A First in Humans Study of Safety and Feasibility of baroloop:
The baroloop Study

2.5. Baroreceptor Modulation for Hypertension (for more inforation see pages
19-23 in the Protocol)
The pivotal role of the autonomic nervous system in the pathogenesis of
hypertension is well established. However, pharmacological therapies that block
sympathetic activity have not achieved the desired outcomes. In the past few
years, there have been efforts to develop medical devices and techniques that
influence sympathetic nervous system activity. These include endovascular renal
sympathetic denervation and continuous electrical baroreceptor nerve pacing.
Neuroloop has developed a device-based treatment of hypertension by activating
the baroreflex through vagal nerve stimulation (VNS).
2.5.1. Baroreflex activation therapy - background information
Due to the lack of available medication for hypertension (Lohmeier and Iliescu,
2011), in the 1950s and 1960s *electrical stimulation of the carotid sinus and
subsequent activation of the baroreflex was conceived to be a therapeutic
option for elevated BP* (Bilgutay and Lillehei, 1966; Braunwald et al., 1967;
Epstein et al., 1969; Plachta et al., 2014; Warner, 1958). The baroreflex, also
known as the arterial baroreflex, controls the arterial blood pressure
continuously and is among the most important blood pressure control mechanisms
(Benarroch, 2008; Plachta et al., 2014). Strain-sensitive fibers of the
baroreceptors are located in the area of the aortic arch and both carotid
sinuses near the carotid bifurcation (Ai et al., 2009; Berthoud and Neuhuber,
2000; Plachta et al., 2014; Wallbach and Koziolek, 2018). The afferent nerve
terminals in the carotid sinus are innervated by the glossopharyngeal nerve and
in the aortic arch by the vagal nerve (Benarroch, 2008). The fibers innervating
the carotid and aortic baroreceptors project to the nucleus of the solitary
tract in the dorsal medulla, and from there, the information ramifies
throughout the central nervous system (Johnson and Wilson, 2018). The
baroreflex consists of a negative feedback loop in which increased
baroreceptors stretch (from which an increase in blood pressure may be
inferred) efferent sympathetic tone is decreased and efferent parasympathetic
tone is increased, which leads to vasodilatation, slowing of the heart rate and
lowering of blood pressure (Kougias et al., 2010).
The current state of the art regarding baroreflex activation therapy uses the
*glossopharyngeal part* of baroreflex activation: a carotid sinus stimulator to
*trick* the baroreceptor into reporting a stretch that is higher than the
actual stretch and blood pressure (Bisognano et al., 2011). The Rheos Pivotal
trial demonstrated sustained efficacy of the first generation baroreflex
activation therapy (BAT) device (sustained reduction in blood pressure) after
12 months, and baroreflex activation therapy was safe. A meta-analysis of BAT
clinical trials (including nine studies, only 2 RCTs, including trials of the
*old* system and *Neo*) found a significant reduction of blood pressure after
BAT of close to 3.6 mm Hg (analyzing the longest follow-up visits, which was a
median of 13.5 months), as well as a blood pressure reduction after short-term
follow up (Wallbach and Koziolek, 2018). The lack of more data from randomized
trials means that these results have to be interpreted with caution.
Nevertheless, these studies established the feasibility of activating the
baroreflex to reduce blood pressures and control hypertension.
2.5.2. Vagal Nerve Stimulation (VNS) - state of the art
Over 100.000 patients have been treated with vagal nerve stimulation (VNS)
therapy for epilepsy. The surgical procedure to implant the vagal nerve
stimulator is well established and appears to be a relatively safe intervention
(Garcia-Navarrete et al., 2013; Kahlow and Olivecrona, 2013; Revesz et al.,
2016). VNS surgery is associated with an overall surgical complication rate of
