Baroreflex Activation Therapy for Heart Failure

The purpose of this clinical trial (NCT02627196) is to develop valid scientific evidence for safety and effectiveness of Baroreflex Activation Therapy with the BAROSTIM NEO System in subjects with heart failure, defined as New York Heart Association (NYHA) functional Class III, left ventricular ejection fraction (LVEF) ≤ 35% and NT-proBNP\<1600 pg/ml despite being treated with the appropriate heart failure guideline directed therapy, excluding subjects eligible for or actively receiving Cardiac Resynchronization Therapy (CRT).

The total trial duration is anticipated to be approximately 5 years; however, the duration of an individual subject enrollment will depend on when he or she entered the trial.

The BAROSTIM NEO - Baroreflex Activation Therapy for Heart Failure is a prospective, randomized trial in subjects with reduced ejection fraction heart failure. Subjects will be randomized in a 1:1 ratio to receive Barostim Activation Therapy with an implanted BAROSTIM NEO System in addition to medical management or to receive medical management alone (no device implant). The trial will be conducted at up to 120 investigational centers in the U.S. and up to 20 investigational centers outside the U.S. These centers will enroll up to 1200 subjects to randomize approximately 480 subjects who meet the entry criteria.

For all subjects, trial visits will occur at 0.5, 1, 1.5, 2, 3, 6, 9 and 12 months post-implant (post anticipated implant for medical management). Visits will occur quarterly from 15 to 24 months and semi-annually thereafter.

Subjects are followed in an identical manner regardless of trial arm.

The data will provide evidence of the safety and efficacy of BAROSTIM THERAPY. The accumulated morbidity and mortality data collected will provide evidence of morbidity and mortality benefit. This trial will involve one or more interim analyses to evaluate when sufficient evidence is reached for the final morbidity and mortality analysis.

Eligibility Criteria:
Inclusion Criteria:

1. Age 21 years or above.
2. Currently NYHA Class II or III heart failure. For NYHA Class II, must have been NYHA Class III at any point in time within 3 calendar months prior to enrollment or at time of screening (enrollment is defined as the date the subject provided written consent).
3. Left ventricular ejection fraction ≤ 35% within 45 days prior to randomization.
4. Heart failure accompanied by either:

   * Core lab NT-proBNP ≥ 400 AND \<1600 pg/ml within 45 days prior to randomization OR
   * Core lab NT-proBNP \< 400 pg/ml within 45 days prior to randomization AND a heart failure hospitalization in the past 12 months.

   Note: Heart failure hospitalization may include an overnight hospital or hospital-based observation unit stay with a primary diagnosis of heart failure or an emergency room visit with a primary diagnosis of heart failure.

   Note: Screening/Baseline core lab NT-proBNP must be collected in an outpatient setting at a time when the subject is thought to be clinically stable.
5. On optimal, stable, Guideline Directed Medical Therapy (GDMT) per country specific guidelines for the treatment of heart-failure throughout screening/baseline evaluation and for at least 4 weeks prior to obtaining any post-consent screening parameters:

   * No more than a 100% increase or a 50% decrease of the dosage of any one medication other than a diuretic.
   * Medication changes within a drug class are allowed as long as the equivalent dosage is within the limits specified above.
   * Unrestricted changes in diuretics are allowed as long as the subject remains on a diuretic.
6. Six-minute hall walk (6MHW) ≥ 150 m AND ≤ 400 m within 45 days prior to randomization.
7. The artery planned for the BAROSTIM implant must meet both of the following criteria:

   * At least one carotid bifurcation as identification by a bilateral carotid duplex ultrasound within 6 months prior to randomization that is:

     1. Below the level of the mandible AND
     2. No ulcerative carotid arterial plaques AND
     3. No carotid atherosclerosis producing a 50% or greater reduction in linear diameter in the internal carotid AND
     4. No carotid atherosclerosis producing a 50% or greater reduction in linear diameter in the distal common carotid
   * No prior surgery, radiation, or endovascular stent placement in the carotid artery or the carotid sinus region.
8. If female and of childbearing potential, must use a medically accepted method of birth control (e.g., barrier method with spermicide, oral contraceptive, or abstinence) and agree to continue use of this method for the duration of the trial. Women of childbearing potential must have a negative pregnancy test within 14 days prior to randomization.
9. Received a standard cardiac work up and is an appropriate candidate for the study and the surgical procedure as determined by a trial cardiologist and a trial surgeon.
10. Subjects implanted with a cardiac rhythm management device that does not utilize an intracardiac lead, or implanted with a neurostimulation device, must be approved by the CVRx Clinical department.
11. Signed a CVRx-approved informed consent form for participation in this trial.

Exclusion Criteria:

If any of the following criteria are met, subjects are not eligible for this trial.

1. Received cardiac resynchronization therapy (CRT) within six months of randomization, or is actively receiving CRT.
2. Currently have a Class I indication for a cardiac resynchronization therapy (CRT) device according to AHA/ACC/ESC guidelines for the treatment of congestive heart failure. ,
3. Known or suspected baroreflex failure or autonomic neuropathy.
4. AHA/ACC Stage D heart failure within 45 days prior to randomization.
5. Body mass index \> 40.
6. Serum estimated glomerular filtration rate (eGFR) \< 25 mL/min/1.73 m2 within 45 days prior to randomization.
7. Recurring resting heart rate of either \< 60 bpm or \> 100 bpm via clinic measurements within 45 days prior to randomization. (Note: Heart rate \<60 bpm is not applicable to subjects with an implanted device capable of pacing.)
8. Recurring symptomatic hypotension within 45 days prior to randomization.
9. Significant uncontrolled symptomatic bradyarrhythmias or unstable ventricular arrhythmias.
10. Subjects with any surgery that has occurred, or is planned to occur, within 45 days of the BAROSTIM NEO implant procedure. This includes pacemaker or ICD implants or battery replacements.
11. Episode of NYHA class IV heart failure with acute pulmonary edema within 45 days prior to randomization.
12. Any of the following within 3 months of randomization:

    * Myocardial infarction
    * Unstable angina
    * Percutaneous coronary intervention (e.g. CABG or PTCA)
    * Cerebral vascular accident or transient ischemic attack
    * Sudden cardiac death
13. Solid organ or hematologic transplant, or currently being actively evaluated for an organ transplant.
14. Has received or is receiving LVAD therapy.
15. Has received or is receiving chronic dialysis.
16. Heart failure secondary to a reversible cause, such as cardiac structural valvular disease, acute myocarditis and pericardial constriction.
17. Primary pulmonary hypertension.
18. Infiltrative cardiomyopathy (e.g. cardiac amyloidosis).
19. Severe COPD or severe restrictive lung disease (e.g. requires chronic steroid use or home oxygen use).
20. Active malignancy.
21. Current or planned treatment with intravenous positive inotrope therapy.
22. Life expectancy less than one year.
23. Clinically significant psychological condition that in the physician's opinion would prohibit the subject's ability to meet the protocol requirements.
24. Unable or unwilling to fulfill the protocol medication compliance, testing, and follow-up requirements (e.g. recent drug abuse).
25. Enrolled and active in another (e.g. device, pharmaceutical, or biological) clinical trial unless approved by the CVRx Clinical department.
26. Subjects with known allergies to silicone and titanium.