Clinical trial NCT03425422: ANTHEM-HFrEF Pivotal Study
Official title: Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure With Reduced Ejection Fraction
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Heart Failure
Heart Failure, Congestive
Heart Failure, Systolic
Keywords: Vagus nerve stimulation
Lead sponsor: LivaNova
Sponsor class: INDUSTRY
First posted: 2018-02-07
Enrollment: 533
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: A multi-center randomized controlled clinical trial to evaluate Autonomic Regulation Therapy with the VITARIA system in patients with symptomatic heart failure and reduced ejection fraction.

Detailed description: ANTHEM-HFrEF is a multi-center, open-label, randomized controlled clinical trial with an adaptive design. Patients with symptomatic heart failure and reduced LVEF will be enrolled and randomized 2:1 to receive VITARIA system implantation on the right cervical vagus nerve in addition to stable guideline-directed medical therapy (therapy), or to continue receiving stable guideline-directed medical therapy alone (control arm).

Subjects in the therapy arm will receive continuous, periodic VNS stimulation after surgery is completed, and will undergo visits for VNS up titration over a period of 3 months. Subjects in the control arm will also undergo scheduled visits at a similar frequency as the titration visits that are scheduled for subjects in the therapy arm. Data for safety and efficacy assessments will be collected for both study arms at 4 weeks post-randomization, every 3 months for the first 12 months, and every 4 months thereafter.

Eligibility criteria: Inclusion Criteria:

1. Age 18 or above
2. Willing and capable of providing informed consent
3. Capable of participating in all testing associated with this clinical investigation
4. Stable, guideline-directed medical therapy for at least 4 weeks before subject screening. Unrestricted changes in diuretics are allowed during the 4 weeks, as long as the subject remains on a diuretic. If the use of an ARNI is being contemplated for a study subject, ARNI should be administered, and GDMT optimized, before the subject is randomized. No more than a 100% increase or 50% decrease of the dosage of any medication other than a diuretic is permitted. For these medications, medication changes within a class are allowed, as long as the equivalent dosage is within these specified limits
5. Stable symptomatic heart failure NYHA class III; or NYHA class II with a heart failure hospitalization in the previous 12 months. HF hospitalization may include an overnight hospital or hospital-based observation unit stay with a primary diagnosis of HF, or an emergency department visit with a primary diagnosis of HF, and will in either case include documentation of intravenous HF therapy administration or other intervention for HF
6. Left ventricular ejection fraction (EF) ≤ 35% and left ventricular end-diastolic diameter (LVEDD) \< 8.0 cm, as confirmed by the core echocardiography laboratory during screening
7. N-terminal pro-BNP (NT-proBNP) level of at least 800 pg/mL, as determined by the core laboratory; or NT-proBNP level of at least 1200 pg/mL, as determined by the core laboratory, for patients with permanent atrial fibrillation or reporting signs or symptoms of atrial fibrillation at the time that the NT-proBNP sample is drawn
8. Received a standard cardiac assessment, including history, physical exam, and electrocardiogram, and determined by a heart failure cardiologist and study surgeon to be an appropriate candidate for the study's surgical procedure
9. Physically capable and willing to perform repeated 6-minute walk tests associated with the study, and having a baseline distance of between 150 and 450 meters. Symptoms limiting the duration of the 6 minute walk test must be due primarily to heart failure

Exclusion Criteria:

1. Refractory symptomatic hypotension (systolic blood pressure below 80 mmHg)
2. Complete AV block treated with unipolar pacemaker therapy
3. Currently implanted vagus nerve stimulation (VNS) device, baroreceptor activation therapy (BAT) device, other nerve stimulator, artificial or donor heart, or ventricular assist device (VAD)
4. Heart failure of non-ischemic origin for less than 6 months, or due to congenital heart disease, hypertrophic obstructive cardiomyopathy, or infiltrative cardiomyopathy (e.g. amyloidosis, sarcoidosis)
5. Moderate (3+) or severe (4+) aortic valve or mitral valve stenosis; moderate (3+) or severe (4+) aortic valve insufficiency; or severe (4+) mitral valve insufficiency
6. Symptomatic uncontrolled bradycardia
7. On renal dialysis
8. Involvement in any concurrent clinical study with an investigational therapy

Primary outcomes:
measure: Event-free rate
timeFrame: 90 days
measure: Cardiovascular mortality and HF hospitalization
timeFrame: Through study completion, an average of 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System
state: Arkansas
city: Long Beach
country: United States
facility: Long Beach Memorial Hospital
state: California
city: Los Angeles
country: United States
facility: Greater Los Angeles VA Medical Center
state: California
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: First Coast Cardiovascular Institute
state: Florida
city: Peoria
country: United States
facility: UnityPoint Health - Methodist Hospital
state: Illinois
city: Muncie
country: United States
facility: Indiana University Health Ball Memorial Hospital
state: Indiana
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Medical Center
state: Massachusetts
city: Ypsilanti
country: United States
facility: Michigan Heart, PC
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: New York
country: United States
facility: Mount Sinai School St. Luke's
state: New York
city: Cleveland
country: United States
facility: MetroHealth System
state: Ohio
city: Toledo
country: United States
facility: ProMedica Northwest Ohio Cardiology Consultants
state: Ohio
city: Hershey
country: United States
facility: Penn State Health Milton Hershey Medical Center
state: Pennsylvania
city: Wormleysburg
country: United States
facility: Pinnacle Health
state: Pennsylvania
city: Houston
country: United States
facility: Baylor St. Luke's Medical Center
state: Texas
city: Tyler
country: United States
facility: Tyler Cardiovascular Consultants
state: Texas
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
References:
citation: Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail. 2014 Nov;20(11):808-16. doi: 10.1016/j.cardfail.2014.08.009. Epub 2014 Sep 1.
citation: Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS. Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study. J Card Fail. 2016 Aug;22(8):639-42. doi: 10.1016/j.cardfail.2015.11.002. Epub 2015 Nov 11.
citation: Konstam MA, Udelson JE, Butler J, Klein HU, Parker JD, Teerlink JR, Wedge PM, Saville BR, Ardell JL, Libbus I, DiCarlo LA. Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design. Circ Heart Fail. 2019 Nov;12(11):e005879. doi: 10.1161/CIRCHEARTFAILURE.119.005879. Epub 2019 Nov 14.