8.5% (Selner et al., 2019). *Surgical complications included infection, vocal
cord palsy, post-operative hematoma, intra-operative bradycardia during test
stimulation, and others, with infection (3.9%)* (Selner et al., 2019). A 6.5%
rate of hardware complications were reported, including lead fracture and
stimulator malfunction. Lead fracture was the most common complication (5.6%)
(Selner et al., 2019). Overall, the implantation is a safe procedure and well
established for more than 25 years (Spuck et al., 2010), and VNS is as a
relatively safe treatment (Giordano et al., 2017; Panebianco et al., 2016;
Selner et al., 2019).
Specifically with respect to vagal nerve stimulation to control blood pressure,
selective stimulation of vagal afferent baroreceptor fibers is preferable to
stimulating efferent fibers that may lead to side effects such as bradycardia
or heart block (Plachta et al., 2014; Timarova and Steno, 2017). Most of the
stimulation associated side effects are derived from stimulation of the
inherent functions of the vagal nerve (Timarova and Steno, 2017). The
feasibility of selective VNS to elicit baroreflex responses has been shown in
rats without occurrence of severe adverse events (bradycardia or heart block)
(Plachta et al., 2014). Even when angiotensin converting-enzyme inhibitors (a
commonly used antihypertensive medicine) were co-administered with VNS,
selective VNS reduced blood pressure (Gierthmuehlen et al., 2016). Moreover,
cardiac-cycle-synchronized stimulation triggered to the R-wave of the
electrocardiogram in rats successfully reduced blood pressure using constant
stimulation parameters with hardly any side-effects (Plachta et al., 2016).
The unique cuff electrode design of the baroloop system permits anatomically
selective, vagal nerve stimulation to activate the baroreflex and reduce blood
pressure. An implantation procedure similar to that used for VNS to treat
epilepsy will be used. However, the lead design of the baroloop system is
different, and lead placement has been adapted to the unique aspects of the
baroloop design. Nevertheless, similar overall surgically related complications
may be expected. Any adverse events associated with VNS using the baroloop
device will be evaluated during the proposed First in Human (FIH) study. The
anatomically selective stimulation used in the neuroloop system may reduce the
occurrence of side-effects associated with VNS, since a relatively higher
proportion of baroreceptor active fibers may be stimulated, although, the
baroloop electrode may include cardiac branches of the vagal nerve. Selective
stimulation delivered by the unique neuroloop electrode design may avoid or
reduce some of the cardiac side effects related to stimulation of efferent
cardiac branches of the vagus, since the targets of baroreflex activation are
the afferent baroreceptor fibers.
2.5.3. Neuromodulation: selection of stimulation parameters
Electrical neuromodulation has a long history in humans and a broad scope of
targets, including the brain, spine, peripheral nerve, retina, cochlea, etc.
(e.g.: ECoG, Retinal Implants, ActiGait, VNS, DBS, SCS). The form and shape of
the electrodes (contacts) have to be designed appropriately to fit the target
area. The baroloop cuff electrode contains multiple individual electrode
contact areas: cathodes with areas of 264.000 µm2 and anodes with areas of
2.34*106 µm2. The combination of electrode geometry and stimulation parameters
(frequency, duty cycle and pulse duration) must be adapted to achieve optimal
output and activation of the target and minimal damage to the electrode
(corrosion) and the surrounding tissue. An electrode can deliver a certain
amount of charge/area without corrosion within the so-called water window
within which the charge does not corrode the electrode material nor is water
subjected to electrolysis (Cogan, 2008). Pulse width and charge balancing are
typical countermeasures to avoid both corrosive processes and cha

