implant of investigational device system	Device	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.

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Faiez Zannad, M.D.	Centre d'Investigation Clinique (CIC), Batiment Louis Mathieu, CHU de Nancy	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
UCL Bruxelles		Brussels		1200	Belgium
Nemocnice Na Homolce

PubMed Identifier	Type	Citation	Retractions
24846173	Background	De Ferrari GM, Tuinenburg AE, Ruble S, Brugada J, Klein H, Butter C, Wright DJ, Schubert B, Solomon S, Meyer S, Stein K, Ramuzat A, Zannad F. Rationale and study design of the NEuroCardiac TherApy foR Heart Failure Study: NECTAR-HF. Eur J Heart Fail. 2014 Jun;16(6):692-9. doi: 10.1002/ejhf.80. Epub 2014 May 20.
25176942	Result

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Therapy	Vagus nerve stimulation system was implanted in the Therapy group as well as in the control group. Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON, Therapy) or control (VNS OFF, Control) for a 6-month period. The experimental arm was receiving vagus nerve stimulation soon after implant. Patients randomized to control arm were not receiving right vagal nerve stimulation for the first 6-months post-implant, after which they did also receive therapy.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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).

The sign (- ) indicates a reduction in the LVESD. Participants without paired endpoint data did not contribute to the analysis.

Posted

Mean

Standard Deviation

LVESD at Baseline and at 6-months post Baseline

ID	Title	Description
OG000	Therapy	Vagus nerve stimulation system was implanted. 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 starting at Baseline.
OG001	Control	Control group was implanted with study system like the experimental arm, but did not receive vagus nerve stimulation for the first 6 months after Baseline, after which they will also receive vagus nerve stimulation. Vagal Nerve Stimulation System was implanted but inactive for the first 6 months.

Units	Counts
Participants	OG00059 OG00128

Title

Denominators

Categories

Title	Measurements
	OG000-0.04± 0.25 OG001-0.08± 0.32

Primary

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.

Therapy group received VNS from implant to 18 months. Control group received VNS from 6 months to 18 months. These follow-up periods contributed to the endpoint analysis. Both groups were combined for mortality endpoint analysis. Control patients who exited the study in the first 6 months, or who did not have a 6 month visit, were excluded.

Posted

Number

90% Confidence Interval

Percentage of participants surving

18-months

ID	Title	Description
OG000	All Patients in Active VNS Periods	All patients in VNS active study periods. Therapy 0-18 months and Control 6-18 months.

Units	Counts
Participants	OG000

Secondary

LVEF, Left Ventricular Ejection Fraction

LVEF, left ventricular ejection fraction.

LVEF echocardiographic measurements were made at Baseline and at 6 months after Baseline. Participants without paired endpoint data did not contribute to the analysis.

Posted

Mean

Standard Deviation

% of blood ejected from ventricle

LVEF at Baseline and at 6-months after Baseline

ID	Title	Description
OG000	Therapy	Vagus nerve stimulation system was implanted. 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 starting at Baseline.
OG001	Control	Control group was implanted with study system like the experimental arm, but did not receive vagus nerve stimulation for the first 6 months after Baseline, after which they also did receive vagus nerve stimulation. Vagal Nerve Stimulation System was implanted but inactive for the first 6 months.

Units	Counts
Participants

Secondary

Exercise Capacity, Peak VO2

Assessment of functional capacity (e.g., peak VO2) as measures related to patient heart failure status.

Participants without paired endpoint data did not contribute to the analysis.

Posted

Mean

Standard Deviation

ml/kg/min

Measurements at Baseline and at 6-months after Baseline

ID	Title	Description
OG000	Therapy	Vagus nerve stimulation system was implanted. 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 starting at Baseline.
OG001	Control	Control group was implanted with study system like the experimental arm, but did not receive vagus nerve stimulation for the first 6 months after Baseline, after which they did also receive vagus nerve stimulation. Vagal Nerve Stimulation System was implanted but inactive for the first 6 months.

Units	Counts
Participants

Secondary

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

Measurements of LVESV, left ventricular end systolic volume at Baseline and at 6-months after Baseline. Participants without paired endpoint data did not contribute to the analysis.

Posted

Mean

Standard Deviation

At Baseline and at 6-months after Baseline

ID	Title	Description
OG000	Therapy	Vagus nerve stimulation system was implanted. 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 starting at Baseline.
OG001	Control	Control group was implanted with study system like the experimental arm, but did not receive vagus nerve stimulation for the first 6 months after Baseline, after which they did also receive vagus nerve stimulation. Vagal Nerve Stimulation. System was implanted but inactive for the first 6 months.

Units	Counts
Participants

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Therapy	Vagus nerve stimulation system was implanted in the Therapy group as well as in the control group. Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON, Therapy) or control (VNS OFF, Control) for a 6-month period. Patients randomized to therapy arm were receiving right vagal nerve stimulation shortly after implant.	1	63	21	63	32	63
EG001	Control	Control group was implanted with study system like the experimental arm, but did receive no therapy until 6-month cross-over. Patients randomized to control arm did not receive right vagal nerve stimulation for the first 6-months post-implant, after which they did also receive therapy.	2	32	18	32	15	32
EG002	All Patients - 6 to 18 Months	All patients were receiving vagus nerve stimulation after the initial 6 months of randomization. Three of the initially 95 randomized patients died before the end of the randomization phase, reducing the number to 92 patients. Note, 5 patients did not complete the Randomization phase with the 6 month follow up visit, but were still participating in the study at the time the Randomization Phase Analysis was done. These 5 patients were at risk to have an AE and were included in this analysis set (N=92)	3	92	44	92	66	92

