A First in Human Study of Feasibility of Baroloop: The Baroloop Study
Phase: NA
Conditions: Hypertension
Sponsor: neuroloop GmbH

A First in Human Study of Safety and Feasibility of baroloop: 
The baroloop Study 
 
Protocol Number: BL_CIP-FIH 
Revision: 2.4 
Date: 03 March 2021 
 
 
 
Sponsor: 
 
neuroloop GmbH 
Breisacher Straße 86 
79110 Freiburg im Breisgau 
Germany 
 
Phone: +49 761 1543390 
Website: www.neuroloop.de/ 
 
 
 
 
Medical/Clinical Monitor: 
 
MAXIS Medical GmbH  
Stichlingstrasse 1 
60327 Frankfurt am Main 
Germany 
Tel:  +49.69.2400.3626 
Fax: +49.69.2400.3627 
Email: maxis-operations@maxismedical.com 
 
This document contains information that is confidential and proprietary. 
The contents of this document may not be copied without written permission from the 
Sponsor. 
baroloop® and neuroloop® are registered trademarks of neuroloop GmbH. 
 
 

 
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CONFIDENTIALITY STATEMENT 
The information contained in this document, especially unpublished data and trade secrets, is 
the property of neuroloop GmbH. This document is provided in confidence to Investigators, 
potential investigators, and research staff for review. This information shall not be disclosed to 
third parties without written authorization from neuroloop GmbH except to the extent necessary 
to obtain informed consent from those patients who may participate in the study described 
herein. Further reproduction of this document, in whole or in part, is not permitted. 
 
 

 
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Table of Contents 
CONFIDENTIALITY STATEMENT .............................................................................. 1 
Table of Contents ...................................................................................................... 2 
Table of Tables........................................................................................................... 7 
Table of Figures ......................................................................................................... 8 
1. 
Protocol Synopsis............................................................................................... 9 
2. 
Introduction and Background .......................................................................... 14 
2.1. 
Rationale for Proposed Research ................................................................. 14 
2.2. 
Treatment targets. ........................................................................................ 14 
2.2.1. 
Treatment according to European Guidelines .................................................. 15 
2.3. 
Resistant hypertension ................................................................................. 15 
2.4. 
Device-based therapies for hypertension ..................................................... 16 
2.5. 
Baroreceptor Modulation for Hypertension ................................................... 19 
2.5.1. 
Baroreflex activation therapy – background information .................................. 19 
2.5.2. 
Vagal Nerve Stimulation (VNS) – state of the art ............................................. 20 
2.5.3. 
Neuromodulation: selection of stimulation parameters .................................... 20 
2.5.4. 
The baroloop System: vagal nerve stimulation to control blood pressure ........ 22 
2.5.5. 
VNS to Treat Hypertension .............................................................................. 23 
2.6. 
Preclinical Experience with the baroloop System ......................................... 23 
3. 
Test System (Investigational Device) .............................................................. 24 
3.1. 
Product name ............................................................................................... 24 
3.2. 
General description ...................................................................................... 24 
3.3. 
Code identification of the device ................................................................... 25 
3.4. 
Intended purpose .......................................................................................... 25 
3.4.1. 
Indication ......................................................................................................... 25 
3.4.2. 
Intended patient group .................................................................................... 25 
3.4.3. 
Target/intended body parts .............................................................................. 25 
3.4.4. 
Target user profile ........................................................................................... 25 
3.4.5. 
User environment ............................................................................................ 26 
3.5. 
Mode of action of the device and principles of operation of the device ......... 26 
3.6. 
Contraindications .......................................................................................... 26 
3.7. 
Warnings ...................................................................................................... 26 
3.8. 
Risk class of the device ................................................................................ 28 

 
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3.9. 
Novel features .............................................................................................. 28 
3.10. 
Accessories of the device .......................................................................... 28 
3.11. 
Available configurations of the device ....................................................... 28 
3.12. 
General description of key functional elements ......................................... 28 
3.13. 
Device Accountability ................................................................................ 31 
3.14. 
Return of Devices ...................................................................................... 32 
4. 
Study Overview ................................................................................................. 32 
4.1. 
Study Design ................................................................................................ 32 
4.2. 
Primary Study Endpoints .............................................................................. 32 
4.2.1. 
Safety .............................................................................................................. 32 
4.2.2. 
Feasibility ........................................................................................................ 32 
4.3. 
Secondary Study Endpoints ......................................................................... 33 
4.4. 
Number of Subjects and Sites ...................................................................... 33 
4.5. 
Study Population .......................................................................................... 33 
4.6. 
Enrollment Criteria ........................................................................................ 33 
4.6.1. 
Inclusion Criteria ............................................................................................. 33 
4.6.2. 
Exclusion Criteria ............................................................................................ 34 
4.7. 
Informed consent .......................................................................................... 35 
4.8. 
Unique Study Identification Code ................................................................. 36 
4.9. 
Subject Recruitment ..................................................................................... 36 
4.10. 
Subject Reimbursement ............................................................................ 36 
4.11. 
Enrollment ................................................................................................. 36 
4.12. 
Duration of Subject Participation ............................................................... 36 
4.13. 
Study Duration........................................................................................... 36 
4.14. 
Withdrawal of Subjects .............................................................................. 37 
4.15. 
Loss to Follow-up Considerations ............................................................. 37 
4.16. 
Subject Confidentiality ............................................................................... 37 
4.17. 
Study Procedures ...................................................................................... 37 
4.17.1. 
Screening and Enrollment ............................................................................ 37 
4.17.2. 
Consent Phase ............................................................................................ 38 
4.17.3. 
Screening Phase ......................................................................................... 39 
4.17.4. 
Eligibility Assessments ................................................................................. 39 
4.18. 
Procedural Treatment and Timing ............................................................. 39 
4.18.1. 
Medication Regimen .................................................................................... 39 

 
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4.19. 
Baseline Assessment: Visit 1 .................................................................... 39 
4.20. 
Baseline Assessment: Visit 2 (four weeks after visit 1) ............................. 39 
4.21. 
Day of Implantation procedure .................................................................. 40 
4.22. 
baroloop System Implantation Procedure ................................................. 40 
4.23. 
14-Day Follow-up Visit (+2 / -3 days) ........................................................ 42 
4.24. 
Stimulation Settings/Titration First-in-Human ............................................ 42 
4.25. 
Follow-up titration every 7 days (± 2-3 days) ............................................. 45 
4.26. 
30-Day Follow-up Visit (+7 / -7 days) ........................................................ 46 
4.27. 
90-Day Follow-up Visit (+14 / -14 days) .................................................... 46 
4.28. 
180-Day Follow-up Visit (+14 / -14 days) .................................................. 46 
4.29. 
365-Day Follow-up Visit (+14 / -14 days) .................................................. 47 
4.30. 
Long Term Follow-up Visits – 18 and 24-Month Follow-up Visit (+14 / -14 
days) 
47 
4.31. 
Unscheduled Follow-up Visit ..................................................................... 47 
4.32. 
4.32 Schedule of Study Visits and Assessments ....................................... 48 
4.33 
Study Completion ...................................................................................... 49 
4.34 
Concomitant medications .......................................................................... 49 
4.35 
Study Exit or Premature Withdrawal .......................................................... 50 
5. 
Risk Benefit Assessment ................................................................................. 50 
5.1. 
Potential Adverse Events.............................................................................. 50 
5.2. 
Potential risks ............................................................................................... 50 
5.3. 
Potential Adverse Events.............................................................................. 50 
5.4. 
Potential Risks to Subject Confidentiality and Privacy .................................. 52 
5.5. 
Minimization of Anticipated Risks ................................................................. 52 
5.6. 
Potential Benefits .......................................................................................... 53 
6. 
Statistical Analysis Plan ................................................................................... 53 
6.1. 
Overview....................................................................................................... 53 
6.2. 
Primary Safety Endpoint ............................................................................... 53 
6.3. 
Primary Feasibility Endpoint ......................................................................... 54 
6.4. 
Secondary Endpoints ................................................................................... 54 
6.5. 
Demographic, Safety, Feasibility and Efficacy Data ..................................... 54 
6.6. 
Imputation of Missing Data ........................................................................... 54 

 
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7. 
Adverse Event and Incident Reporting ........................................................... 54 
7.1. 
Adverse Event (AE) ...................................................................................... 55 
7.2. 
Serious Adverse Events (SAE) ..................................................................... 55 
7.3. 
Serious Adverse Device Effect (SADE) ........................................................ 56 
7.4. 
Unanticipated Serious Adverse Device Effect (USADE) ............................... 56 
7.5. 
Anticipated Serious Adverse Device Effect (ASADE) ................................... 56 
7.6. 
Unanticipated Adverse Device Effect (UADE) .............................................. 56 
7.7. 
Anticipated Adverse Device Effect (AADE)................................................... 56 
7.8. 
Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) .... 56 
7.9. 
Documentation, Evaluation and Notification of Serious Adverse Events ...... 57 
8. 
Monitoring ......................................................................................................... 57 
9. 
Study Management ........................................................................................... 58 
9.1. 
Key Contributors ........................................................................................... 58 
9.1.1. 
Study Sponsor ................................................................................................. 58 
9.1.2. 
Authorized CRO / Representative ................................................................... 58 
9.1.3. 
Clinical Sites .................................................................................................... 59 
9.2. 
Ethical Considerations .................................................................................. 59 
9.3. 
Insurance ...................................................................................................... 59 
9.4. 
Study Conduct .............................................................................................. 59 
9.5. 
Audits and Inspections ................................................................................. 59 
9.6. 
Sponsor Responsibilities .............................................................................. 59 
9.7. 
Monitor Responsibilities ................................................................................ 60 
9.8. 
Investigator Responsibilities ......................................................................... 61 
9.9. 
Study Funding .............................................................................................. 63 
9.10. 
Investigator Training .................................................................................. 63 
9.11. 
Medical Monitor ......................................................................................... 63 
9.12. 
Data Management ..................................................................................... 63 
9.13. 
Study Suspension or Early Termination .................................................... 63 
9.14. 
Criteria for Suspending / Terminating a Study Center ............................... 64 
9.15. 
Final Report ............................................................................................... 64 
9.16. 
Protocol Deviations ................................................................................... 64 
10. 
Regulatory Considerations ........................................................................... 65 

 
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10.1. 
Maintaining Records .................................................................................. 65 
10.2. 
Site Record Retention Policy ..................................................................... 65 
10.3. 
Ethics Committee (EC) and Competent Authority (CA) Approval .............. 65 
11. 
Publication Policy .......................................................................................... 66 
12. 
Definitions ...................................................................................................... 67 
13. 
Acronyms ....................................................................................................... 71 
14. 
Bibliography ................................................................................................... 75 
 
 
 

 
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Table of Tables 
 
Table 1: Guidelines for Blood Pressure Categorization. ........................................................ 14 
Table 2: Overview device-based therapy for hypertension (from Lobo et al (2017) ............... 16 
Table 3: Schedule of Study Visits and Assessments ............................................................ 48 
 
 
 

 
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Table of Figures 
 
Figure 1: Schematic of the elementary parameterization of a stimulation pulse  ................... 22 
Figure 2: baroloop Trial Screening and Enrollment Scheme ................................................. 38 
 
 

 
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1. Protocol Synopsis 
 
Sponsor 
neuroloop GmbH 
Breisacher Straße 86 
79110 Freiburg im Breisgau 
Germany 
Phone: +49 761 1543390 
Email: study@neuroloop.de 
Website: www.neuroloop.de 
Principal 
Investigators 
Netherlands: 
Dr. med. Wilko Spiering 
Division Internal Medicine and Dermatology 
Dept. of Vascular Medicine 
UMC Utrecht 
Heidelberglaan 100 
3584 CX Utrecht 
Germany: 
Univ. Prof. Dr. med. Florian P. Limbourg 
Experimentelle Gefäßmedizin und Transplantationsforschung 
Klinik für Nieren- und Hochdruckerkrankungen 
Medizinische Hochschule Hannover 
Carl-Neubergstr. 1 
30625 Hannover 
Sponsor 
Representative 
MAXIS Medical GmbH 
Karpfenweg 12 
60327 Frankfurt am Main 
Germany 
Tel:  +49.69.2400.3626 
Fax: +49.69.2400.3627 
Email: maxisoperations@maxismedical.com 
Medical Monitor 
James C. Leiter, M.D. 
Chief Medical Officer 
MAXIS Medical GmbH 
Protocol Title 
A First in Human Study of Safety and Feasibility of baroloop 
Short Title 
The baroloop Study 
Protocol number 
Protocol Number: BL_CIP-FIH 
Revision: 2.4 
Date: 03 March 2021 
Device 
baroloop System 
Indication for Use 
The baroloop System is intended to be used to treat hypertension.  

 
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Objectives 
The primary objectives are to assess the safety and feasibility of the 
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). 
Study Design 
Non-randomized, prospective, single-arm, multi-center feasibility trial for 
subjects with hypertension  
Number of Subjects 
Up to ten (10) subjects   
Number of Sites 
Up to three (3) centers in Europe 
Primary Safety 
Endpoint 
Composite Major Adverse Event (MAE) Rate at six (6) month post-
treatment including: 
• All causes of death 
• Hospitalization for hypertensive crisis post-titration 
• Any device or procedure-related serious adverse event 
All MAEs to be adjudicated by an independent Data Safety Management
Board (DSMB). 
Primary 
Feasibility
Endpoint 
 
The ability of the baroloop System to be placed around a vagal nerve 
and to stimulate at Day 14/21 post-implantation. 
 
Secondary Endpoints 
• 
The change in blood pressure recorded during intraoperative 
stimulation at the time of implantation. 
• 
Mean reduction in 24-hour ambulatory systolic and diastolic blood 
pressure (ambulatory blood pressure monitoring - ABPM) at one 
(1), three (3), six (6), twelve (12), eighteen (18) and twenty-four 
(24) months post-treatment versus baseline. 
• 
The composite MAE rate at 1, 3, 6, 12, 18 and 24 months post-
procedure defined: 
o All-causes of death 
o Hospitalization for hypertensive crisis post-titration 
o Any device or procedure-related serious adverse event 
• 
The mean reduction in office diastolic and systolic blood 
pressure, and diastolic and systolic blood pressure at 1, 3, 6, 12, 
18, and 24 months. 
• 
Changes in antihypertensive medicines/doses through 1, 3, 6, 12, 
18 and 24 months post-implantation as analyzed by Daily Defined 
Dosages (WHO Definition) and total medications. 
• 
Quality of Life as measured by the Medical Outcomes Study 36-
Iterm Short-Form Health Survey (SF-36). 