The primary objectives are to assess the safety and feasibility ofthe baroloop
device for the treatment of subjects with hypertension (HTN).
The secondary objective is to document the effect of the baroloop device on the
blood pressure and quality of life in subjects with hypertension (HTN).

4.1. Study Design
The baroloop Study is a First in Human (FIH) study of the safety and
feasibility of using the baroloop System in subjects with uncontrolled
hypertension. As described above, an adequate body of historical data
pertaining to device-based treatment of uncontrolled hypertension exists
against which neuroloop can test the safety and performance of the baroloop
System in a FIH study.
As described in the Background for the current study, the appropriate safety
endpoint is defined by the occurrence of device- and treatment-related (both
procedural and postprocedural) adverse events. Previous studies have used a
similar definition of safety and, therefore, results of these previous studies
provide useful historical comparison data to evaluate the safety of the
baroloop System. Similarly, feasibility is defined as the ability to implant
the baroloop Cuff electrode and IPG, and the ability to reduce blood pressure
by VNS. The secondary objective is to document the effect of the baroloop
device on the blood pressure and quality of life in subjects with hypertension.

5.1. Potential Adverse Events
There are Adverse Events associated with any endovascular / cardiovascular
intervention and complications may develop. The following anticipated events
have been identified as possible complications of transcatheter procedures in
general and these and others may be associated with the baroloop System:
5.2. Potential risks
Adverse events which might occur with the usage of baroloop are listed as below
in alphabetical order and are based on potential risks which are reported
during the usage of other vagus nerve stimulators and/or baroreflex activation
therapy:
5.3. Potential Adverse Events
Surgery-related
• hematoma
• infection
• pain
• voice alteration (hoarseness)
Stimulation-related
• bradycardia
• dyspepsia (indigestion)
• dysphagia (difficulty swallowing)
• dyspnea (difficulty breathing, shortness of breath)
• hypotension
• increased coughing
• laryngismus (throat, larynx spasms)
• pain
• paresthesias (prickling of the skin)
• pharyngitis (inflammation of the pharynx, throat)
• satiety (reduced appetite)
• sensation of stimulation
• syncope
• voice alteration (hoarseness)
It is anticipated that subjects will be exposed to operative and post-operative
risks similar to related surgical procedures involving the neck and/or a
pacemaker implant. These risks and potential risks of chronic device based
baroreflex activation may include, but are not limited to:
• Surgical or anesthetic complications
• Infection - the need for antibiotics or possible removal of the system
• Wound Complication -including hematoma (i.e. bruising and/or swelling)
• Arterial damage -including carotid artery rupture or hemorrhage (sudden and
significant blood loss at a site of blood vessel rupture that may require
reoperation or transfusion)
• Pain - an unpleasant sensory experience
• Nerve Damage/Stimulation -including injury to or stimulation of Cranial,
Marginal Mandibular, Glossopharyngeal, Recurrent Laryngeal, Vagus and
Hypoglossal Nerves (numbness in head and neck, facial palsy/paralysis, altered
speech, altered sense of taste, respiratory constriction, stertorous breathing,
excessive salivation, dry cough, vomiting and/or regurgitation, altered sensory
and motor function of tongue, altered sensory function of pharynx and
oropharynx, altered sensation in external auditory canal), stimulation of
extravascular tissue (muscle twitching (fasciculation), pain, tingling, oral
sensations)
• Hypotension - a decrease in systolic and diastolic blood pressure below
normal levels that may result in dizziness, fainting, and/or falls
• Hypertensive crisis - uncontrolled rise in blood pressure
• Respiratory - including low oxygen saturation, respiratory distress,
shortness of breath
• Exacerbation of heart failure
• Cardiac arrhythmias
• Tissue erosion/IPG migration - movement of device resulting in need for
reoperation
• Fibrosis - replacement of normal tissue by the ingrowth of fibroblasts and
the deposition of connective tissue
• Allergic Reaction
• General injury to user or patient -may be due to surgical procedure, device
use, or interaction with other devices
• Need for reoperation - operation to explant/replace IPG or Cuff electrode or
Lead due to tissue damage, infection, and/or device failure
• Secondary operative procedure -An increase in the complexity and risk of
secondary operative procedures of the neck due to scar tissue and the presence
of prosthetic material implanted for this device.
• Death
5.4. Potential Risks to Subject Confidentiality and Privacy
In all clinical studies, confidentiality of protected health information may be
breached due to study-related activities beyond those of routine clinical care.
This also includes risks of privacy and release of protected health information
(PHI). This risk will be minimized through the use of a unique and anonymous
study identification code. No identifying information will be reported in the
data collection system or other study related documentation that is provided to
the Sponsor.

5.5. Minimization of Anticipated Risks
Efforts to minimize risk include the following:
1. Clearly defining the subject inclusion / exclusion criteria.
2. Selecting a sufficient number of intended users and only qualified,
experienced Investigators who have participated in a training program to assure
thorough knowledge of the Investigational Plan and proper technique for
implantation of the baroloop System.
3. Monitoring electrocardiographic and hemodynamic parameters during placement
of the device to evaluate for any compromise of the subject*s condition.
4. Ensuring that treatment and follow-up of subjects is consistent with
standard and current medical practice.
5. Providing clinical support for device-related guidance during the
implantation, titration and follow-up procedures.
6. Safety oversight by Medical Monitor and the DSMB, for individual subjects as
well as across the entire study population.
7. If the Investigator and / or the Medical Monitor or DSMB determine that an
AE is sufficiently severe to remove the subject from the study, a termination
assessment will be performed. The subject will then be given appropriate
treatment under medical supervision.
8. If the Medical Monitor or DSMB determines a negatively high rate for a
particular safety issue across the subject population, a termination assessment
will be performed, and the Medical Monitor or DSMB may recommend enrollment in
the study to be stopped.
PHI protection measures, such as use of a unique study identification code and
a commitment from all participants to protect subject confidentiality at every
step during the investigation, must be maintained.
5.6. Potential Benefits
Based upon literature review and pre-clinical evaluations performed to date, it
is expected that the baroloop system may provide benefit to the subject by
reducing blood pressure to or toward recommended target blood pressure values
as outlined in the 2018 ESC/ESH Guidelines for the management of arterial
hypertension. Without the baroloop system, blood pressure may remain poorly
controlled in this population. The potential benefits include a reduction in
blood pressure toward more normal values, which has been associated with a
reduction in cardiovascular risks associated with hypertension (the 2018
ESC/ESH Guidelines for the management of arterial hypertension).
However, the actual benefits are not known and are the subject of this
investigational study. There may be no direct benefits of study participation.
Nevertheless, subject participants will undergo an enhanced level of clinical
scrutiny of health compared to routine clinical care, which may provide some
indirect health benefits.