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
HF hospitalization, anticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Heart Failure hospitalizations	EG00010 events7 affected63 at risk EG0019 events5 affected32 at risk EG00232 events18 affected92 at risk
Cardiovascular - Non Heart Failure, anticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Cardiovascular Serious Adverse events, which were not related to Heart Failure	EG0009 events7 affected63 at risk EG0017 events5 affected32 at risk EG00226 events16 affected92 at risk
Pulmonary Serious Adverse Events, anticipated	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Pulmonary Serious Adverse Events	EG0000 events0 affected63 at risk EG0013 events3 affected32 at risk EG0026 events5 affected92 at risk
Genitourinary, anticipated	Renal and urinary disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Genitourinary Serious Adverse Events	EG0001 events1 affected63 at risk EG0012 events2 affected32 at risk EG0022 events1 affected92 at risk
Other Non Cardiocascular, anticipated	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	Other anticipated Non Cardiocascular serious adverse events	EG0007 events7 affected63 at risk EG0017 events7 affected32 at risk EG00233 events22 affected92 at risk
Investigational device system related, anticipated	Product Issues	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Investigational device system related serious adverse device effects	EG0009 events9 affected63 at risk EG0014 events4 affected32 at risk EG0022 events2 affected92 at risk
Heart Failure Hospitalizations, unanticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	unanticipated Heart Failure Hospitalizations	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Cardiovascular - Non Heart Failure, unanticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	unanticipated Cardiovascular - Non Heart Failure	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Pulmonary Serious Adverse Events, unanticipated	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	unanticipated Pulmonary Serious Adverse Events	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Genitourinary, unanticipated	Renal and urinary disorders	MedDRA (Unspecified)	Non-systematic Assessment	unanticipated Genitourinary	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Investigational device system related, unanticipated	Product Issues	MedDRA (Unspecified)	Non-systematic Assessment	unanticipated Investigational device system related	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0021 events1 affected92 at risk
Other Non Cardiocascular, unanticipated	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	Other unanticipated Non Cardiocascular	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Death, anticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticpated death due to any cause	EG0001 events1 affected63 at risk EG0012 events2 affected32 at risk EG0023 events3 affected92 at risk
Death, unanticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	Death, unanticipated, due to any cause	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Cardiovascular HF related, anticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Cardiovascular Heart Failure related non serious adverse events	EG00020 events15 affected63 at risk EG0019 events7 affected32 at risk EG00231 events21 affected92 at risk
Cardiovascular - not HF related, anticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Cardiovascular - not Heart Failure related adverse events	EG00031 events21 affected63 at risk EG00118 events13 affected32 at risk EG00240 events28 affected92 at risk
Pulmonary non serious adverse events, anticipated	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	anticipated Pulmonary non serious adverse events (non-cardiovascular)	EG0002 events2 affected63 at risk EG0012 events2 affected32 at risk EG0028 events8 affected92 at risk
Genitourinary, anticipated	Renal and urinary disorders	MedDRA (Unspecified)	Non-systematic Assessment	Genitourinary non - serious, anticipated	EG0001 events1 affected63 at risk EG0012 events1 affected32 at risk EG0023 events3 affected92 at risk
Other Non-cardiovascular, anticipated	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	Other Non-cardiovascular non-serious adverse events, anticipated	EG00028 events19 affected63 at risk EG00120 events13 affected32 at risk EG00256 events34 affected92 at risk
Investigational System-Related anticipated	Investigations	MedDRA (Unspecified)	Non-systematic Assessment	Investigational System-Related non-serious adverse events, anticipated	EG00055 events32 affected63 at risk EG00118 events11 affected32 at risk EG00234 events25 affected92 at risk
Cardiovascular HF related, unanticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	unanticipated Cardiovascular HF related non-serious adverse events	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Cardiovascular - not HF related, unanticipated	Cardiac disorders	MedDRA (Unspecified)	Non-systematic Assessment	Cardiovascular - not HF related, unanticipated	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Pulmonary non serious adverse events, unanticipated	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	Pulmonary non serious adverse events, unanticipated	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Genitourinary, unanticipated	Renal and urinary disorders	MedDRA (Unspecified)	Non-systematic Assessment	Genitourinary, unanticipated non serious	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Other Non-cardiovascular, unanticipated	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	Other Non-cardiovascular, unanticipated	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk
Investigational System-Related unanticipated	Product Issues	MedDRA (Unspecified)	Non-systematic Assessment	Investigational System-Related unanticipated	EG0000 events0 affected63 at risk EG0010 events0 affected32 at risk EG0020 events0 affected92 at risk

ID	Title	Description
BG000	Therapy	Therapy group was implanted with study system like the control arm, but did receive therapy soon after implant
BG001	Control	Control group was implanted with study system like the experimental arm, but will receive no therapy until 6-month cross-over. Vagal Nerve Stimulation System was implanted but inactive for the first 6 months: Patients randomized to therapy arm with receive right vagal nerve stimulation. Patients randomized to control arm will not receive right vagal nerve stimulation for the first 6-months post-implant, after which they will also receive therapy.
BG002	Total	Total of all reporting groups

ID	Term
D006331	Heart Diseases
D002318	Cardiovascular Diseases

ID	Term
D013048	Specimen Handling
D019411	Clinical Laboratory Techniques
D019937	Diagnostic Techniques and Procedures
D003933	Diagnosis
D011677	Punctures
D013514	Surgical Procedures, Operative
D008919	Investigative Techniques