 
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Follow-up Schedule 
All subjects will be evaluated at 14 days (+2/-3 days), 1 month (± 7 
days), 3 months (± 14 days), 6 months (± 14 days), 12 months (±14 
days), 18 months (±14 days), and 24 (±14 days) months post-
procedure. 
Study Duration 
Three (3) years to complete enrollment in this study. 
Inclusion Criteria 
Each subject must meet all the following criteria: 
1. Aged 18 years or older and less than 80 years of age. 
2. Persistent office systolic blood pressure (SBP) ≥ 140 mm Hg and 
diastolic blood pressure (DBP) > 90 mm Hg on antihypertensive 
medicines on two visits separated by a minimum of four weeks.  
3. Mean 24-hour systolic ABPM ≥ 130 mm Hg and mean 24 hour 
diastolic ABPM ≥ 80 mm Hg conducted after direct observed 
therapy to confirm that antihypertensive medicines were taken as 
prescribed during the ABPM measurement. 
4. Stable drug regimen of 4 antihypertensive medicines consisting 
of a renin-angiotensin blocker(ACE) or Angiotensin II Receptor 
Blocker (ARBs), a calcium channel blocker (CCB), a diuretic and 
spironolactone for 4 weeks at treatment. If spironolactone is not 
tolerated, the regimen must include instead the addition of further 
diuretic therapy with either eplerenone, amiloride, higher-dose 
thiazide/thiazide-like diuretic or a loop diuretic, or the addition of 
bisoprolol or doxazosin. If none of these medicines are tolerated, 
then patients on a 3-drug regimen may be included. 
5. The Investigator has confirmed that the patient has already tried 
and/or is not suitable for treatment with currently CE-marked 
device-based therapies for resistant hypertension as an 
alternative to baroloop therapy. 
6. Willingness and ability to comply with follow-up requirements. 
7. Signed informed consent. 
Exclusion Criteria  
Each subject may meet none of the following criteria: 
1. Any patient in whom access to the vagal nerve is limited by the 
size of the vagus (a size not compatible with the baroloop cuff). 
2. Any patient with a history of injury to the vagus nerve or its 
branches (e.g., the recurrent laryngeal nerve). 
3. Secondary causes of hypertension. 
4. Calculated eGFR < 30 mL/min/1.73m2. 
5. Type 1 diabetes mellitus or poorly controlled type 2 diabetes 
mellitus (HbA1c > 10%). 
6. One or more episodes of orthostatic hypotension in the past year 
7. Requirement for chronic oxygen therapy or mechanical 
ventilation. 
8. Untreated (no CPAP therapy) sleep apnea (AHI > 15)  

 
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9. Morbid obesity, defined as Body Mass Index >40 kg/m2 or arm 
circumference 46 cm. 
10. Pacemaker and/or implantable defibrillators. 
11. History of transient ischemic accident or cerebrovascular 
accident during six (6) months prior to screening. 
12. Symptomatic carotid artery disease or > 70% occlusion of either 
carotid artery; any carotid malformation or lesion, a carotid bruit 
or other abnormal carotid sound. 
13. Prior surgery, radiation therapy or scarring in the neck in the 
region of the carotid artery (e.g., patients with a tracheostomy, 
extensive thymectomy or thyroid surgery). 
14. Limited mobility of the neck secondary to vertebral disease or 
prior vertebral surgery, including patients who wear a cervical 
support. 
15. History of heart failure (NYHA class III-IV or ejection fraction < 
30%), myocardial infarction, unstable angina, coronary bypass or 
coronary angioplasty during six (6) months prior to screening. 
16. Cardiac arrythmias (atrial fibrillation, atrial flutter, etc.) that require 
anticoagulation or interfere with a consistent measurement of 
blood pressure. 
17. Syncope in the last 6 months. 
18. History of bleeding disorders, thrombocytopenia, hemophilia or 
significant anemia (hemoglobin (Hgb) < 10 gm/dl). 
19. Current anticoagulation therapy (excluding antiplatelet therapy 
with aspirin as a sole therapy). 
20. Works night shifts. 
21. History of unresolved drug or alcohol use. 
22. Active treatment of a psychiatric ailment. 
23. Life expectancy of less than 12 months due to other disease. 
24. Subject has a condition that, in the opinion of the investigator, 
precludes participation, including willingness to comply, with all 
follow-up procedures. 
25. Participation in another clinical study for which follow-up is 
currently on-going. 
26. Women who are of child-bearing age or who have the potential 
to become pregnant 
27. Resting heart rate of <40 beats/min for patients on beta blockers 
or <60 beats/min for all other patients, confirmed at both baseline 
visits. 
28. Baroreflex failure or autonomic neuropathy  
29. Symptomatic, uncontrolled bradyarrhythmias   
30. Atrioventricular block of any grade  

 
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31. Patients who are treated with Pacemaker and/or implantable 
defibrillators  
32. Presence of a vagus stimulator   
33. Patients who expect to require magnetic resonance imaging 
(MRI) of the cervical area  
34. Occupational exposure to high levels of non-ionizing radiation 
that may interfere with therapy  
35. Patients with a limited ability to read, understand and execute 
adjustment procedures (for example, persons suffering from 
dementia). 
36. Likely exposure to diathermy.  
Statistical Model 
• 
This is a single arm study in which each subject acts as his or her 
own control. Demographic variables will be tabulated in summary 
form. Adverse events will be tabulated and summarized. 
Outcome variables will be compared qualitatively to historical 
performance of other device-based therapies for hypertension. 
 
 
 
 
 

 
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2. Introduction and Background 
2.1. Rationale for Proposed Research 
Hypertension is a disease that affects more than 77.9 million adults in the United States  
and approximately one billion individuals worldwide (Chobanian et al., 2003; Go et al., 2013). 
According to a 2014 report from the American Heart Association (AHA), based on 
NHANES/NCHS data through 2010, one in three adults has high blood pressure (BP), and 
74.9% of these subjects are undergoing treatment for hypertension. The overall prevalence 
has declined in past few decades, according to the trend for high-income countries 
(Collaboration, 2017). However, “the overall number of adults with raised blood pressure 
increased from 594 million to 1.13 billion in 2015, also part of a net effect of increase due to 
population growth and ageing” (Collaboration, 2017).  In Germany, in 2015, 31% of males and 
25% of females had raised blood pressure (Collaboration, 2017). The high prevalence of  
hypertension is a major public health issue in developed and developing countries (Vega and 
Bisognano, 2014). Inevitably, the disease burden causes huge health costs: Gaziano 
estimated that “high blood pressure will cost nearly US $1 trillion in health spending if current 
blood pressure levels persist over a 10-year period, and if hypertension goes untreated, indirect 
costs could be as high as US$ 3.6 trillion annually” (Gaziano et al., 2009).  
The 2018 ESC/ESH (European Society of Cardiology/ European Society of Hypertension ) 
Guidelines for the management of arterial hypertension (Williams et al., 2018) defines 
hypertension as systolic BP ≥ 140 mm Hg and a diastolic BP ≥ 90 mm Hg measured in the 
office, a mean 24 hour ambulatory BP measurement (ABP) ≥ 130 mm Hg systolic or 80 mm 
Hg diastolic or a daytime ABMP  ≥ 135 mm Hg systolic or 85 mm Hg diastolic. The ESC/ESH 
Guidelines (Williams et al., 2018) classifies blood pressure as follows: 
Table 1: Guidelines for Blood Pressure Categorization. 
Category 
Systolic (mmHg) 
 
Diastolic (mmHg) 
Optimal 
<120 
and 
<80 
Normal 
120-129 
And/or 
80-84 
High normal  
130-139 
And/or 
85-89 
Grade 
1 
hypertension 
140-159 
And/or 
90-99 
Grade 
2 
hypertension 
160-179 
And/or 
100-109 
Grade 
3 
hypertension 
≥180 
And/or 
≥110 
Isolated 
systolic 
hypertension 
≥140 
And 
<90 
2.2. Treatment targets. 
The EACTS (European Association for Cardio-Thoracic Surgery) recommended treatment for 
patients with hypertension is to lower blood pressure <140/90 mm Hg in all patients using 
treatment that is well tolerated. Treated systolic blood pressure values should be reduced to 
120–129 mm Hg in most patients. In patients page 65 - 80 years, SBP should be targeted to a 

 
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BP range of 130–139 mmHg. In patients > 80 years of age, SBP should be targeted to a BP 
range of 130–139 mmHg, if tolerated. DBP is targeted to <80 mmHg in all patient groups 
(Williams et al., 2018).The American Guidelines (ACC/AHA) defines the treatment target for all 
patient as a blood pressure < 130/80 mm Hg.  
2.2.1. Treatment according to European Guidelines 
According to the ESH guidelines, standard management for elevated pressures should include 
a thorough patient work-up, medical history, physical examination, evaluation of lifestyle and 
underlying conditions such as sleep apnea, and evaluation of medications, including 
compliance to antihypertensive regimens (Williams et al., 2018). Arterial hypertension 
treatment includes lifestyle changes and drug treatment. Drug treatment has a variety of 
different medication combination with angiotensin-converting enzymes,  angiotensin receptor 
blocker, calcium channel blocker and diuretics depending on grade of hypertension and 
therapeutic response to the different drug classes (Williams et al., 2018). However, the AHA 
further reported that hypertension is under control in only 53% of these patients (Go et al., 
2014).   
Patient non-adherence and non-persistence using medicines is recognized as a cause of 
treatment failure, but solutions are limited.  The first line of treatment is to simplify complicated 
medical regimens. However, many hypertensive patients receiving three or more medications 
continue to have blood pressures above clinical targets due to ineffective therapy and high 
rates of noncompliance. Moreover, there is significant morbidity associated with taking multiple 
antihypertensive medications. Diuretics can cause weakness, leg cramps, pain in lower 
extremities, erectile dysfunction; beta blockers can cause asthma symptoms, depression, 
erectile dysfunction, insomnia; angiotensin-converting-enzyme inhibitors (ACEi) can cause 
rashes; Angiotensin II Receptor Blockers (ARBs) can cause dizziness; calcium channel 
blockers can cause constipation, dizziness, headaches, swollen ankles; α-antagonists can 
cause dizziness, tachycardia; and centrally acting drugs can cause constipation, dizziness and 
drowsiness. Thus, it is not surprising that hypertension is associated with high rates of non-
adherence (Irvin et al., 2012) and non-persistence (Van Wijk et al., 2005) to medication.  In an 
observational cross-sectional study (Yiannakopoulou et al., 2005), compliance to 
antihypertensive medication was observed in only 15% of patients.  Beyond pharmacologic 
non-compliance, genuine failure of neuro-humeral interventions to attain adequate control of 
BP may be due to inherent physiological unresponsiveness – some patients have genuinely 
difficult to control BP despite adherence to multidrug treatment regimens.  
2.3. Resistant hypertension 
Hypertension remains uncontrolled in the majority of treated patients, especially those with 
multiple cardiovascular risk factors. Thus, resistant hypertension is a widely prevalent 
condition, which is estimated to affect approximately 30% of the population in the United 
States. The ESC/ESH guidelines define resistance to treatment “when the recommended 
treatment strategy fails to lower office SBP and DBP values to < 140 mm Hg and /or < 90 mm 
Hg when the inadequate control of BP is confirmed by ABMP (ambulatory blood pressure 
measurement) or HBMP (homecare blood pressure measurement) in patients whose 
adherence to therapy has been confirmed” (Williams et al., 2018). The prevalence of resistant 
hypertension varies from 5-30% in hypertensive patients depending on the particular definition 
of resistant hypertension. The AHA defines resistant hypertension as “blood pressure that 
remains above goal in spite of the current use of 3 antihypertensive agents of different classes 
(ideally one drug is from the class of diuretics) and all agents should be prescribed at optimal 

 
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dose amounts.” (Judd and Calhoun, 2014) Patients who require 4 or more medications to 
control blood pressure should also be considered resistant to treatment (Calhoun et al., 2008). 
Patients with pseudo-resistant hypertension have elevated blood pressure due to white-coat 
hypertension, improper blood pressure measurement or medication nonadherence (Judd and 
Calhoun, 2014) or secondary reasons for hypertension (Williams et al., 2018). For a better 
differentiation, some studies use the term apparent resistant hypertension, when BP > 140/90 
mm Hg while taking ≥ 3 antihypertensive medications. If “pseudo-resistance can be excluded 
the differentiation of true resistance can be made from apparent resistance“ (Calhoun et al., 
2008). Therefore, the prevalence of true resistant hypertension is probably <10% (Calhoun et 
al., 2008; Williams et al., 2018). Nonadherence is one of the main causes of uncontrolled blood 
pressure (Brinker et al., 2014): Abegaz et al. found nonadherence in 45% of hypertensive 
patients, and in patients with poorly controlled BP, nonadherence was nearly 84% (Abegaz et 
al., 2017). Other studies reported a 47% prevalence of noncompliance (Strauch et al., 2013) 
and inadequate adherence or failing to take 75% of prescribed medications (Egan, 2015). 
Failure to comply with medical therapy for hypertension and the development of resistant 
hypertension clearly contribute to the continued high rates of cardiovascular disease 
attributable to hypertension (Daugherty et al., 2012; Pimenta and Calhoun, 2012). 
2.4. Device-based therapies for hypertension 
Whether patients simply are not compliant with the prescribed medical regimens for treatment 
of hypertension or the drugs are genuinely ineffective in particular patients, too many patients 
fail to reach recommended targets for control of hypertension. Even when patients are 
compliant with lifelong polypharmacy, there remain significant side effects and morbidities 
caused by the medicines. For these reasons, new therapies for treatment resistant 
hypertension are being developed. Devices used for hypertension do not require patient’s 
adherence or compliance and may, therefore, fill an unmet clinical need. Therefore, many 
efforts have been made to develop device-based therapies for hypertension that are effective 
and durable and less dependent on patient compliance with pharmacological therapies that 
are too often associated with unwanted or even harmful side-effects. Device-based therapies 
for treatment of hypertensions are not currently recommended for routine treatment according 
to ESC/ESH guidelines (Williams et al., 2018). Currently, device-based therapies mentioned 
in European Guidelines include carotid-baroreceptor stimulation with a pacemaker or a stent, 
renal denervation or creation of an arteriovenous fistula (Williams et al., 2018).  
Table 2: Overview device-based therapy for hypertension (from Lobo et al (2017) 
Technology 
Mode 
of 
action 
Stage of development 
limitations 
Renal 
(sympatheti
c) 
denervation  
Ablation 
catheters 
and 
generators 
available 
from several 
Sympatho-
modulatory—
results 
in 
destruction of 
renal afferent 
and efferent 
sympathetic 
nerves 
and 
BP reduction 
through 
mechanisms 
that 
remain 
CE Mark approval for 
hypertension for most 
catheters  
A 
variety 
of 
catheters/platforms 
now 
available 
includes: 
Radiofrequency 
ablation, 
ultrasound 
ablation, 
chemical 
ablation, 
and 
cryoablation 
using 
Lack of markers of procedural 
success Inability to screen for 
increased renal nerve signaling 
prevents 
identification 
of 
best 
responders 
Damage 
to 
renal 
artery from 
endovascular 
approach 
using 
thermal energy 

