Clinical trial NCT01303718: INcrease Of VAgal TonE in CHF
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Left Ventricular Dysfunction
Heart Failure
Keywords: LV Dysfunction
Heart Failure
Lead sponsor: BioControl Medical
Sponsor class: INDUSTRY
First posted: 2011-02-25
Enrollment: 730
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Chronic symptomatic heart failure in New York Heart Association functional class III.
2. Age of at least 18 years.
3. Subjects should be predominately in sinus rhythm at the time of enrollment.
4. On stable optimally uptitrated medical therapy recommended according to current guidelines as standard of care for heart failure therapy.
5. LVEF ≤ 40% per site measurement within three months before enrollment.
6. The left ventricular end diastolic diameter, per site measurement, should be between 50 and 80 mm.
7. The subject is a male or postmenopausal female. Females of childbearing age may be included if an acceptable contraception measure is used.
8. Subject must sign an approved informed consent form. Subject agrees to attend all followup evaluations.
9. Subjects with CRT devices may be included in the trial provided they have had CRT for at least 12 months.

Exclusion Criteria:

1. Presence of a life threatening condition or disease other than heart failure, that is likely to lead to death within 6 months.
2. Acute myocardial infarction (MI), variant angina pectoris, unstable angina or acute coronary syndrome in the previous one month.
3. 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.
4. Coronary Artery Bypass Surgery (CABG), valve replacement or repair, aortic surgery or PCI) in the prior 3 months or planned/anticipated within 6 months.
5. Heart failure due to acute myocarditis, restrictive cardiomyopathy, constrictive pericarditis or hemodynamically significant aortic valve insufficiency, aortic stenosis, or mitral valve stenosis.
6. Severe renal failure (creatinine level \> 3 mg/dL (265 micromole/liter).
7. Severe hepatic failure (transaminase level four times ULN, or total bilirubin level \> 1.8 mmol/dL).
8. 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.
9. 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.
10. Current hypotension (systolic blood pressure below 80 mmHg).
11. Active peptic ulcer disease or history of upper GI bleeding, or ulcer within 6 months.
12. History of lung disease such as severe asthma, COPD (e.g., FEV1\<1.5 liter) or continuous oxygen dependence.
13. 2nd or 3rd degree AV block or other pacemaker indication that is not treated with a pacemaker.
14. 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.
15. Use of unipolar sensing
16. Congenital or acquired long QT syndrome.
17. Documented recorded or suspected vaso-vagal syncope or vaso depressor syncope.
18. Treatment by investigational drug or device within the past 3 months.
19. 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.
20. 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.
21. 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.
22. Immunosuppressed subjects; subjects under systemic steroid treatment.
23. 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.
24. Untreated obstructive sleep apnea ("OSA") with apnea-hypopnea index of 15 or more; or OSA that is treated for less than 3-months.

