Prospective non-randomised post-market study collecting clinical data on safety and effectiveness of the remed*®-System

Central sleep apnea (CSA) is a sleep disturbance that manifests as periods of
shallow or no breathing followed by resumption of breathing, often with periods
of rapid, deep breathing.
Central sleep apnea may occur in an idiopathic form, but more often occurs in
patients with co-morbidities associated with an increase in sympathetic drive.
Most commonly, these conditions are related to cardiovascular diseases such as
heart failure and atrial fibrillation, but may be seen in patients with chronic
kidney disease, diabetes mellitus and stroke. In contrast to obstructive sleep
apnea (OSA), closure of the airway is not causative of the hypopnea or apnea
with CSA. Instead, CSA results from a failure of the brain to send appropriate
signals to the respiratory muscles to stimulate a breath. In heart failure, the
most common cause of CSA, the breathing signal failure is due to a delay in
feedback of changes in carbon dioxide (CO2) levels to the respiratory control
center in the brain coupled with an increase loop gain in respiratory control.
Consequently, the brain does not initiate breathing until the CO2 level has
raised significantly above the normal level, and then responds withrapid deep
breathing that continues until the CO2 level is far below normal levels which
leads to a *pause* of breathing.
The sleep disturbances caused by CSA have devastating effects. Each apnea and
hypopnea event experienced with CSA contributes to a progressive cycle of
hypoxia, arousals from sleep, and sympathetic activation, all of which have
multiple deleterious effects. The
hypoxia and arousals diminish the quality of sleep and are associated with
fatigue and decreased mental acuity. The hypoxia caused by CSA leads to
myocardial ischemia and poor cerebral perfusion, which has been associated with
dementia. Increased sympathetic drive
results in increased blood pressure, fluid retention, myocardial fibrosis, and
ventricular and
atrial arrhythmias. These physiologic disturbances related to CSA have been
independently associated with morbidity and mortality. Based on the
pathophysiological mechanisms summarized above, it is clear that CSA has a
detrimental effect, and treatment is
needed to minimize the downstream effects of the disease.

The sponsor of the trial ZOLL Respicardia Inc. developed a treatment option for
adult patients, the remed*® system, to treat moderate and severe CSA. The
device is an implantable system that stimulates a nerve in the chest cavity
(the diaphragmatic nerve) so that it sends signals to the large muscle between
your chest cavity and your abdominal cavity (the diaphragm). These signals
stimulate breathing just as the brain stimulates breathing.
The remed*® system activates the therapy automatically and throughout the night.

The remed*® system is an implantable nerve stimulator approved and CE-marked by
the US Food and Drug Administration (FDA) for the treatment of moderate to
severe central sleep apnea in adult patients.

This study aims to assess the safety and efficacy of the remed*® system in
adult patients with moderate to severe central sleep apnea in real life.

This is a multi-center, prospective, open label, non-randomized study to
collect safety and
effectiveness data in subjects implanted with the remed*®-System. Enrollment
will continue
until approximately 500 enrolled subjects are successfully implanted.
Approximately 50 sites
in the United States and Europe will participate.

An individual subject*s participation is expected to continue through five
years post remed*®-System therapy activation. Subjects will be seen for an
in-office visit 45 days post implant for a PSG prior to therapy activation and
then to activate therapy activation. At 6, 12, 24, 36, 48 and 60 months post
therapy activation, subjects will be seen in-office for assessments such as
sleep studies, questionnaire completion, and other assessments. Subjects who
have been clinically diagnosed with heart failure (HF) that has been documented
in their medical records (signs or symptoms or prior heart failure
hospitalization or BNP >=150 pg/mL or NT-proBNP >= 600 pg/mL) will follow the
same visit schedule, but undergo additional HF specific assessments. All
subjects will be contacted by phone at 18, 30, 42 and 54 months post remed*®-
System activation to assess patient status and adverse events.

All study sites in The Netherlands will participate in a sub-study involving
the WatchPAT home sleep apnea testing (HSAT) device.
WatchPAT is a simple home sleep apnea device that utilizes a wrist-worn unit,
finger probe, and chest sensor to identify respiratory events and determine
which events are centrally mediated based on Peripheral Arterial Tonometry
(PAT) signal and other physiologic signals. WatchPAT is an FDA-cleared home
sleep apnea test (HSAT) approved for the identification of central sleep apnea
and is well established for use in home sleep testing.The purpose of the
WatchPAT sub-study is to compare in-lab attended polysomnogram (PSG) data with
simultaneous WatchPAT data in patients with historical evidence of central
sleep apnea and implanted with the remed*®-system.
The WatchPAT device will be placed on the non-dominant hand during the Therapy
Activation visit (prior to activation) and 12-month (active therapy) PSG
completed as part of the r*ST study.

The potential risks of participating in this study are listed below. Patients
participating in this study are subject to similar risks as all patients
receiving the remed*® system but not participating in this study.

- There is a risk that the needle prick of blood collection may hurt. There is
a small risk of bruising and fainting as a result of the blood draw, and in
rare cases there is a risk of infection.
- There is a risk of skin irritation due to the adhesive tape and electrode
contact with your skin during your polysomnogram and echocardiogram taken at
the sleep centre.
- In rare cases, there is a risk that pressure from the echocardiography probe
may cause minor bruising.
- There is a risk that your heart failure symptoms may be worsened by the
6-minute walk test
worsened. If you are concerned about anything during the test, alert the person
taking the test immediately.
- There are no additional risks associated with the study for you if you let
your study doctor collect data about you and the remed*® system.

Benefit:
New Therapy of Central Sleep Apnea where the patient can have a benefit and
availability of the therapy (no reimbursement in the Netherlands) can be a
difference for patient and additional co-morbidities that are associated with
the disease can be avoided.