 
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manufactur
ers 
including 
Medtronic, 
St 
Jude 
Medical, 
Boston 
Scientific, 
Terumo, 
and 
Verve 
Medical 
unclear 
in 
human 
hypertension 
 
balloon/non-balloon 
and irrigated catheters 
Baroreflex 
activation 
therapy 
Barostim 
neoTM 
(CVRx Inc, 
Minneapolis
, MN, USA) 
Sympatho-
modulatory: 
unilateral 
electrical 
field 
stimulation of 
the 
carotid 
sinus 
stimulates 
the 
baroreflex 
and 
down-
regulates 
sympathetic 
outflow while 
increasing 
parasympath
etic tone 
CE Mark approval for 
hypertension 
Pivotal 
study published with 
the 
first-generation 
device (Bisognano et 
al., 2011). 
Small proof of concept 
study with the second-
generation 
device 
(Hoppe et al., 2012) 
Open loop system lacks feedback 
mechanism  
Exceedingly high cost  
Implantable generator must be 
replaced at end of battery life 
(currently 3 years) 
Barorecepto
r 
amplificatio
n 
therapy 
Mobius 
HDTM 
(Vascular 
Dynamics, 
Mountain 
View, 
CA, 
USA) 
Sympatho-
modulatory: 
dramatic 
increase 
in 
carotid 
bulb 
strain causes 
durable 
amplification 
of 
baroreceptor 
feedback and 
BP reduction 
European 
and 
US 
studies now enrolling 
Case report and early 
report 
from 
first-in-
man study published 
(Devireddy and Bates, 
2014; van Kleef et al., 
2018)  
Concerns over instrumentation of 
the carotid artery, risks of distal 
embolization. Open loop system 
with no feedback mechanism 
Carotid 
body 
ablation 
Cibiem 
Carotid 
Body 
Modulation 
SystemTM 
(Cibiem, 
Sympatho-
modulatory: 
unilateral 
carotid body 
ablation 
reduces 
sympathetic 
vasomotor 
tone without 
affecting 
Proof of concept study 
using 
unilateral 
surgical 
excision 
in 
resistant hypertension 
(Narkiewicz 
et 
al., 
2016) 
Endovascular ablation 
planned using novel 
Only appears effective in those with 
high carotid body tone. Screening 
for 
this 
will 
be 
essential 
Endovascular 
approach 
is 
complicated by the difficulty of 
accessing the target and risks to 
important adjacent structures 
 

 
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Los 
Altos, 
CA, USA) 
respiratory 
drive 
catheter-based 
system 
Deep brain 
stimulation 
Activa 
Neurostimul
ator, 
(Medtronic 
Inc., 
Minneapolis
, MN, USA) 
VerciseTM 
DBS 
System 
(Boston 
Scientific, 
Marlboroug
h, MA, USA) 
Sympatho-
modulatory: 
electrical 
field 
stimulation of 
the 
dorsal 
and 
ventrolateral 
periaqueduct
al grey region 
within 
the 
midbrain 
reduces 
BP 
through 
mechanisms 
that are not 
clearly 
defined 
in 
human 
hypertension 
The technology was 
primarily developed for 
management 
of 
movement 
disorders 
and 
chronic 
pain 
syndromes. 
(O'Callaghan et al., 
2014) 
Isolated reports of BP-
lowering independent 
of pain control  (Green 
et al., 2007; Patel et 
al., 2011) 
Limited efficacy/safety data High 
costs of therapy Open loop system 
Frequent 
generator 
recharging 
required 
Vagal nerve 
stimulation 
CardioFITTM 
Systems 
(BioControl 
Medical, 
Yehud, 
Israel) 
PrecisionTM 
System, 
(GUIDANT 
Europe/Bost
on 
Scientific) 
Sympatho-
modulatory—
unilateral 
vagal 
nerve 
stimulation 
restores 
vagal 
tone 
and improves 
sympatho-
vagal 
balance 
Under investigation for 
use in heart failure and 
hypertension.  
Lack 
of 
efficacy 
regarding reduction of 
death/heart 
failure 
events in chronic HF 
patients (Gold et al., 
2016) 
Animal data only for 
hypertension 
indication (Plachta et 
al., 2014; Sevcencu et 
al., 2018) 
Inability to selectively target 
nerve fibers to avoid 
bradycardia and 
bradypnea 
Median 
nerve 
stimulation 
Subcutaneo
us 
Neuromodul
ation 
System 
(Valencia 
Technologie
s, 
Sympatho-
modulatory—
subcutaneou
s 
unilateral 
implantation 
of a 
coin-sized 
device (in a 
20-min office 
According 
to 
clinicaltrial.gov 
the 
study 
NCT02926495 
was withdrawn  
https://clinicaltrials.go
v/ct2/show/NCT02926
495?intr=ecoin+syste
m&rank=1  
Proof of concept study 
has shown profound 
reductions in systolic 
BP (Bang et al., 2018) 
No published randomized 
controlled data 

 
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Valencia, 
CA, USA) 
procedure) 
causing 
electrical 
stimulation of 
the 
median 
nerve and 
subsequent 
down-
regulation of 
sympathetic 
outflow 
2.5. Baroreceptor Modulation for Hypertension 
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 

 
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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 

 
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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 changing pH values. The amount of 
charge to be applied via the electrode contacts is limited not only by material parameters as 
described above. Thresholds also arise from physiological constraints. The “Shannon Criteria” 
provide a conservative estimate of the limits of charge that may be safely applied in terms of 
the amount of charge/area/cycle to avoid neural damage (Shannon, 1992). In most cases, the 
Shannon Criteria are below the water window of the working electrode.  
To evaluate the safety of the stimulation presets used by the baroloop system it is necessary 
to consider the total energy delivered and the potential for tissue damage of the electrodes 
used for neural stimulation, rather than the individual values within each preset. The amount 
of energy absorbed by the tissue is dependent on many variables, including the stimulus 
intensity (typically measured in microamperes), the duty cycle, the frequency of stimulation, 
and the duration of stimulation. Different combinations of these parameters can result in the 
delivery of the same equivalent energy to the tissue. To provide a common scale to assess 
ranges of stimulation characteristics, scientists focus on the number of electrons delivered. 
This value is the total electrical charge which is measured in coulombs. One coulomb is 
equivalent to one ampere x one second (1 C = 1 A × 1 s).  
In addition to the number of electrons delivered to tissue, the potential for tissue damage also 
varies as a function of the area over which the electrons are delivered (smaller electrode 
area for any given charge increases the risk of tissue damage), and so the size of the electrode 
is a consideration. To account for this, the charge delivered is divided by the geometric surface 
area of the electrode and expressed as the charge density. 
The charge delivered per phase also affects the risk of tissue damage. These terms are 
captured by the Shannon equation and the Shannon limit. 
The presets defined for use in the baroloop Study are all well below the Shannon limit and 
within the range tested in animals. In this way, the electrical charge delivered to tissue in all of 
the FIH preset stimulation sequences is covered by the animal studies. The variety of charges 
delivered to tissue in the Sponsor’s animal studies were all shown to be safe. For more details, 
please see also Section 2.20 of the Investigator’s Brochure. 
Based on these considerations, the baroloop device has performance characteristics similar 
to the LivaNova VNS systems in terms of charge, pulse width and frequency used. The charge 
is biphasic and balanced asymmetrically so that the intensity of depolarizing stimulation is 
greater, but of shorter duration than the repolarizing phase which is of lower intensity and 
longer duration. In addition, the baroloop device is a multichannel stimulation device, and 
optimal electrode pairs may be selected to active the vagus with the lowest possible energy 
input. The baroloop cuff electrode has multiple, small active electrode areas, rendering the 
charge injection in any electrode pair closer to the Shannon Criteria, without reaching it. The 
pulse width can be as long as 500 µs, and this enables the baroloop implant to reach and 
stimulate small axonal fibers. The physician may choose among a variety of presets, which are 
pre-defined sets of stimulation parameters (e.g., duty cycle, stimulus amplitude, and pulse 

 
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width) that may be selected through the Programmer to activate the baroreflex. The wave form 
of an individual stimulus for the baroloop system is shown below (Figure 1.). 
Figure 1: Schematic of the elementary parameterization of a stimulation pulse  
 
In Figure 1 above, the stimulation channel (not shown here) was set to apply a given number 
of pulses with a defined strength (current I), a given pulse width (PW) and repetition interval 
(1/F). Not shown either is the duty cycle based on intervals between bursts of pulses. To avoid 
polarization of the cathode, the pulses are biphasic and charge balanced (Q1=Q2).  
In summary, the strength and magnitude of baroloop stimulation is comparable to existing VNS 
stimulation parameters. The conditioning of the stimulation is slightly better as the baroloop 
device applies charge balanced, biphasic pulses. The spatial pattern of selective stimulation 
made possible by the multielectrode baroloop cuff permits application of strong, local stimuli to 
activate specific, small circumferential sectors of the vagal nerve, where the relative number 
of baroreceptor active fibers may be increased The temporal pattern of stimulation (in 
intermittent bursts) is unique as well, since the baroloop stimulation pattern may mimic the 
grouping of afferent sensory activity triggered by the blood pressure wave of the expelled blood 
that passes the aortic arch and carotid bifurcation.  
2.5.4. The baroloop System: vagal nerve stimulation to control blood 
pressure 
neuroloop has developed a novel cuff electrode for use with a safe and effective mechanism 
of vagal nerve stimulation to activate the baroreflex and lower blood pressure in the context of 
hypertension. The neuroloop device fits well within the current trends of treatment of 
hypertension in that resistant hypertension is remarkably common, and inadequate treatment 
of hypertension to achieve treated blood pressure levels less than 140/90 mm Hg (and better 
still according to current recommendations less than 130/80 mm Hg) is associated with 
increased risks of adverse cardiovascular outcomes from hypertension. Pharmacological 
therapy of hypertension is inadequate in many patients either because patients do not take the 
medicines, suffer side-effects from the medicines, or the medicines are ineffective controlling 
blood pressure. Given the novel design and treatment features of the neuroloop device, the 
Sponsor will conduct a First in Human Study to evaluate the safety and feasibility of treating 
hypertension using VNS. 

 
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2.5.5. VNS to Treat Hypertension 
The vagal nerve consists of afferent and efferent fibers for visceral organs carrying information 
regarding autonomic functions. The vagus transmits afferent information about the internal 
state of the body to the central nervous system, and transmits efferent information from the 
central nervous system, especially autonomic control information from the brainstem to effector 
organs of the autonomic nervous system (largely the parasympathetic part of the autonomic 
nervous system) (Johnson and Wilson, 2018). Among many autonomic functions, which are 
under control of the vagal nerve, it is known that baroreceptive fibers merge with the vagal 
nerve (Benarroch, 2008). It is, however, not clear where they are located within the vagal nerve. 
In some mammals, the fibers are bundled in the aortic depressor nerve (ADN) (Kobayashi et 
al., 1999). Stimulation of ADN-fibers activates the baroreflex and therefore leads to a drop of 
blood pressure (De Paula et al., 1999; Fan and Andresen, 1998; Gao et al., 2006; Tosato et 
al., 2006). The cardiovascular efferents differs between the right and left vagal nerves; the right 
innervates the sinoatrial node ,and the left innervates the atrioventricular node (Johnson and 
Wilson, 2018; Panebianco et al., 2016). Saxena et al. described the effect of acute vagal 
stimulation in humans, which resulted in blood pressure lowering that was dependent on the 
current- and frequency of stimulation (Ng et al., 2016). At higher currents, atrio-ventricular (AV) 
block and ventricular asystole were observed as side-effects during stimulation, which may 
result from direct activation of efferent cardiac fibers (Mirkovic et al., 2012). However, this was 
not a systematic evaluation of VNS and baroreflex activation as a therapy for hypertension, 
and the efficacy of chronic vagal nerve stimulation in humans to activate the baroreflex has not 
been proven. Therefore, neuroloop has developed a clinical feasibility study: A First-in-Human 
study will be performed to assess the efficacy/ feasibility and safety of blood pressure lowering 
in humans via stimulation of the left vagal nerve to activate the baroreflex.  
2.6. Preclinical Experience with the baroloop System 
The baroloop System has been subjected to a comprehensive pre-clinical testing program to 
verify design, safety, and performance against pre-specified engineering, mechanical and 
system requirements. Pre-clinical testing included bench, biocompatibility, animal, and 
sterilization testing. In addition to evaluation against internal specifications and international 
standards, the baroloop System was also tested in accordance with appropriate international 
standards as described in the Investigators Brochure for this First in Human Study. 
Complete biocompatibility evaluation was performed on the baroloop device according to 
ISO10993, Biological Evaluation of Medical Devices Part 1: Evaluation and testing within a risk 
management process .After gathering physical and chemical data on the device, based on risk 
assessment, further studies were performed on baroloop device included physical and/or 
chemical information, cytotoxicity, sensitization, irritation, material related pyrogenicity, 
implantation studies (also included acute, subacute, sub-chronic and chronic studies), and 
genotoxicity. Based on overall biological evaluation performed on the device, baroloop device 
can be considered biocompatible without the need to perform pre-clinical additional tests and 
could be considered suitable for its clinical application study. 
In conclusion, the baroloop System has been fully evaluated through pre-clinical testing per 
the identified risks and demonstrates compliance with its predetermined performance 
specifications. 
Animal studies have been performed to further support the safety and performance of the 
baroloop System. The device elicited no adverse blood or tissue response, and no gross 
injuries were associated with the placement of the device, thereby demonstrating the safety 

 
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and feasibility of the device in an animal model (BL_ER_Efficacy_Report; BL_Safety_GLP_19-
55_Interim_Report, BL_PCS2_Safety_GLP_19-55_Study_Report). Pre‐clinical animal studies 
have been conducted and support the safety and performance of the baroloop System through 
simulated use under in vivo conditions in a porcine model (performance in minipig) and in an 
ovine model (safety in sheep). 
3. Test System (Investigational Device) 
3.1. Product name 
baroloop® 
3.2. General description 
neuroloop has developed a platform based on thin-film technology for selective stimulation of 
the vagus nerve. The core part of the platform is a multi-channel electrode based on a thin-film 
cuff. 
The goal of baroloop therapy is to achieve clinically effective blood pressure control while 
minimizing adverse reactions and provide superior usability of the implant for the surgeon, 
treating physician and the patients. 
The system includes auxiliary devices and services to allow the patient to recharge the device 
and treating physicians to adjust the therapy. 
The neuroloop product baroloop® is a stimulator platform for treating hypertension. The 
implantable parts of the stimulator platform will be used by the surgeon only. The non-
implantable parts, as described in the following sections, interact with and direct the activity of 
the implanted system and will be used only by professionals in this study. 
The implanted parts of the stimulator platform are intended to remain in the patient, whereas 
the programmer and recharging platform remain outside each patient’s body. The recharging 
interval is every 1 to 4 weeks (depending on the stimulation parameters). However, patients 
enrolled in the study will have the device charged by professionals during protocol-required 
follow-up visits to the study site.  
The nomenclature in the technical documentation for the implanted parts is as follows: 
- 
The Lead consists of four elements: the “Cuff”, “Pill”, the “Cable” and the “Connector”.  
- 
The Cuff is a thin film electrode, which surrounds the nerve. The Cuff is wrapped 
around the left vagus nerve to establish an electrical connection to the nerve. 
▪ 
Please see the Instructions for Use, Section 2.11 of the Investigators 
Brochure and p. 8 of the Implantation Manual for information regarding 
available cuff sizes and selection criteria. 
- 
The Pill is the interface between Cuff and Cable, which is required to establish 
the electrical connection between thin-film and wires that communicate with the 
Implantable Pulse Generator (IPG). 
- 
The Cable consists of medical-grade, insulated wires encapsulated in a 
biocompatible mantle. 
- 
The Connector is the electrical interface between the Lead and the IPG. 