Primary outcomes:
measure: Number of participants reaching all-cause mortality or unplanned heart failure hospitalization or equivalent.
timeFrame: Until the end of the study
measure: 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
timeFrame: a) 90 days and b) Until the end of the study
Secondary outcomes:
measure: The rate of unplanned heart failure hospitalization equivalents
timeFrame: Until the end of the study
measure: Mean improvement in LVESVi from baseline to 12-months
timeFrame: 12 Months
measure: Mean improvement in the summary score of the KCCQ from baseline to 12-months
timeFrame: 12 Months
measure: Mean improvement in 6 minute walk test from baseline to 12-months
timeFrame: 12 Months
measure: All cause mortality and the number of unplanned heart failure hospitalization equivalents
timeFrame: Until the end of the study
measure: Rate of hospitalization-free days
timeFrame: Until the end of the study
measure: Secondary Safety Endpoints: Mortality and Complications
timeFrame: Until the end of the study
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Mesa
country: United States
facility: Banner Research Institute
state: Arizona
city: Glendale
country: United States
facility: Glendale Memorial Hospital
state: California
city: Sacramento
country: United States
facility: Sutter Memorial Hospital
state: California
city: San Diego
country: United States
facility: Chula Vista Heart Clinic
state: California
city: Denver
country: United States
facility: South Denver Cardiology
state: Colorado
city: Clearwater
country: United States
facility: Clearwater Cardiovascular Consultants/Morton Plant
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Orlando
country: United States
facility: Florida Hospital, CV Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: St. Joseph's Hospital
state: Georgia
city: Macon
country: United States
facility: Georgia Arrhythmia Consultants
state: Georgia
city: Oak Lawn
country: United States
facility: Advocate Christ Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Community Heart and Vascular Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Saint Vincent Medical Group
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Detroit Medical Center - Harper Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Farmington Hills
country: United States
facility: Detroit Clinical Research Center/Botsford Hospital
state: Michigan
city: Saginaw
country: United States
facility: Michigan Cardiovascular Institute
state: Michigan
city: Traverse
country: United States
facility: Munson Medical Center/Traverse Heart and Vascular
state: Michigan
city: Saint Paul
country: United States
facility: United Heart & Vascular
state: Minnesota
city: St. Louis Park
country: United States
facility: Park Nicollet / Methodist
state: Minnesota
city: Tupelo
country: United States
facility: Cardiology Associates of North Mississippi
state: Mississippi
city: Kansas City
country: United States
facility: St. Luke's Mid America Heart Institute
state: Missouri
city: St Louis
country: United States
facility: St. Louis Heart and Vascular
state: Missouri
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: Lincoln
country: United States
facility: Bryan Heart Institute
state: Nebraska
city: Las Vegas
country: United States
facility: Health Care Partners Cardiology/St. Rose Hospital
state: Nevada
city: Bronx
country: United States
facility: Montefiore Medical Center/Albert Einstein Colelge of Medicine
state: New York
city: New York
country: United States
facility: Mount Sinai
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: The Ohio State
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Cardiovascular Research Group
state: Oklahoma
city: Hershey
country: United States
facility: Hershey Medical Center/Penn State
state: Pennsylvania
city: Lancaster
country: United States
facility: Lancaster Heart and Stroke Foundation
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: VA Tennessee Valley Healthcare System
state: Tennessee
city: Amarillo
country: United States
facility: Lone Star Heart Center
state: Texas
city: Austin
country: United States
facility: Texas Cardiac Arrhythmia (TCA)
state: Texas
city: Dallas
country: United States
facility: Dallas Cardiovascular Associates (CRSTI)
state: Texas
city: Houston
country: United States
facility: EP Heart/ETHSC at Houston
state: Texas
city: Houston
country: United States
facility: St Lukes Episcopal
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Norfolk
country: United States
facility: Sentara Norfolk Hospital
state: Virginia
city: Spokane
country: United States
facility: Kootenai Heart Clinic
state: Washington
city: Tacoma
country: United States
facility: Multicare Health System
state: Washington
city: Lake Geneva
country: United States
facility: Aurora Health Care
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Aalst
country: Belgium
facility: Onze Lieve Vrouwziekenhuis
city: Genk
country: Belgium
facility: Ziekenhuis Oost Limburg
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Campus Gasthuisberg
city: Aachen
country: Germany
facility: Uniklinikum Aachen
city: Berlin
country: Germany
facility: Charite Benjamin Franklin Campus
city: Berlin
country: Germany
facility: Charite Campus Virchow-Klinikum Medizinische Klinik mit Schwerpunkt Kardiologie
city: Bochum
country: Germany
facility: St. Josef Hospital
city: Hamburg
country: Germany
facility: Asklepios St Georg Hospital
city: Hamburg
country: Germany
facility: Albertinen-Krankenhaus
city: Hannover
country: Germany
facility: MHH Klinik für Kardiologie und Angiologie
city: Mannheim
country: Germany
facility: University of Medicine Mannheim
city: Muenster
country: Germany
facility: Uniklinikum Muenster
city: Haifa
country: Israel
facility: Bnai-Zion Hospital
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center Rotterdam
city: Wroclaw
country: Poland
facility: Fourth Military Hospital Wroclaw
city: Łodź
country: Poland
facility: Medical University of Łodź
city: Belgrade
country: Serbia
facility: Clinical Centre of Serbia
city: Belgrade
country: Serbia
facility: Clinical Hosptial Centre Bezanijska Kosa
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital
state: Scotland
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Chertsey
country: United Kingdom
facility: St. Peter's Hospital
city: Cottingham
country: United Kingdom
facility: University of Hull/Castle Hill Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
city: London
country: United Kingdom
facility: Royal Brompton Hospital
city: Oxford
country: United Kingdom
facility: Oxford University/John Radcliffe Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Washington University School of Medicine
name: Douglas L. Mann, MD
role: STUDY_CHAIR
affiliation: Medical University of South Carolina
name: Michael Gold
role: STUDY_CHAIR
References:
citation: Gold MR, Van Veldhuisen DJ, Hauptman PJ, Borggrefe M, Kubo SH, Lieberman RA, Milasinovic G, Berman BJ, Djordjevic S, Neelagaru S, Schwartz PJ, Starling RC, Mann DL. Vagus Nerve Stimulation for the Treatment of Heart Failure: The INOVATE-HF Trial. J Am Coll Cardiol. 2016 Jul 12;68(2):149-58. doi: 10.1016/j.jacc.2016.03.525. Epub 2016 Apr 4.
citation: Hauptman PJ, Schwartz PJ, Gold MR, Borggrefe M, Van Veldhuisen DJ, Starling RC, Mann DL. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J. 2012 Jun;163(6):954-962.e1. doi: 10.1016/j.ahj.2012.03.021.