ANTHEM-HFrEF Pivotal Study

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.

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. Currently in sinus rhythm

5. Stable, guideline-directed medical therapy for at least 4 weeks.

6. Stable symptomatic heart failure NYHA class III; or NYHA class II with a heart failure
hospitalization in the previous 6 months

7. Left ventricular ejection fraction (EF) ≤ 35%, as confirmed by core echocardiography
laboratory during screening

8. N-terminal pro-BNP (NT-proBNP) level of at least 800 pg/mL within 45 days of
randomization; or NT-proBNP level of at least 400 pg/mL with a heart failure
hospitalization in the previous 12 months

9. 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

10. 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. Pacemaker dependence (permanent pacemaker implantation for third-degree AV block)

3. Currently implanted vagus nerve stimulation (VNS) device, cardiac resynchronization
therapy (CRT) device, baroreceptor stimulation (BRS) device, 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. Severe mitral or aortic valve disorder

6. Symptomatic uncontrolled bradycardia

7. Chronic (permanent) atrial fibrillation

8. Involvement in any concurrent clinical study with an investigational therapy