 
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- 
This stimulator device, the “Implantable Pulse Generator” (IPG) completes the 
stimulator platform. The IPG generates the stimulus as well as recording 
electrical signals derived from the Cuff electrodes and other components of the 
device. The IPG is controlled by an external programmer (see below). 
The non-implanted parts are the following: 
- 
A free-standing, wearable, transcutaneous charging device, the “Charger,” will be used 
to recharge the batteries within the IPG. The Charger is designed for professional use 
only . Besides the transfer of power, the Charger also transfers data from and to the 
IPG. 
- 
A programming device, the “Programmer,” directs the IPG to provide vagal nerve 
stimulation tailored to the needs of each patient and accepts data from the IPG that 
was recorded to monitor the performance of the internal components of the baroloop. 
The Programmer is for professional use only.  
- 
For the First-in-Human study, the Charger will be recharged using a laptop computer 
or USB power supply and a USB cable. The Charger will be used only in the 
professional environment (hospital or doctor’s office). 
3.3. Code identification of the device 
IPG: A-1-I-# 
Lead A-1-L-# 
Charger: A-1-C-# 
Programmer: A-1-P-# 
Strap: A-1-S-# 
3.4. Intended purpose 
3.4.1. Indication 
The baroloop device is indicated for the treatment of hypertension. 
3.4.2. Intended patient group 
The intended patient group is adults greater than or equal to 18 years of age. 
3.4.3. Target/intended body parts 
The implantable pulse generator (IPG) is implanted subcutaneously in the left upper chest 
outside the rib cage, and the Lead is tunneled subcutaneously from IPG on the chest wall to 
the left side of the neck. The Cuff is wrapped around the left vagus nerve in the neck. 
3.4.4. Target user profile 
Medical professional surgical implantation of the device - surgeon: The implantable parts of 
the stimulator will be used by surgeons who are trained and experienced in the field of 
neurosurgery or in carotid sheath-related surgical procedures (e.g. vascular surgeons or 
otorhinolaryngologists). 

 
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Medical professional adjustment of vagal nerve stimulation to control blood pressure - 
physician: the physician should be board-certified and have experience and expertise treating 
hypertension. 
3.4.5. User environment 
The Charger is used in a professional environment (hospital or doctor's office). 
Programmer is used in a professional environment (hospitals, clinics, doctors’ offices) 
3.5. Mode of action of the device and principles of operation of the device 
baroloop uses adjustable electrical pulses to neuromodulate the left vagus nerve. The pulses 
generated by the implantable pulse generator (IPG) are delivered selectively over the 
neuroelectronic interface of the Cuff. The cathodes of the Cuff surround the vagus nerve. 
The Programmer is used to select cathodes to stimulate segments of the nerve. Stimulation of 
an appropriate segment of the vagus nerve triggers the baroreflex and lowers blood pressure. 
3.6. Contraindications 
Vagotomy (no usage of device after bilateral or left cervical vagotomy possible) 
Diathermy – The use of shortwave diathermy, microwave diathermy, or therapeutic 
ultrasound diathermy on patients with an implanted VNS device is contraindicated 
Baroreflex failure or autonomic neuropathy 
Symptomatic, uncontrolled bradyarrhythmia’s  
Atrioventricular block of any grade 
Patients who are treated with Pacemaker and/or implantable defibrillators 
Presence of a vagus stimulator  
Patients who require magnetic resonance imaging (MRI) 
Occupational exposure to high levels of non-ionizing radiation that may interfere with 
therapy 
Patients with a limited ability to read, understand and execute adjustment procedures 
(for example, persons suffering from dementia) 
3.7. Warnings 
The warnings are also included in the manuals. 
General warnings, warnings and precautions must be followed to avoid system failures. 
The baroloop system is indicated only for the treatment of hypertension. Implantation 
for other treatments or indications has not been tested and is NOT permitted. 
The baroloop system must be implanted by surgeons experienced and trained in the 
field of neurosurgery or in carotid sheath-related surgical procedures. 
The physician who is treating the patient with baroloop system should be board-certified 
and have experience and expertise treating hypertension. 

 
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Patients with an implanted baroloop system should not be subjected to MRI. The 
baroloop system has not been tested for MRI use. Exposure to the magnetic field in an 
MRI might result in dislocation, heating of metallic components of the device, induced 
electrical currents in the Lead and/or tissue damage. 
Shortwave diathermy, microwave diathermy, or therapeutic ultrasound (all of which 
may result in diathermy) should not be used on patients in whom the baroloop system 
has been implanted. Energy generated by diathermy may be transferred through 
implanted baroloop system and could lead to tissue or nerve damage or result in severe 
injury or death. Furthermore, the IPG may be damaged by the energy generated by 
diathermy.   
Ultrasound energy may damage the Lead of the baroloop system. Therefore, 
physicians must avoid using ultrasound focused on regions containing implanted 
components of the baroloop device. 
Extracorporeal lithotripsy may damage the IPG. Therefore, physicians must avoid using 
extracorporeal lithotripsy in the region containing the implanted IPG. 
Radiation therapy may damage the baroloop system.  Physicians must avoid using 
radiation therapy in the region of the implanted components of the baroloop system 
X-ray and CT Scans may affect the IPG, if the IPG is active and turned on. Physicians 
must be aware that the baroloop device must be turned off prior obtaining X-rays or CT 
scans in the region of the implanted components of the baroloop device. 
Images obtained using X-ray and CT Scanning may be influenced by the presence of 
implanted components of the baroloop system when the components of the baroloop 
system overlay or distort the X-ray or CT scan images. 
Magnetic fields may influence the function of the IPG and temporarily interrupt therapy 
by the baroloop system. 
Potential effects of the baroloop system on the function of other implanted devices, e.g. 
cardiac pacemakers, defibrillators and other electronic devices and neurostimulators, 
are unknown. Therefore, use of the baroloop system in individuals with any of the 
aforementioned devices is not recommended. Moreover, the aforementioned implanted 
devices could affect the functionality of the baroloop system. 
Physicians must advise each patient or the patient’s caregivers to avoid manipulation 
of the baroloop system through the skin. Manipulation of any implanted components of 
the baroloop system could damage the device, cause lead migration and/or skin 
damage, or damage the vagus nerve. 
Physicians should advise the patient that external mechanical forces may damage the 
implanted components of the baroloop system. For this reason, physicians should 
discuss with each patient his or her activities so that physical activities that might 
damage the baroloop system may be avoided. 
Physicians must advise each patient that strong electromagnetic fields may influence 
the performance of the implantable components of the baroloop device. Sources of 
strong electromagnetic fields can lead to system failures or disrupted communication 
between Charger and IPG. 

 
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Physicians must advise each patient that excessive movement during the ingrowth 
phase may displace implanted components of the baroloop system and must be 
avoided. 
Physicians must advise each patient or the patient’s caregivers that the Charger should 
not be covered with any material (e.g., a blanket, sheet, or clothing) that could prevent 
heat loss from the Charger during the charging process. If the patient feels any 
discomfort during charging of the IPG through the skin, the charging should be stopped. 
3.8. Risk class of the device 
The baroloop device is an active implant intended for use in humans for the treatment of 
hypertension. 
The baroloop device is a programable vagal nerve stimulator for the monitoring, treatment and 
alleviation of hypertension. Its mode of action is electrical and mechanical, and it does NOT 
rely on any biological, immunological or metabolic means to alter the function of the human 
body. It contains no products derived from animal or human tissue. 
The Lead + IPG and the Charger are Class III devices and the Programmer Software is also a 
Class III device.  
3.9. Novel features 
Selective stimulation of segments of the left vagus nerve for blood pressure reduction. 
3.10. 
Accessories of the device 
The Programmer is intended to be used together with the stimulator platform to directly assist 
medical functionality of the IPG (via the Charger) in terms of its intended purpose. 
The Strap is an adjustable, external holder that keeps the Charger in close proximity to the IPG 
during battery charging and data transfer. 
3.11. 
Available configurations of the device 
The baroloop system consists of the IPG, the Lead and the Charger. The Programmer is 
provided to the professional medical user and can be used in combination with more than one 
baroloop system. 
3.12. 
General description of key functional elements 
Lead 
The Lead is an assembly that consists 
of the Cuff, the Pill, the Cable, and the 
Connector. It is used to transfer 
electrical energy from the IPG to the 
vagus nerve. 
 
 
 
      Cuff 
      Pill 
      Cable 
      Connector 
 
 
 
 

 
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Cuff 
The Cuff is the interface between the 
epineurium of the vagus nerve with the 
stimulator. It contains 12 fractal-
shaped, cathodic electrode contacts 
and two anodal rings. The substrate of 
the Cuff is made of flexible polyimide, 
and a flexible extension of the Cuff, the 
Ribbon, 
connects 
the 
electrode 
contacts to the Pill. The Cuff is pre-
shaped and wraps (curls) around the 
nerve in conformity with preset shape of 
the Cuff. The implantation of the Cuff is 
suture-less. 
 
 
Pill 
The Pill consists of a ceramic interface 
with a silicone overmoulding. The 
ceramic element is the electrical 
interface between the Cuff and the 
Cable. The silicone overmoulding has 
two notches in its external surface that 
may be used to facilitate surgical 
fixation 
of 
the 
Pill 
near 
the 
neurovascular bundle that contains the 
vagus nerve. 
 
 
Cable 
The Cable passes subcutaneously from 
the Cuff to the IPG and is used for 
transmission of the electrical signals to 
and from the Cuff electrode to the IPG. 
 
See above. 
Connector 
The Connector is the electrical interface 
between the Lead and the IPG. 
 
 
 
 
Suture Sleeve 
The Suture Sleeves provide anchoring 
brackets to fix the cable to the 
surrounding tissue. 
 
Ribbon 
Ribbon 
Pill 
Cable 

 
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IPG 
The IPG is the active part of the 
baroloop 
stimulator 
system. 
It 
generates the stimulation pulses, which 
are transmitted via the Lead to the 
vagus nerve. The IPG also records 
information related to the impedance 
and continuity of each electrode 
element in the Cuff and the heart rate. 
The IPG contains a rechargeable 
battery as an energy source and a 
wireless power transmission module for 
charging. 
 
 
 
Torque key 
The torque key is a tool for fastening or 
loosening the fixation screws to fix the 
Connector in the header of the IPG. 
 
 
 
 
Charger 
The Charger is an external device, 
which is used to program the IPG, to 
transfer recorded data from, and 
electrical energy (recharge) to the IPG. 
It acts as the interface between the 
implanted IPG and the Programmer. 
The power for the Charger is derived 
from a rechargeable battery. The 
Charger communicates wirelessly with 
the IPG and allows configuration of the 
IPG through the Programmer. 
 
 
 
Charger 

 
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The Charger fits into an adjustable, 
external Strap to hold the Charger close 
to 
the 
IPG 
during 
charging, 
programming, and data transfer. 
 
 
 
Strap 
 
Programmer 
(software) 
The Programmer is used to adjust the 
stimulation parameters of the IPG. For 
this purpose, it communicates with the 
Charger, which is the interface to the 
IPG. The Programmer itself does not 
establish a direct connection to the IPG. 
The programming device used will be 
obtained from third-party manufacturer 
and consists of a computer or tablet. 
The 
software 
is 
developed 
by 
neuroloop. 
 
3.13. 
Device Accountability 
Access to baroloop System inventory will be controlled and will be housed in a secure location. 
Records will be maintained to document the physical location of inventory from shipment / 
removal from the Sponsor’s facility through use and / or return or disposal. 
The site will be responsible for keeping a Device Accountability Log provided by the Sponsor 
or its designated representative in which will be recorded, at a minimum, date of receipt, 
baroloop System identification number, expiration date, date of use, subject unique identity 
code and date of disposal of the device. 
If there is a product malfunction or other need to return the system or system components to 
the Sponsor, the Sponsor should be contacted for safe product disposal and / or return details.  
NOTE: Please complete a Device Malfunction Form and immediately email to 
maxisoperations@maxismedical.com or fax to  +49 69 2400 3627 if a device malfunction / 
failure has occurred. 
The Investigator is responsible for ensuring that the investigational devices are used only under 
the Investigator’s supervision and are only used according to this protocol and any approved 
amendments. The Investigator will not supply an investigational device to any person not 
authorized to participate in the study. The Investigator shall document in the Case Report 
Forms the lot numbers of the devices used during each case. 

 
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3.14. 
Return of Devices 
All unused investigational devices will be returned to the study Sponsor upon completion of the 
clinical study. Any investigational device that fails to perform correctly will be returned to the 
study Sponsor or its designated representative for analysis. The study Sponsor or its 
designated representative will conduct device reconciliation during monitoring, the completion 
of subject enrollment, and at the conclusion of the study. 
4. Study Overview 
The Sponsor plans to conduct a clinical trial of the baroloop System. The study plan was 
developed according to the guidance given by EN ISO 14155 and the Declaration of Helsinki. 
The rationale for the trial design, endpoints and variables selected for study are described 
below. The justification for the study design and the content of the study are fully described 
below. 
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. 
4.2. Primary Study Endpoints 
4.2.1. Safety 
Composite Major Adverse Event (MAE) Rate at six (6) months post-treatment including: 
• 
All-causes of death 
• 
Hospitalization for hypertensive crisis post-titration 
• 
Any device or procedure-related serious adverse event 
All MAEs will be adjudicated by an independent Data Safety Management Board (DSMB). 
4.2.2. Feasibility 
The ability of the baroloop Systems to be placed around a vagal nerve and the ability to 
stimulate at Day 14/21 post-implantation. 

