AUTONOMIC REGULATION THERAPY TO ENHANCE MYOCARDIAL FUNCTION AND REDUCE PROGRESSION OF HEART FAILURE WITH REDUCED EJECTION FRACTION
(ANTHEM-HFrEF)

Previous pre-clinical and clinical studies have shown that vagus nerve
stimulation restores autonomic balance, reduces systemic inflammation, and
provides a functional benefit in heart failure. Based on this research, the
ANTHEM- HF feasibility study was conducted to test the VITARIA system in 60
patients receiving stable guideline-directed medical therapy (GDMT) for heart
failure with reduced ejection fraction (LVEF * 40%). Chronic therapy with the
VITARIA system significantly improved ejection fraction, a variety of other
measures of cardiac function including 6 minute walk distance, and heart
failure symptoms. The positive results of the ANTHEM-HF study need to be
confirmed in a larger, controlled clinical study.

Autonomic Regulation Therapy (ART), delivered via vagus nerve stimulation (VNS)
using the VITARIA system, significantly improves clinical outcomes in patients
who have symptomatic heart failure and a reduced left ventricular ejection
fraction while receiving stable
guideline-directed medical therapy.

Primary Objective: The primary objective of this randomized controlled study is
to assess the safety and efficacy of the VITARIA* System when added to stable,
guideline-directed medical therapy for patients with heart failure and reduced
left ventricular ejection fraction. The data from this study may be used to
support marketing applications for the VITARIA system in the United States and
other International markets.

Study Design: 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 (therapy) in addition to stable GDMT (therapy
arm), or to continue receiving stable GDMT alone (control arm). Randomization
will be stratified by region (as determined by the Steering Committee);
distance walked in baseline 6-minute walk test (300 m or less, or more than 300
m); type of study site (cardiac transplantation site or not); and by use of
Entresto® (sacubitril/valsartan; yes/no), to ensure proper balance of the
treatment groups across the study, and will incorporate blocking of sizes 3, 6,
or 9 patients within each strata

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 the same 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 postrandomization, every 3 months for the first 12
months, and every 4 months thereafter.

Efficacy will be determined by time-to-first-event of cardiovascular mortality
or heart failure hospitalization following randomization. Device safety will be
determined by the event-free rate from all system and implantation-related
serious adverse events during the 90 day period after randomization. An interim
assessment of symptomatic improvement will be made and potentially used to
support an early regulatory
submission.

The VITARIA System lead will be implanted on the right cervical vagus nerve.
After the lead and IPG are connected, the surgical/cardiovascular team will
perform standard diagnostic testing to ensure proper implantation. In the event
that right cervical implantation cannot be accomplished, the subject will not
be implanted but will continue to be followed, based on the "intention to
treat" design of the study. VNS stimulation will be activated after completion
of implantation, before the patient departs from the procedure room. VNS
stimulation will be activated using the following stimulation parameters:
output current = 0.25 mA; frequency = 5 Hz; pulse width = 130 µs; duty cycle =
14 seconds on, 66 seconds off

Visit schedule: patients require a considerable number of titration visits to
reach the right treatment level of the device. The protocol leaves room for a
maximum of 9 titration visits in a period of 3 months (weekly visits the first
6 weeks, and bi-weekly the next 6 weeks).

Risks:
The most commonly reported side effects of VITARIA are voice alteration, pain,
paresthesia, dyspnea, pharyngitis, and increased cough.
Other potential risks are:
Surgery-related; hematoma, infection, pain, voice alteration (hoarseness).
Stimulation-related: dyspepsia (indigestion), dysphagia (difficulty
swallowing), dyspnea (difficulty breathing, shortness of breath), increased
coughing, laryngismus (throat, larynx spasms), pain, paresthesia (prickling of
the skin), pharyngitis (inflammation of the pharynx, throat), satiety (reduced
appetite), sensation of stimulation, voice alteration (hoarseness).