INcrease Of VAgal TonE in CHF (INOVATE-HF)

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

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.

Study Overview

• Status: Terminated
• Conditions: Heart Failure; Left Ventricular Dysfunction
• Intervention / Treatment: Device: CardioFit® System; Other: Standard of Care

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.

• Study Type: Interventional
• Enrollment (Actual): 730
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Onze Lieve Vrouwziekenhuis
  • Genk, Belgium, 3600
    • Ziekenhuis Oost Limburg
  • Leuven, Belgium, 03000
    • Universitair Ziekenhuis Campus Gasthuisberg
• Germany
  • Aachen, Germany, 52074
    • Uniklinikum Aachen
  • Berlin, Germany, 12203
    • Charite Benjamin Franklin Campus
  • Berlin, Germany, 13353
    • Charite Campus Virchow-Klinikum Medizinische Klinik mit Schwerpunkt Kardiologie
  • Bochum, Germany, 44791
    • St. Josef Hospital
  • Hamburg, Germany, 22457
    • Albertinen-Krankenhaus
  • Hamburg, Germany, 20099
    • Asklepios St Georg Hospital
  • Hannover, Germany, 30625
    • MHH Klinik für Kardiologie und Angiologie
  • Mannheim, Germany, 68167
    • University of Medicine Mannheim
  • Muenster, Germany, 48149
    • Uniklinikum Muenster
• Israel
  • Haifa, Israel, 31048
    • Bnai-Zion Hospital
• Netherlands
  • Groningen, Netherlands
    • University Medical Centre Groningen
  • Maastricht, Netherlands
    • Maastricht University Medical Center
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus University Medical Center Rotterdam
• Poland
  • Wroclaw, Poland, 50981
    • Fourth Military Hospital Wroclaw
  • Łodź, Poland, 91425
    • Medical University of Łódź
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Centre of Serbia
  • Belgrade, Serbia, 11080
    • Clinical Hosptial Centre Bezanijska Kosa
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
  • Blackpool, United Kingdom, FY3 8NR
    • Blackpool Victoria Hospital
  • Chertsey, United Kingdom, KT16 0PZ
    • St. Peter's Hospital
  • Cottingham, United Kingdom, HU16 5JQ
    • University of Hull/Castle Hill Hospital
  • Coventry, United Kingdom, CV2 2DX
    • University Hospital Coventry
  • Leicester, United Kingdom, LE3 9QP
    • Glenfield Hospital
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • Oxford, United Kingdom, OX3 9DU
    • Oxford University/John Radcliffe Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
  • Scotland
    • Clydebank, Scotland, United Kingdom, G81 4DY
      • Golden Jubilee National Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Birmingham
  • Arizona
    • Mesa, Arizona, United States, 85206
      • Banner Research Institute
  • California
    • Glendale, California, United States, 91204
      • Glendale Memorial Hospital
    • Sacramento, California, United States, 95819
      • Sutter Memorial Hospital
    • San Diego, California, United States, 91910
      • Chula Vista Heart Clinic
  • Colorado
    • Denver, Colorado, United States, 80120
      • South Denver Cardiology
  • Florida
    • Clearwater, Florida, United States, 33756
      • Clearwater Cardiovascular Consultants/Morton Plant
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Orlando, Florida, United States, 32803
      • Florida Hospital, CV Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30342
      • St. Joseph's Hospital
    • Macon, Georgia, United States, 31201
      • Georgia Arrhythmia Consultants
  • Illinois
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Medical Group
    • Indianapolis, Indiana, United States, 46250
      • Community Heart and Vascular Clinic
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Detroit Medical Center - Harper Hospital
    • Farmington Hills, Michigan, United States, 48334
      • Detroit Clinical Research Center/Botsford Hospital
    • Saginaw, Michigan, United States, 48601
      • Michigan CardioVascular Institute
    • Traverse, Michigan, United States, 49684
      • Munson Medical Center/Traverse Heart and Vascular
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • United Heart & Vascular
    • St. Louis Park, Minnesota, United States, 55426
      • Park Nicollet / Methodist
  • Mississippi
    • Tupelo, Mississippi, United States, 38801
      • Cardiology Associates of North Mississippi
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • St. Luke's Mid America Heart Institute
    • St Louis, Missouri, United States, 63136
      • St. Louis Heart and Vascular
    • St. Louis, Missouri, United States, 63110
      • Washington University
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Bryan Heart Institute
  • Nevada
    • Las Vegas, Nevada, United States, 89169-2579
      • Health Care Partners Cardiology/St. Rose Hospital
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center/Albert Einstein Colelge of Medicine
    • New York, New York, United States, 10029
      • Mount Sinai
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0542
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • The Ohio State
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Oklahoma Cardiovascular Research Group
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center/Penn State
    • Lancaster, Pennsylvania, United States, 17602
      • Lancaster Heart and Stroke Foundation
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • VA Tennessee Valley Healthcare System
  • Texas
    • Amarillo, Texas, United States, 79106
      • Lone Star Heart Center
    • Austin, Texas, United States, 78705
      • Texas Cardiac Arrhythmia (TCA)
    • Dallas, Texas, United States, 75230
      • Dallas Cardiovascular Associates (CRSTI)
    • Houston, Texas, United States, 77030
      • EP Heart/ETHSC at Houston
    • Houston, Texas, United States, 77030
      • St Lukes Episcopal
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk Hospital
  • Washington
    • Spokane, Washington, United States, 99204
      • Kootenai Heart Clinic
    • Tacoma, Washington, United States, 98405
      • MultiCare Health System
  • Wisconsin
    • Lake Geneva, Wisconsin, United States, 53147
      • Aurora Health Care
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CardioFit® System; Vagal nerve stimulation with the CardioFit® system	Device: CardioFit® System; Vagal nerve stimulation with the CardioFit® system
Active Comparator: Standard of Care; Usual care (no CardioFit System implant)	Other: Standard of Care; Usual care for LV dysfunction and heart failure (no CardioFit System implant)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: BioControl Medical
• Investigators: Study Chair: Michael Gold, Medical University of South Carolina; Study Chair: Douglas L. Mann, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• CardioFit Pilot Study Description and Results

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: February 18, 2011
• First Submitted That Met QC Criteria: February 23, 2011
• First Posted (Estimate): February 25, 2011

Study Record Updates

• Last Update Posted (Estimate): December 15, 2015
• Last Update Submitted That Met QC Criteria: December 11, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: Heart Failure; LV Dysfunction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Ventricular Dysfunction; Ventricular Dysfunction, Left
• Other Study ID Numbers: CP-05-026