 
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4.3. Secondary Study Endpoints 
• 
The change in blood pressure recorded during intraoperative stimulation at the time of 
implantation. 
• 
Mean reduction in 24-hour ambulatory systolic and diastolic blood pressure 
(ambulatory blood pressure monitoring - ABPM) at one (1), three (3), six (6), twelve 
(12), eighteen (18) and twenty-four (24) months post-treatment versus baseline. 
• 
The composite MAE rate at 1, 3, 6, 12, 18 and 24 months post-procedure defined as: 
o All-causes of death 
o Hospitalization for hypertensive crisis post-titration 
o Any device or procedure-related serious adverse event 
• 
The mean reduction in office diastolic and systolic blood pressure, and diastolic and 
systolic blood pressure at 1, 3, 6, 12, 18, and 24 months. 
• 
Changes in antihypertensive medicines/doses through 1, 3, 6, 12, 18 and 24 months 
post-implantation as analyzed by Daily Defined Dosages (WHO Definition) and total 
medications. 
• 
Quality of Life as measured by the Medical Outcomes Study 36-Item Short-Form Health 
Survey (SF-36). 
4.4. Number of Subjects and Sites 
Up to 10 subjects may be enrolled at up to 3 clinical study centers. 
4.5. Study Population 
The study population comprises subjects with resistant hypertension as defined in the 2018 
ESC/ESH Guidelines for the management of arterial hypertension. 
4.6. Enrollment Criteria 
A potential subject must meet all of the criteria as outlined below in order to be considered 
eligible to participate in this study. 
4.6.1. Inclusion Criteria 
Subjects eligible to participate must meet all of the following criteria at screening and / or 
baseline visits: 
1. Aged 18 years or older and less than 80 years of age. 
2. Persistent office systolic blood pressure (SBP) ≥ 140 mm Hg and diastolic blood 
pressure (DBP) > 90 mm Hg on antihypertensive medicines on two visits separated 
by a minimum of four weeks.  
3. Mean 24-hour systolic ABPM ≥ 130 mm Hg and mean 24 hour diastolic ABPM ≥ 80 
mm Hg conducted after direct observed therapy to confirm that antihypertensive 
medicines were taken as prescribed during the ABPM measurement. 
4. Stable drug regimen of 3 antihypertensive medicines consisting of a renin-
angiotensin blocker(ACE) or Angiotensin II Receptor Blocker (ARBs), a calcium 
channel blocker (CCB), a diuretic and spironolactone for 4 weeks at treatment. If 
spironolactone is not tolerated, the regimen must include instead the addition of 

 
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further 
diuretic 
therapy 
with 
either 
eplerenone, 
amiloride, 
higher-dose 
thiazide/thiazide-like diuretic or a loop diuretic, or the addition of bisoprolol or 
doxazosin. If none of these medicines are tolerated, then patients on a 3-drug 
regimen may be included. 
5. The Investigator has confirmed that the patient has already tried and/or is not 
suitable for treatment with currently CE-marked device-based therapies for 
resistant hypertension as an alternative to baroloop therapy. 
6. Willingness and ability to comply with follow-up requirements. 
7. Signed informed consent. 
4.6.2. Exclusion Criteria 
Potential subjects with one or more of the following criteria shall be excluded from the study 
even if they meet the inclusion criteria: 
1. Any patient in whom access to the vagal nerve is limited by the size of the vagus (a 
size not compatible with the baroloop cuff). 
2. Any patient with a history of injury to the vagus nerve or its branches (e.g., the recurrent 
laryngeal nerve). 
3. Secondary causes of hypertension. 
4. Calculated eGFR < 30 mL/min/1.73m2. 
5. Type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus (HbA1c > 10%). 
6. One or more episodes of orthostatic hypotension in the past year 
7. Requirement for chronic oxygen therapy or mechanical ventilation. 
8. Untreated (no CPAP therapy) sleep apnea (AHI > 15)  
9. Morbid obesity, defined as Body Mass Index >40 kg/m2 or arm circumference 46 cm. 
10. Pacemaker and/or implantable defibrillators. 
11. History of transient ischemic accident or cerebrovascular accident during six (6) months 
prior to screening. 
12. Symptomatic carotid artery disease or > 70% occlusion of either carotid artery; any 
carotid malformation or lesion, a carotid bruit or other abnormal carotid sound. 
13. Prior surgery, radiation therapy or scarring in the neck in the region of the carotid artery 
(e.g., patients with a tracheostomy, extensive thymectomy or thyroid surgery). 
14. Limited mobility of the neck secondary to vertebral disease or prior vertebral surgery, 
including patients who wear a cervical support. 
15. History of heart failure (NYHA class III-IV or ejection fraction < 30%), myocardial 
infarction, unstable angina, coronary bypass or coronary angioplasty during six (6) 
months prior to screening. 
16. Cardiac arrythmias (atrial fibrillation, atrial flutter, etc.) that require anticoagulation or 
interfere with a consistent measurement of blood pressure. 
17. Syncope in the last 6 months. 
18. History of bleeding disorders, thrombocytopenia, hemophilia or significant anemia 
(hemoglobin (Hgb) < 10 gm/dl). 

 
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19. Current anticoagulation therapy (excluding antiplatelet therapy with aspirin as a sole 
therapy). 
20. Works night shifts. 
21. History of unresolved drug or alcohol use. 
22. Active treatment of a psychiatric ailment. 
23. Life expectancy of less than 12 months due to other disease. 
24. Subject has a condition that, in the opinion of the investigator, precludes participation, 
including willingness to comply, with all follow-up procedures. 
25. Participation in another clinical study for which follow-up is currently on-going. 
26. Women who are of child-bearing age or who have the potential to become pregnant 
27. Resting heart rate of <40 beats/min for patients on beta blockers or <60 beats/min for 
all other patients, confirmed at both baseline visits. 
28. Baroreflex failure or autonomic neuropathy  
29. Symptomatic, uncontrolled bradyarrhythmias   
30. Atrioventricular block of any grade  
31. Patients who are treated with Pacemaker and/or implantable defibrillators  
32. Presence of a vagus stimulator   
33. Patients who are likely to require magnetic resonance imaging (MRI) of the cervical 
area 
34. Occupational exposure to high levels of non-ionizing radiation that may interfere with 
therapy  
35. Patients with a limited ability to read, understand and execute adjustment procedures 
(for example, persons suffering from dementia). 
36. Likely exposure to diathermy. 
 
4.7. Informed consent 
Subjects who meet the entry criteria will be asked to sign a Patient Informed Consent form as 
approved by the relevant regulatory authorities before any study-specific tests or procedures 
are performed. The Investigator or a designated member of his / her staff should approach the 
subject to obtain written informed consent. As far as possible, non-technical language should 
be used that is understandable to the subject. The background of the proposed study and the 
benefits and risks of the procedures and study should be explained. The subject should be 
provided with ample time to read the consent form and discuss it with his / her family and/or 
physician. The subject shall be informed that his / her participation in the clinical investigation 
is completely voluntary, may be withdrawn at any time without consequences, and is 
confidential. The Informed Consent Form must be read and understood by the subject and the 
subject’s questions answered and must include information and a separate explicit consent 
regarding the patient’s rights under the GDPR and/or national data protection laws or 
regulations. The form must be signed and dated by both the subject and Investigator. Each 
subject is to receive a copy of his / her signed and dated Informed Consent Form. A copy of 
the approved informed consent form along with a copy of each patient’s signed consent form 
will be maintained by each Investigator in a designated clinical study administrative file. 

 
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Investigator Study personnel should explain that even if a subject agrees to participate in the 
study and signs the Patient Informed Consent form, the subject may not be eligible to 
participate if he / she fails to meet the inclusion or exclusion criteria. 
Once written consent has been obtained, the subject’s information will be entered on a Consent 
and Screening Log, which will be maintained at each site. All subjects who provide written 
informed consent will be entered on the log regardless of whether or not they are enrolled in 
the study. 
As appropriate, important and new information will be provided to new and existing subjects 
throughout the duration of the study. 
4.8. Unique Study Identification Code 
Each subject will be assigned a unique study identification code in an effort to protect subject 
confidential information. The unique study identity code will be pseudonymized and will not 
include date of birth or subject’s first and last initials and will be used to link study data and 
other study information to the subject in lieu of the subject name. The Subject Name Log will 
be used to link the unique study identity code to the subject and will be maintained at each 
site. This log will remain confidential and will not be provided to the Sponsor, but only used for 
reference when monitoring at the study site. 
4.9. Subject Recruitment 
Subjects who present with resistant hypertension consistent with the 2018 ESC/ESH 
Guidelines for the management of arterial hypertension will be considered potential study 
candidates. The Sponsor does not intend to advertise or otherwise actively recruit subjects. 
4.10. 
Subject Reimbursement 
Subjects will not be reimbursed or compensated for participating in the trial. Reasonable travel 
costs associated with follow-up visits may be reimbursed upon request. 
4.11. 
Enrollment 
Patient eligibility will be confirmed prior to insertion of the investigational device, and subjects 
will be considered enrolled in the study at the time that the skin is broken to implant the 
baroloop System. 
Subjects who sign consent but are excluded before enrollment will not be included in the 
primary analysis of the study endpoints. The reason for exclusion will be documented in the 
Consent and Screening Log and the consent document maintained in the site’s study records. 
4.12. 
Duration of Subject Participation 
Subjects enrolled in the trial will participate for approximately 2 years and 2 months. 
4.13. 
Study Duration 
This study is expected to enroll up to 10 subjects within approximately 36 months. The closeout 
phase of the study is expected to be completed within 6 months following the last subject 
follow-up visit. The total duration of the study is estimated to be 5.5 years. 

 
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4.14. 
Withdrawal of Subjects 
Each subject may voluntarily withdraw his / her participation from the study at any time. 
Investigators may discontinue a subject’s participation in the study as deemed appropriate for 
safety considerations and / or if the subject’s medical condition contraindicates further study 
participation. All enrolled subjects will undergo the complete study follow-up for safety 
evaluation. 
4.15. 
Loss to Follow-up Considerations 
A subject will be considered lost to follow-up and terminated from the study when all of the 
following criteria have been met: 
➢ Documentation of three unsuccessful attempts on three different days over a period of 
three (3) months by the Investigator or his / her designee to contact the subject or next 
of kin, one of which should be by certified mail with signature confirmation. 
➢ Prior agreement of the Sponsor to remove the subject from the clinical investigation. 
If permitted by the subject in the informed consent, contact with the family doctor may be made 
only after three unsuccessful attempts have been made to contact the study subject.  
4.16. 
Subject Confidentiality 
All information concerning subjects or their participation in this trial will be considered 
confidential. Only authorized representatives, designated personnel of the CRO, designated 
consultants, or regulatory agencies will have access to these confidential files. Subject names 
or other non-pseudonymous data that could directly identify a patient will not be captured on 
the case report forms. In addition, all patient identifiers except the unique study identification 
code will be redacted from any X-ray, CT and MRI images submitted from the participating site 
to the Sponsor or the Sponsor’s designated reviewers for analysis. 
4.17. 
Study Procedures 
4.17.1. Screening and Enrollment 
The overall screening and enrollment scheme for the study is shown in schematic form in 
Figure 2 and identifies the various phases for screening, consenting, continued eligibility 
assessment and assignment into the subject cohorts for the study. 
 
 

 
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Figure 2: baroloop Trial Screening and Enrollment Scheme 
 
 
4.17.2. Consent Phase 
Prior to obtaining written informed consent, the subject’s existing medical records may be 
reviewed by the site to determine whether or not the subject might be an acceptable candidate 
for this study. 
If initial review of the medical records indicate that the subject may be eligible (i.e., the patient 
has uncontrolled or resistant hypertension as defined in the 2018 ESC/ESH Guidelines for the 
management of arterial hypertension), the informed consent process may commence. 

 
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4.17.3. Screening Phase 
Each patient’s medical records will be reviewed to assess compliance with the eligibility of the 
baroloop Study. Patients who are eligible based on the study enrollment criteria will proceed 
to the next phase of the study. 
4.17.4. Eligibility Assessments 
Baseline evaluation will be performed after the subject has provided written informed consent 
in order to ensure that the subject is an appropriate candidate for this study and to obtain 
baseline values for study endpoint evaluation. 
If the subject continues to meet the study’s enrollment criteria and continues to be willing and 
able to participate in the study protocol, the subject will be enrolled. 
All subjects will undergo a series of baseline evaluations (if not already available as part of the 
existing medical records). Baseline visit and data collection can occur anytime within 6 months 
before the implantation procedure of the baroloop System (see Figure 2). 
4.18. 
Procedural Treatment and Timing 
4.18.1. Medication Regimen 
All participants in the study will be on a minimum of three (3) anti-hypertensive drugs such as, 
but not limited to, a diuretic (usually a thiazide or loop diuretic), a calcium channel blocker and 
an angiotensin converting enzyme inhibitor. Patients may be on additional antihypertensive 
drugs such as alpha- or beta-blockers, direct acting vasodilators angiotensin receptor blockers 
or combinations of these drugs. Where possible, simpler (fewer drug) regimens are preferred. 
Regardless of the of the particular three or greater combination of drugs, every effort should 
be made to maintain each patient on a stable regimen of antihypertensive medicines during 
the course of the study. 
4.19. 
Baseline Assessment: Visit 1 
The following information will be assessed, and the documentation will be maintained as 
source records at the study site: 
• 
Medical history; 
• 
Office cuff blood pressure; 
• 
Check for orthostatic blood pressure and orthostatic pulse assessments; 
• 
Current medication history including all hypertensive medication; 
• 
Physical examination; 
• 
Laboratory testing;  
• 
Quality of Life SF-36 questionnaire. 
 
4.20. 
Baseline Assessment: Visit 2 (four weeks after visit 1) 
• 
Office cuff blood pressure; 

 
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• 
Current medication history including all hypertensive medication including changes 
of medication regimen; 
• 
Review and assessment of adverse events; 
• 
24 hour ambulatory blood pressure measurement (24hr ABPM) after observed 
therapy for hypertension.  
• 
Medication compliance testing 
• 
Quality of Life SF-36 questionnaire. 
 
4.21. 
Day of Implantation procedure  
• 
Physical examination; 
• 
Changes of medication regimen; 
• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; and 
• 
Assessment of all Inclusion/Exclusion criteria. 
 
4.22. 
baroloop System Implantation Procedure 
The implantation operation should be performed as described in the baroloop Implantation 
Manual (BL_IM_Implantation_Manual_FIH). In brief, the procedure should be performed using 
a neurosurgical microscope after the initial incision in the left side of the neck is made over the 
location of the vagus nerve (from point 3 on). A subcutaneous pocket (size 6 x 7 cm) should 
be created under the skin and over the pectoralis muscle below the left clavicle to house the 
IPG. To access the left vagal nerve, a horizontal cervical skin incision 4-5 cm in length on the 
left neck should be made between the clavicle and mandible. The tissue should be carefully 
dissected to expose the neurovascular sheath containing the vagus. The sheath should be 
opened to expose the left vagus nerve over a length of approximately 3 cm. A neuroloop Cuff 
size should be select that matches the approximate size of the vagal nerve diameter. Before 
placing the Cuff, the Pill should be fixed to the underlying tissue according to the instructions 
in the baroloop Implantation Manual. After fixing the Pill, the Cuff should be wrapped around 
the vagus nerve, and proper rim alignment of the Cuff edges should be reviewed to make sure 
that both ends of the cuff are square and perpendicular to the long axis of the cuff. Strain relief 
loops in the Cable leading to the IPG should be created using the suture sleeves. The Lead 
should be passed subcutaneously from the cervical incision site to the pectoral pocket where 
the IPG is placed. The Connector should be cautiously passed through tunnelling device to the 
subcutaneous pectoral pocket. After removing the Tunnelling device by pulling in pectoral 
direction, which was inserted from the pectoral pocket to the neck, the Connector to the IPG 
should be cleaned, if necessary, prior to connecting it to the IPG. The Connector should be 
fixed in the appropriate receiving slot in the IPG using the torque key. Perform initial device 
testing, described below, before closing the surgical incisions. 
After the Cuff, Pill, Lead and IPG are connected, the device must be tested. Please see the 
Implantation Manual and Programmer Manual for complete details of testing. Briefly, an 
impedance test should be performed before the IPG is placed. If impedance test is ‘Passed’, 

 
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place the IPG in the prepared pectoral pocket. If impedance is ‘Failed’, follow the steps in flow 
chart in the Implantation Manual to obtain a ‘Passed’ impedance test. After the Impedance test 
is passed, place the IPG in the pectoral pocket with the neuroloop logo pointing to the skin 
surface. Perform a 2nd impedance test. If impedance ‘Passed’, follow the tests. If impedance 
‘Failed’, follow steps in Implantation Manual flow chart to obtain a ‘Passed’ impedance test. 
Once the impedance tests have been passed, both surgical sites should be irrigated with saline 
before closure of each surgical incision. Incision closure should be completed with sutures in 
layers, and a stapler must NOT be used to close the wounds! 
After wound closure, a brief ‘intraoperative’ stimulation test must be performed to confirm 
proper functioning of the neuroloop device. Please consult the Programmer Manual and 
Implantation Manual for detailed instructions (BL_PM_Programmer_Manual_FIH and the 
BL_IM_Implantation_Manual_FIH). To begin, place the Charger within its sterile cover on the 
implanted IPG. Use the programmer to select ‘Surgery Mode’ and login into the Programmer. 
The Charger and the IPG will connect automatically, which will be reflected on the Programmer 
screen. Once the ‘Surgery Mode’ screen appears, press the ‘START STIMULATION TEST’ 
button on the Programmer screen. The electrode that is currently being tested will be 
highlighted. The stimulation or pause time is displayed. The stimulation time for each electrode 
is 30 seconds, and the pause time between two stimulations is 30 seconds. The overall test 
time, if all electrodes are functional, will be 12 minutes. Once the test is finished, completion of 
the test is displayed in the Programmer screen. The data from the intraoperative testing may 
be downloaded for analysis by neuroloop. 
Please note that intra-operative testing is done to confirm that the device is properly connected, 
that the batteries effectively drive and control the device, and that the device contacts the 
proper therapeutic anatomical target. The stimulation parameters used to test the device and 
its relationship to each patient’s anatomy in the operating room are not suitable as a guide for 
subsequent therapy. The nature of the anatomical relationship between the electrode(s) and 
the device is modified by the processes of wound granulation and healing so that the 
impedance characteristics and the exact anatomical relationship of the electrode to the target 
neurological tissue change during the post-operative period. As with other neuro-modulatory 
devices, the baroloop device is tested in the operating room, but the therapeutic stimulation 
delivered by the device is titrated only after ca. 2-3 weeks of healing has occurred. The intra-
operative stimulation characteristics are not used to guide the titration to therapeutic effect - 
the device is tested in the operating room to make sure that it is operational, and the actual 
titration of stimulation to modify blood pressure will begin only after a period of post-surgical 
healing. 
WARNING: Be aware of severe side effects, such as profound bradycardia.  
If a severe side effect occurs (including severe bradycardia), stimulation must be stopped 
immediately, and appropriate corrective actions taken.  
Any stimulation-related effects (blood pressure decrease, heart rate decrease, or any other 
possible response due to stimulation) should be recorded in the study Case Report Forms. 
After intraoperative impedance, self-test and stimulation testing, set the IPG in shelf-mode by 
selecting ‘Activate Shelf Mode’ in the status dropdown menu on the Programmer screen. 
WARNING: The IPG must be in INACTIVE MODE after implantation during the recovery from 
surgery. 

 
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4.23. 
14-Day Follow-up Visit (+2 / -3 days) 
• 
Clinical assessment of the subject; 
• 
Physical examination; 
• 
Changes of medication regimen; 
• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; and 
• 
Initial testing and titration of stimulation to achieve up to a 20% reduction in systolic 
blood pressure or age-adjusted 2018 ESC/ESH treatment target office blood 
pressure (OBP), whichever blood pressure achieved during stimulation is lower. 
N.B.:  
1. If the patient is not judged to be ready for a first titration on day 14, the patient may return 
on or before day 21 for the first titration. 
2.The first titration of blood pressure using baroloop stimulation (not earlier than 14 days after 
surgery when wound healing is complete) will be followed by a brief, one day hospitalization to 
observe the initial response to baroloop therapy. 
4.24. 
Stimulation Settings/Titration First-in-Human 
Blood pressure titration using VNS will take several ‘titration sessions’ to obtain optimal control 
of blood pressure. The titration sessions will take place weekly after the first titration is 
completed 14 days after surgery until the blood pressure has reached a target value less than 
the age-adjusted 2018 ESC/ESH treatment target office blood pressure (OBP). In between 
each titration session for the first four (4) weeks, the patient will return to the hospital or office 
where the titration takes place to have the IPG recharged, data downloaded from the IPG, and 
a check of OBP. Thus, there will be two alternating types of visits each week for the first 4 
weeks of titration, one for titration, data downloading from the IPG and IPG charging and one 
for an OBP check, data downloading from the IPG and IPG charging.  
After 4 weeks, titration may be done weekly, and the IPG charging may be done weekly when 
the titration is conducted. The titration process will continue until the target OBP is reached or 
the patient’s responses to VNS are sufficiently reliable to allow less frequent follow-up after 
each new titration of OBP. Once a stable, target OBP is reached, blood pressure follow-up 
may occur at an interval appropriate for blood pressure control as determined by the treating 
physician. 
During the first titration of baroloop stimulation, the Investigator should explore as fully as 
possible the range of responses to different electrode positions and stimulation settings so that 
an optimal set of stimulation settings may be selected with full knowledge of the range of 
responses in each subject at each visit. 
During the titration of blood pressure responses to baroloop stimulation, each subject’s blood 
pressure should be monitored continuously using a Finapres device. The patient should be 
supine and blood pressure and heart rate should be recorded continuously. After stable BP 
and HR are observed in the patient, the titration of the VNS may begin. Blood pressure 
responses to specific stimulation tests should be recorded by the Finapres device, and it is 
also important to record the baseline blood pressure and recovery periods after stimulation to 
characterize each patient’s response to baroloop stimulation. The blood pressure should also 

 
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be measured using an arm cuff 60 seconds after the onset of the stimulation sequence. Each 
titration stimulation should last at least 2 minutes, and the arm cuff blood pressure should be 
measured 1 minute after the stimulation starts while the stimulation is still present, and once 
again 1 minute after the titration stimulation has stopped. These values establish the correlation 
between arm cuff blood pressure and Finapres readings, which will be useful for subsequent 
titration visits in each patient. 
The Cuff completely surrounds the vagus, and some combinations of stimulation parameters 
can optimally increase the effective depth of penetration of the stimulating electric field into the 
vagus nerve. The IPG provides a biphasic charge-balanced stimulation to achieve cathodal 
activation of the vagus nerve, and the IPG has been programmed to provide specific 
combinations of the following stimulation parameters, so called presets, which may be selected 
using the Programmer: 
- 
Amplitude in µA 
- 
Pulse width in µs 
- 
Repetition rate in Hz 
- 
Duty cycles in ratios of ON-OFF-Sequences 
 

 
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The purpose of titration is to determine which electrode(s) and which preset stimulation 
parameters (which deliver different levels of energy and strength of stimulation) provide an 
optimal blood pressure reduction at the lowest and most effect stimulation intensity. The preset 
collections of stimulation parameters were derived from animal studies and represent a limited 
range of the values tested in animals so that the minimally effective stimulation parameters 
determined during animal studies may be used in humans. The general strategy during the 
titration should be to select all individual active electrodes (inactive electrodes do not need to 
be tested) and deliver a low and a high intensity stimulation from among the preset stimulation 
sequences provided by the Sponsor to define the range of blood pressure responses possible 
in each patient. Thus, the presets may be used during the process of selecting an optimal dose 

 
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of baroloop stimulation, and the preset stimulation that provides an effect blood pressure 
reduction may be selected for therapeutic stimulation.  
The immediate goal of each titration is to reduce the blood pressure slowly and modestly over 
a sequence of weeks. Therefore, the reduction in blood pressure should not exceed 20% of 
the blood pressure preceding the titration effort. Moreover, if the blood pressure at the time the 
patient returns for a titration visit is at or below the age-adjusted OBP target values described 
in the 2018 ESC/EHS Guidelines, then no additional titration need be done. If this is obtained 
during any one of the titration tests described above, the stimulation characteristics that 
achieved a blood pressure less than the age-adjusted OBP may be used as the therapeutic 
level of stimulation until the next follow-up visit so long as the titrated blood pressure is not 
lower than 80% of the baseline value just prior to the titration, and the patient has no symptoms 
of dizziness, orthostatic hypotension or other adverse effects.  
If a 20% reduction in baseline blood pressure is greater than the age-adjusted OBP target, 
then the target blood pressure should be approached in a series of incremental steps in which 
an intermediate target blood pressure not below 80% of the baseline blood pressure is 
targeted. This intermediate target blood pressure should then be maintained for a week (at 
least) until the next visit for further titration, when a further 20% reduction in blood pressure 
may be targeted so long as the patient has no symptoms of dizziness, orthostatic hypotension 
or other adverse effects 
Once an effective set of stimulation parameters has been selected, this setting should be used 
for treatment until the next study visit, when the blood pressure response can be re-evaluated, 
and stimulation parameters may be adjusted as appropriate to reach the goal of a blood 
pressure less than the age-adjusted OBP target. 
Once the first treatment stimulation level has been selected, the patient should be observed in 
the hospital for 24 hours (as noted above). The titration of blood pressure will be retested after 
24 hours prior to discharge following the titration strategy described above over a more limited 
range of electrode combinations and preset stimulation values. If the treatment is well tolerated 
and no adverse effects of VNS are identified during the hospital stay, the patient may be 
discharged on the prescribed pattern of VNS. Patients need not be hospitalized following 
subsequent blood pressure/stimulation titrations so long as the patient has no symptoms of 
dizziness, orthostatic hypotension or other adverse effects. 
It is the Sponsor’s expectation that most patients will achieve  an OBP less than the age-
adjusted target of hypertension treatment within a small number of weekly titration sessions. If 
the titration process persists beyond 12 sessions (~ 3 months), it is permissible to extend the 
interval between titrations up to six weeks. The patient and physician may work together to 
achieve a titration schedule that achieves the age-adjusted target OBP as quickly as is safe. 
N.B.: The IPG should be charged at every visit to the physician’s office for follow-up. In the 
first four weeks of titration, the IPG will be recharged twice a week. After four weeks of titration, 
the IPG may be charged weekly when the well-being of the patient will also be assessed. There 
is no home charging possible in this First in Human Study. 
4.25. 
Follow-up titration every 7 days (± 2-3 days) 
• 
Clinical assessment of the subject; 
• 
Physical examination; 
• 
Changes of medication regimen; 

 
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• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; and 
• 
Titration of vagal nerve stimulation should be repeated weekly to achieve up to a 
20% reduction in systolic blood pressure or office BP < the age-adjusted 2018 
ESC/ESH treatment target office blood pressure (OBP), whichever blood pressure 
achieved during stimulation is lower. The titration protocol described above should 
be followed each time the patient returns for adjustment of baroloop stimulation. 
The data from the IPG will also be downloaded at each visit for subsequent 
analysis. 
4.26. 
30-Day Follow-up Visit (+7 / -7 days) 
• 
Clinical assessment of the subject; 
• 
Physical examination; 
• 
Changes of medication regimen; 
• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; 
• 
Medication compliance testing; 
• 
24hr ABPM after observed therapy for hypertension; 
• 
Quality of Life SF-36 questionnaire; and 
• Further testing and titration of stimulation to achieve an OBP less than the age-
adjusted target of hypertension treatment, as described in the titration directions. 
4.27. 
90-Day Follow-up Visit (+14 / -14 days) 
• 
Clinical assessment of the subject;  
• 
Physical examination;  
• 
Changes of medication regimen;  
• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure;  
• 
Medication compliance testing;  
• 
24hr ABPM after observed therapy for hypertension;  
• 
Quality of Life SF-36 questionnaire; and  
• 
Further testing and titration of stimulation to achieve an OBP less than the age-
adjusted target of hypertension treatment, as described in the titration directions 
4.28. 
180-Day Follow-up Visit (+14 / -14 days) 
• 
Clinical assessment of the subject; 
• 
Physical examination; 
• 
Changes of medication regimen; 

 
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• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; 
• 
Medication compliance testing; 
• 
24hr ABPM after observed therapy for hypertension; 
• 
Quality of Life SF-36 questionnaire; and  
• 
Further testing and titration of stimulation to achieve an OBP less than the age-
adjusted target of hypertension treatment, as described in the titration directions 
4.29. 
365-Day Follow-up Visit (+14 / -14 days) 
• 
Clinical assessment of the subject; 
• 
Physical examination; 
• 
Changes of medication regimen; 
• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; 
• 
Medication compliance testing; 
• 
24hr ABPM after observed therapy for hypertension; 
• 
Quality of Life SF-36 questionnaire; and 
• 
Further testing and titration of stimulation to achieve an OBP less than the age-
adjusted target of hypertension treatment, as described in the titration directions 
4.30. 
Long Term Follow-up Visits – 18 and 24-Month Follow-up Visit (+14 
/ -14 days) 
• 
Clinical assessment of the subject; 
• 
Physical examination; 
• 
Changes of medication regimen; 
• 
Review and assessment of adverse events; 
• 
Office cuff blood pressure; 
• 
Medication compliance testing; 
• 
24hr ABPM after observed therapy for hypertension; 
• 
Quality of Life SF-36 questionnaire; and 
• 
Further testing and titration of stimulation to achieve n OBP less than the age-
adjusted target of hypertension treatment, as described in the titration directions 
4.31. 
Unscheduled Follow-up Visit 
If an unscheduled follow-up visit is required, the study subject should be assessed for new or 
unresolved adverse events. Any testing required, including imaging studies, should be 
provided to the study Sponsor for DSMB adjudication. Office cuff blood pressure will be taken 

 
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and will be reviewed. Change of medications, diagnostic test results, or interventions should 
be documented. 
4.32. 
4.32 Schedule of Study Visits and Assessments 
Table 3: Schedule of Study Visits and Assessments 
 
 
Follow-up 
Long Term 
Follow-up 
Visit 
Visit 1 
Visit 2 
Visit 
3/ 
Procedure 
Discharge 
14 Days (+2/-3 
days) 
Weekly Office 
visits (1x/2x)* 
30 Days (+/- 7 
days) 
90 Days (+/- 14 
days) 
180 Days (+/- 
14 days) 
365 Days (+/- 
14 days) 
18, and  24, 
Months 
(+/- 14 days) 
Eligibility 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Informed Consent 
✓ 
 
 
 
 
 
 
 
 
 
 
Medical History  
✓ 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
✓ 
 
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Concomitant 
medications 
✓ 
✓ 
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Baseline 12 lead 
ECG 
✓ 
 
 
 
 
 
 
 
 
 
 
Blood Testing 
✓ 
 
 
✓ 
 
 
 
 
 
 
 
24 hour ABPM 
 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Medication 
compliance 
testing 
 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
Quality of Life SF-
36 
✓ 
✓ 
 
 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
neuroloop 
implantation 
 
 
✓ 
 
 
 
 
 
 
 
 
neuroloop 
titration*,** 
 
 
 
 
✓ 
(✓) 
✓ 
✓ 
✓ 
✓ 
✓ 
IPG 
recharging 
and 
data 
downloading* 
 
 
 
 
✓ 
✓ 
 
 
 
 
 
Office 
cuff 
BP 
Measurement 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Discharge  
 
 
 
✓ 
 
 
 
 
 
 
 
Adverse Events 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
*Titration after Day 14 takes place 1x per week. The second weekly visit through Day 30 is for Office BP and IPG 
battery charging only. After Day 30, only one visit per week for charging and (if necessary) titration is required. 
**The heart rate and blood pressure will be recorded using a Finapres device during each titration. 

 
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4.33 
Study Completion 
After the subject has completed the 2-Year follow-up visit, the Subject Termination must be 
recorded and completed within the EDS. During the course of the study, it is possible that 
subjects will be withdrawn from the study early. Factors leading to subject withdrawal may 
include, but are not limited to, the following: 
• 
Subject Withdrawal - A subject may voluntarily withdraw from the study at any time 
without affecting his or her future medical treatment or benefits. In addition, the 
Investigator may withdraw a subject from the study if the subject refuses further 
testing or follow-up evaluations, or for any other reason as determined by the 
Investigator.   
• 
Subject Lost to Follow-Up – If the Investigator has attempted to contact a subject 
at least three (3) times and receives no response, the subject may be lost to follow-
up. The research staff should document at minimum three (3) attempts to contact the 
subject prior to terminating the subject from the trial, one of which should be a 
registered letter to the subject’s address.   
• 
Subject Death - When a subject expires, the Serious Adverse Event and Report of 
Patient Death must be completed in the data collection system. must be completed 
promptly. Source documents such as death summary, autopsy report (if done), and 
a copy of the death certificate should be redacted of personal identifiers and provided 
to the designated clinical monitor and DSMB to describe the cause of the subject’s 
death. The Investigator will notify Sponsor or designated CRO within 24 hours of 
learning of the event. 
The Study Exit Case Report Form should be completed for each study subject, to record date 
and reason for early termination (if subject does not complete the study) or at the final visit (if 
subject completes all study time points). 
The Sponsor or the designated CRO will notify the competent authority of Serious Adverse 
Events in accordance with national regulations and requirements. . 
4.34 
Concomitant medications 
To be eligible for enrollment, study participants be taking a minimum of three (3) anti-
hypertensive medications at the time of entry into the study. Additionally, all subjects will remain 
on at least three (3) anti-hypertensive medications for the duration of the study, ideally the 
same medications at the same dosages. 
Appropriate management of subject’s individual risk factors such as statins, smoking 
cessation, nutrition, diabetes will remain as standard of care and any changes to this regimen 
will be documented by the study team. 
Subjects should be advised of the importance of continuing their medical therapy regimen. 
Subjects should not reduce or stop their anti-hypertensive medication dosage until the 6-month 
time point, at which time the Principal Investigator may decide to reduce medication per the 
site’s standard of care protocol. 
All medications will be recorded on the Concomitant Medication log.  

 
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4.35 
Study Exit or Premature Withdrawal 
Subjects will be exited from the study by completion of a Study Exit  form in the data collection 
system at the time of study completion provided the subject has not experienced an adverse 
event that is ongoing and unexplained. 
Subjects may be terminated or withdrawn from the study early for, including but not limited to, 
the following reasons: 
• 
Subject death. 
• 
Voluntary withdrawal – meaning that the subject voluntarily chooses not to further 
participate in the study. 
• 
Lost to follow-up – meaning that the subject is more than 14 days late to a study 
visit and 3 documented attempts to contact the subject are unsuccessful. A subject 
who misses a study visit but attends a subsequent visit will no longer be considered 
lost to follow-up. A missed visit will be considered a protocol deviation and the 
deviation will be documented and reported. 
• 
In the physician’s opinion, it is not in the best interest of the subject to continue 
study participation. 
All subjects enrolled (including those withdrawn or lost to follow-up) shall be accounted for and 
documented. 
5. Risk Benefit Assessment 
Sponsor has conducted an analysis of the benefits and risks of the baroloop System and 
procedures necessary for implantation and use of the baroloop System. A detailed Risk 
Assessment has been completed, and the conclusion of this review is that this investigational  
study is justified because the overall potential benefit to the population outweighs its attendant 
risks. 
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) 

 
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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 

 
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• 
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. 

 
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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. 
6. Statistical Analysis Plan 
6.1. Overview 
The primary objective of this study is to characterize the safety and feasibility of the baroloop 
System in subjects with uncontrolled or resistant hypertension. All subjects will be followed on 
an intent-to-treat basis (ITT). The device performance will also be assessed based on a per-
protocol analysis of the primary safety and feasibility endpoints and secondary efficacy 
endpoints. An intent-to-treat analysis, along with other secondary analyses, will also be 
completed and reported. 
This is not a hypothesis driven study, and no formal power analysis or hypothesis-driven 
statistical analysis has or will be performed. Standard summary statistics will be calculated for 
all study variables. For continuous variables, statistics will include means, standard deviations, 
medians and ranges. Categorical variables will be summarized using frequency distributions. 
The primary endpoints will be analyzed on an intent-to-treat (ITT) basis, for which data from all 
subjects enrolled will be included. In order to evaluate a true treatment effect, the primary 
analysis will include those subjects achieving technical success, the definition of which 
includes successful completion of the study procedure. 
If there are no more than 4 failures to implant, combined with a safety level that is determined 
by the independent DSMB to be acceptable, together with any reduction in blood pressure as 
a result of the baroloop therapy, this will be considered a successful outcome to this First-in-
Human study. 
6.2. Primary Safety Endpoint 
The primary safety endpoint is: 
Composite Major Adverse Event (MAE) Rate at six (6) months post-treatment including: 
• 
All-causes of death 

 
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• 
Hospitalization for hypertensive crisis  
• 
Any device or procedure-related serious adverse event 
All MAEs to be adjudicated by an independent Data Management Safety Board (DSMB).:  
6.3. Primary Feasibility Endpoint 
The primary feasibility endpoint is technical success, defined as the ability of the baroloop 
System to be placed around a vagal nerve and the ability to stimulate at 14 days post-
implantation. 
6.4. Secondary Endpoints 
• 
The change in blood pressure recorded during intraoperative stimulation at the time of 
implantation. 
• 
Mean reduction in 24-hour ambulatory systolic and diastolic blood pressure 
(ambulatory blood pressure monitoring - ABPM) at one (1), three (3), six (6), twelve 
(12) and eighteen (18) and twenty-four (24) months post-treatment versus baseline. 
• 
The composite MAE rate at 1, 3, 6, 12, 18 and 24 months post-procedure defined: 
o All-causes of death 
o Hospitalization for hypertensive crisis post-titration 
o Any device or procedure-related serious adverse event 
• 
The mean reduction in office diastolic and systolic blood pressure, and diastolic and 
systolic blood pressure at 1, 3, 6, 12, 18, and 24 months. 
• 
Changes in antihypertensive medicines/doses through 1, 3, 6, 12, 18 and 24 months 
post-implantation as analyzed by Daily Defined Dosages (WHO Definition) and total 
medications. 
• 
Quality of Life as measured by the Medical Outcomes Study 36-Iterm Short-Form 
Health Survey (SF-36). 
6.5. Demographic, Safety, Feasibility and Efficacy Data 
Demographic and baseline clinical and disease characteristics will be summarized in tables. 
For continuous variables, the summary will include number, mean, and standard deviation and 
95% confidence intervals. Summaries for categorical variables will include the number and 
percent of subjects in each category. 
6.6. Imputation of Missing Data 
Imputations for missing data in (e.g. withdrawn subjects, loss to follow-up, missing data) will 
not be performed. Analyses will be performed with all available data only. 
7. Adverse Event and Incident Reporting 
The occurrence of Adverse Events will be monitored during this study. All Adverse Events will 
be recorded on the Adverse Event Form and followed until resolved. The study will be 
conducted in accordance with EN ISO 14155: 2018-08: Clinical investigation of medical 
devices for human subjects - Good Clinical Practice. All Serious Adverse Event will be 
adjudicated by an independent DSMB and adjudicated results will be included in the data 
analysis.  

 
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7.1. Adverse Event (AE) 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or 
any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or 
other persons whether or not related to the medical device. This includes events related to the 
device or events related to the procedures involved. 
An Adverse Device Effect is an adverse event related to the use of a medical device, including 
adverse events resulting from insufficient or inadequate Instructions for Use, deployment, 
implantation, installation or operation, or any malfunction of the medical device or any event 
resulting from user error or intentional misuse of the medical device. 
The Investigator is responsible for assessing the severity of the AE, the causal relationship 
between any events and the clinical study procedure, activities or device. Additionally, the 
Investigator is responsible for providing appropriate treatment for the event and for adequately 
following the event until resolution. The following categories of adverse event severity are to 
be used: 
• 
Mild: Awareness of a sign or symptom that does not interfere with the subject’s usual 
activity or is transient, resolved without treatment and with no clinical sequelae. 
• 
Moderate: Interferes with the subject’s usual activity. 
• 
Serious: Any fatal or immediately life-threatening clinical experience that requires a 
subject to be hospitalized, or hospitalization is unduly prolonged because of potential 
disability or danger to life or because an intervention has been necessitated. This 
includes any permanently disabling event. 
7.2. Serious Adverse Events (SAE) 
A Serious Adverse Event (SAE) is any problem or unwanted event encountered in a clinical 
trial or a performance evaluation that has led, or could have led, directly or indirectly to death 
or to a serious deterioration in the health of a subject or user or any other person, without 
regard to whether the event was caused by a medical product. The following events (including 
laboratory results and outcome events) will be considered to be SAEs and must immediately 
(within 24 hours) be reported to the study Sponsor and / or designated representative by 
telephone, fax and / or email. These events must be reported whether or not the Investigator 
believes they are related to study procedures, activities or device: 
• 
Death 
• 
Serious deterioration in the health of the subject, that either resulted in 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
o chronic disease 
• 
Fetal distress, fetal death or a congenital physical or mental impairment or birth defect 

 
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7.3. Serious Adverse Device Effect (SADE) 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of the 
consequences of a Serious Adverse Event. 
NOTE: Planned hospitalization for a pre-existing condition, a condition unrelated to the 
treatment or a procedure required by this study, that is without serious deterioration in health, 
is not considered a serious adverse event. 
7.4. Unanticipated Serious Adverse Device Effect (USADE) 
Unanticipated Serious Adverse Device Effect (USADE): Serious adverse device effect 
which, by its nature, incidence, severity or outcome has not been identified in the risk analysis. 
7.5. Anticipated Serious Adverse Device Effect (ASADE) 
Anticipated Serious Adverse Device Effect (ASADE): An effect, which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
7.6. Unanticipated Adverse Device Effect (UADE) 
Unanticipated Adverse Device Effect (UADE): An adverse device effect which by its nature, 
incidence, severity or outcome has not been identified in the risk analysis report. 
7.7. Anticipated Adverse Device Effect (AADE) 
Anticipated Adverse Device Effect (AADE): An effect, which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
7.8. Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Documentation of all AEs / SAEs: All incidents will be captured as a part of this clinical study. 
At each contact with the subject, the Investigator will seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events will 
be recorded immediately on the Adverse Event Form in the data collection system. All clearly 
related signs, symptoms, and abnormal diagnostic procedures results should be recorded. . 
Reporting of SAEs: All SAEs, UADEs and possible device and / or procedure- related adverse 
events must be recorded in the Adverse Event Form in the data collection system by the 
Investigator (or his / her designee) and reported to the Sponsor and its designated 
representative (MAXIS Medical GmbH) within 24 hours via fax or email. The report should 
include: Description of incident, severity, duration, action taken, treatment outcome and 
relationship of the adverse event to the study device, procedure, concomitant medications, 
pre-existing condition, etc. (i.e., unrelated, relation or relationship unknown).  
In the case of serious adverse events (SAE), procedure and / or device failures and 
malfunctions, medical record documentation (e.g., procedure notes, operative notes, discharge 
summary, relevant progress notes, imaging or lab studies) must be provided to the Sponsor 
and its designated representative, if requested .This information shall be faxed or sent by email 
as requested as soon as possible but latest within 24 hours to the MAXIS Medical / Sponsor. 
If appropriate, Sponsor shall inform the Competent Authority and the relevant Ethics 
Committee about the event within the appropriate timelines and in accordance with all national 
regulations. Reporting of Device Failures and Malfunctions  

 
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All reported device malfunctions or failures of the baroloop System are required to be 
documented and must be immediately reported to the study Sponsor or its designated 
representative (MAXIS Medical GmbH) by telephone, fax and / or email within 24 hours. Device 
failures and malfunctions should also be documented in the subject’s medical record. 
Instructions for returning the investigational device will be provided. 
NOTE: Device failures or malfunctions are NOT to be reported as adverse events. However, if 
there is an adverse event that results from a device failure or malfunction, that specific event 
would be recorded in the usual way as per the previous chapter. 
7.9. Documentation, Evaluation and Notification of Serious Adverse Events 
The Investigator shall report all serious adverse events (anticipated or unanticipated) to 
Sponsor and Sponsor’s designated representative within 24 hours upon becoming aware of 
events. 
Authorized Representative / CRO Contact Information: 
MAXIS Medical GmbH 
Stichlingstrasse 1 
60327 Frankfurt am Main 
Germany 
Tel: +49 69 2400 3626 
Fax: +49 69 2400 3627 
Email: maxisoperations@maxismedical.com 
Sponsor: 
  
neuroloop GmbH 
Breisacher Straße 86 
79110 Freiburg im Breisgau 
Tel: + 49 151 7305 5089  
Email: study@neuroloop.de 
The Sponsor and / or its designated representative will ensure compliance with all country-
specific reporting requirements to the appropriate Ethics Committees and Competent 
Authorities. 
8. Monitoring 
The Sponsor or its designated representative, qualified by training and experience, will be 
responsible for monitoring and overseeing the conduct of the trial. The accuracy of all collected 
data will be verified for: 
• 
Eligibility criteria 
• 
Baseline characteristics 
• 
Primary safety and feasibility endpoints 
• 
Adverse events 
• 
Secondary endpoints. 
Source documents including, but not limited to, medical records, office / clinic notes, procedure 
reports, laboratory results, physician and nursing progress notes will be verified. Verification 

 
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and quality of data, monitoring of clinical study progress and Investigator compliance with the 
approved protocol will be conducted by the Sponsor or its designated representative (MAXIS 
Medical GmbH). 
The Sponsor or its designated representative (MAXIS Medical GmbH) must be allowed to visit 
the clinical site and have direct access to all study records throughout the duration of the study. 
The monitor will review all source data and compare them to the data documented in the case 
report forms, in addition to performing a review of the Regulatory Binder and conducting device 
accountability. The Investigator and / or institution will provide direct access to source data / 
documents for trial-related monitoring, audits, and regulatory review and inspection. 
It is important that the Investigator and relevant study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
Additionally, telephone, email contact, and onsite visits will be conducted on a regular basis 
with the Investigator and the site staff to ensure that the protocol is being followed and to 
address any issues that may occur during the trial. 
If a deficiency is noted during the course of the trial the clinical monitor is required to discuss 
the situation with the site and the Sponsor (if required) to secure compliance. 
9. Study Management 
The Sponsor has overall responsibility for the conduct of the study according to EN ISO 14155 
as well as any conditions imposed by local and national regulatory authorities. 
For this study, Sponsor will have direct responsibilities and will delegate other responsibilities 
to appropriate and qualified consultants, contractors and / or Contract Research Organizations 
(CROs). Together, the Sponsor, consultants and CROs will ensure that the study is conducted 
according to the Clinical Investigational Plan and all applicable and governing regulations. All 
personnel to participate in the conduct of this clinical trial will be qualified by education and / or 
experience to perform their tasks. 
9.1. Key Contributors 
9.1.1. Study Sponsor 
neuroloop GmbH 
Breisacher Straße 86 
79110 Freiburg im Breisgau 
Germany 
Tel: +49 761 1543390  
Fax: +49 151 7305 5089 
Email: study@neuroloop.de 
9.1.2. Authorized CRO / Representative 
MAXIS Medical GmbH 
Stichlingstrasse 1 
D-60327 Frankfurt am Main 
Tel.: +49 69 2400 3626 
Fax: +49 69 2400 3627 
Email: maxisoperations@maxismedical.com 

 
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9.1.3. Clinical Sites 
A complete listing of all clinical sites will be maintained by the Sponsor and will be available 
upon request. 
9.2. Ethical Considerations 
The rights, safety and well-being of clinical investigation subjects shall be protected consistent 
with the ethical principles as defined in the Declaration of Helsinki 2013. These principles shall 
prevail over interests of science and society and shall be understood, observed and applied at 
every step in this clinical investigation. 
It is expected that all parties will share in the responsibility for ethical conduct in accordance 
with their respective roles in the investigation. The Sponsor and the Investigator(s) shall avoid 
improper influence or inducement of the subject, monitor, the clinical investigator(s) or other 
parties participating in or contributing to the clinical investigation. 
9.3. Insurance 
The Sponsor will maintain the appropriate and necessary insurance coverage for the duration 
of the study. 
9.4. Study Conduct 
This study will be performed in accordance with EN ISO 14155:2018-08 Clinical investigation 
of medical devices for human subjects, -, the Declaration of Helsinki 2013, Council Directive 
93/42/EEC, and any applicable regional and / or national regulations. The clinical investigation 
shall not begin until the required approval has been obtained from the relevant national 
regulatory authority and the local Ethics Committee. Any additional requirements imposed by 
the regulatory authority or EC shall be followed. 
9.5. Audits and Inspections 
The Principal Investigator will also allow and support representatives of the governing EC, the 
Competent Authority, and other applicable regulatory agencies to inspect all study records, the 
content of the data collection system, and corresponding portions of the subject’s office and / 
or hospital medical records at regular intervals throughout the trial. The Principal Investigator 
will provide direct access to source data / documents. These inspections are for the purpose 
of verifying adherence to the protocol, completeness and exactness of the data and compliance 
with European Union or other regulatory agency regulations. 
The Principal Investigator will inform the Sponsor or the Sponsor’s designee should they be 
inspected by any regulatory agencies. The Sponsor or the Sponsor’s designee will also inform 
the site if they are made aware of a pending inspection by a regulatory agency. 
Audits may also be conducted by the Sponsor or the Sponsor’s designee to evaluate 
compliance with the protocol, written procedures, EN ISO 14155:2018-08, and other applicable 
regulatory requirements. These audits are independent of and separate from routine 
monitoring visits. The audit results will be documented and communicated to relevant parties, 
if applicable. 
9.6. Sponsor Responsibilities 
Sponsor has the overall responsibility of the study and will: 

 
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• 
Select qualified Principal Investigators, clinical investigators and study sites 
• 
Select qualified monitors 
• 
Provide the Investigational Plan and any subsequent amendments 
• 
Provide appropriate information and baroloop System training to Investigators and 
study site staff 
• 
Ensure that all deviations from the Investigational Plan are reviewed with the 
appropriate Investigator(s) and reported in the data collection system and the final 
report and that any necessary preventative or corrective action is taken 
• 
Ensure that all adverse events and all adverse device effects (ADEs) are reported and 
reviewed with the Investigator(s), and where appropriate, that all serious adverse 
events (SAEs) and all serious adverse device effects (SADEs) are appropriately 
reported 
• 
During the course of the investigation, inform in writing all Investigators about adverse 
events and adverse device effects that have been reported to Sponsor (this information 
shall be sent to each Investigator based on perceived risk) 
• 
Promptly inform the Investigators and where applicable, any regulatory authorities, if 
the study is prematurely terminated or suspended and the reason for the termination or 
suspension 
• 
Ensure proper device usage, uniform data collection and protocol compliance 
• 
Provide protocol initiation training to include review of the baroloop system instructions 
for use, the Investigational Plan, entry of complete data into the data collection system, 
and guidelines for obtaining informed consent 
• 
Provide the baroloop System to participating study sites, in quantities to support study 
activities 
• 
Coordinate ongoing communication with CRO(s), consultants and study sites to resolve 
any problems concerning the protocol or data collection 
• 
Every effort will be made to ensure compliance with the protocol 
• 
Retain ownership of all clinical data generated in this study, and control the use of the 
data for purposes of regulatory submissions to CAs 
• 
Protect subject confidentiality 
 
A description of this clinical study will be made available on http://clinicaltrials.gov. 
9.7. Monitor Responsibilities 
The Sponsor has contracted MAXIS Medical as the Clinical Monitor to support the Sponsor in 
implementing and monitoring the clinical investigation until its termination. Clinical monitors, 
qualified by training and experience, will be responsible for monitoring and overseeing the 
conduct of the trial. 
Clinical monitors will conduct site initiation visits at each investigational site to ensure that the 
Principal Investigator and other investigational site personnel involved in the conduct of this 
investigation have received and understood the requirements and contents of the clinical 
investigational protocol, the Investigators Brochure, the patient informed consent form, the data 
collection system, the Instructions for Use and the institution and / or Investigator agreement. 

 
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Clinical monitors will ensure that the site facilities are adequate for the conduct of this 
investigation and that resources, laboratories, equipment and personnel remain adequate 
throughout the investigation. 
The clinical monitors will conduct routine on-site monitoring visits and phone calls to evaluate 
compliance with the protocol, any specific recommendations made by the site’s Ethics 
Committee (EC) and the signed Institution and/or Investigator Agreement and to ensure that 
the protocol is being followed and that any protocol deviations are properly documented on 
respective form. Clinical monitoring will include a verification that Informed Consent Form was 
properly obtained for all enrolled trial participants, a review of clinical records for accuracy and 
completeness, resolution of missing or inconsistent results and a review of source documents. 
Clinical monitoring will include a review of all adverse events and device malfunctions to ensure 
that all information has been reported to the sponsor, EC and regulatory authorities as required 
by this investigational plan and applicable standards and laws. 
The clinical monitor will verify that the information in the data collection system is complete and 
in agreement with the source documentation and other records. The clinical monitor will ensure 
that data has been entered into the data collection system and is signed and dated by the 
investigator. 
The Investigator will make available to the clinical monitor for review all Informed Consent 
documents, all completed information in the data collection system, source documentation and 
other relevant records for all enrolled subjects at the site. It is important that the Investigator 
and other relevant site personnel are available for consultation with the clinical monitors during 
the monitoring visits and that sufficient time is devoted at the site for the monitoring process. 
If a deficiency is noted during an on-site visit or at any other time during the course of the trial, 
the clinical monitor is required to discuss the situation with the Investigator and the Sponsor, 
and to subsequently monitor the implementation of corrective actions that are required to 
address the situation. 
All monitoring activities will be documented by the clinical monitor and will include, at a 
minimum, the date, investigational site visited, names of all personnel involved in the visit, a 
listing of all documents reviewed and a summary of all findings, facts, deviations conclusions 
and recommended actions to be taken. Key findings will be reviewed with the clinical 
investigator. 
Upon completion of the study, a study close out visit will be conducted to ensure that all data 
collection and study requirements are complete. 
9.8. Investigator Responsibilities 
At a minimum, the following documents will be provided by the investigational site to the 
Sponsor prior to study start (consent of the first subject): 
• 
Signed Clinical Trial Agreements 
• 
Signed Financial Disclosure Form 
• 
Signed Clinical Investigational Plan Signature Page 
• 
Relevant regulatory approvals 
• 
Investigator and Co-Investigator’s current Curriculum Vitae 
• 
Any other additional documents as required by the Sponsor 

 
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The Investigator is responsible for ensuring that the investigation is conducted according to all 
signed agreements, the study protocol, governing regulations, data protection regulations, the 
Declaration of Helsinki and any other conditions imposed by the relevant regulatory authorities. 
The Investigator is responsible for maintaining medical and study records for every subject 
participating in the clinical study (including information maintained electronically such as digital 
imaging). The Investigator will also maintain original source documents from which study-
related data are derived. 
The Investigator(s) shall be responsible for the day to day conduct of the investigation as well 
as for the safety and well-being of the human subjects involved in the clinical investigation. 
The Investigator(s) shall: 
• 
Have the resources to conduct the investigation properly 
• 
Ensure that conducting the investigation will not give rise to a conflict of interest 
• 
Obtain from the Sponsor the information which the Investigator(s) judges essential 
about the device and be familiar with this information 
• 
Be well acquainted with the Clinical Investigation Protocol (CIP) before signing the 
signature page 
• 
Support the monitor, auditor, if applicable, in their activities to verify compliance with 
the CIP, to perform source data verification and to correct the information in the data 
collection system where inconsistencies or missing values are identified 
• 
Discuss with the Sponsor management any question of modification of the CIP 
• 
Make sure that the CIP is followed by all responsible for the conduct of the study at his 
/ her institution. Any deviation shall be documented and reported to the study Sponsor 
• 
Make the necessary arrangements to ensure the proper conduct and completion of the 
investigation 
• 
Make the necessary arrangements for emergency treatment, as needed, to protect the 
health and welfare of the subject 
• 
Ensure that appropriate regulatory approval is obtained prior to the start of the 
investigation 
• 
Provide regulatory approvals to the Sponsor 
• 
Inform Sponsor about adverse events in a timely manner 
• 
Endeavor to ensure an adequate recruitment of subjects 
• 
Ensure that the subject has adequate information to give informed consent 
• 
Ensure that informed consent is obtained and documented 
• 
Ensure that clinical records are clearly marked to indicate that the subject is enrolled in 
this study 
• 
Provide subjects with well-defined procedures for any emergency situation and 
safeguard the subject’s interest. Under these circumstances, deviations from the CIP 
shall not require the prior approval of the Sponsor or the national and local regulatory 
authorities. Such deviations shall not be considered as a breach of agreement but shall 
be documented and reported to Sponsor 
• 
Ensure that information which becomes available as a result of the clinical investigation 
which may be of importance to the health of a subject and the continuation of the 

 
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investigation shall be made known to the Sponsor and, if pertinent to the safety or well-
being of the subject, and the private clinician 
• 
Inform the subject and / or the subject’s physician about any premature termination or 
suspension of the investigation with a rationale for study termination 
• 
Have primary responsibility for the accuracy, legibility and security of all investigation 
data, documents and subject records both during and after the investigation 
• 
Sign each subject’s data in the data collection system, as applicable 
• 
Be responsible for the supervision and assignment of duties at his / her clinical center 
• 
Ensure that all investigational devices are kept in a secure location and that all Systems 
are accounted for (number of devices used, discarded and returned to Sponsor) 
9.9. Study Funding 
This clinical investigation is fully funded by the Sponsor. The Sponsor will enter into clinical 
research / clinical trial agreements with all clinical sites participating in the study. Comparable 
research agreements will be executed with core laboratories or other contributors in this clinical 
investigation, if applicable. 
9.10. 
Investigator Training 
The baroloop System is intended for use by experienced physicians. A limited number of 
Investigators at each site will be authorized to use the study device. These Investigators will 
be trained by Sponsor personnel (or designated representative) in a didactic session using a 
‘briefing checklist’ to make sure that all user-related, risk mitigations for the baroloop System 
are fully understood by each investigator. 
9.11. 
Medical Monitor 
A Medical Monitor will be responsible for overseeing the overall progress of the protocol. The 
Medical monitor will review patient recruitment, any Serious Adverse Events, any 
Unanticipated Adverse Events, and non-compliance with the protocol at individual centers. All 
Serious Adverse Events will be reviewed and adjudicated by the Medical Monitor.  
9.12. 
Data Management 
Investigators are responsible for the accurate completion and timely submission of the data 
collected during the trial. All data from the trial will be entered into a data collection system. 
Incoming data will be frequently reviewed to identify inconsistent or missing data and any 
adverse events. Any data issues are to be promptly addressed with the Investigator by the 
CRO (MAXIS Medical). By quality assurance procedures it is ensured that complete, accurate 
and timely data are submitted; that protocol requirements are followed; and that complications, 
adverse events and adverse device effects are correctly reported and investigated, as 
appropriate.  
9.13. 
Study Suspension or Early Termination 
The study will be terminated early if the DSMB determines at any time during the study that 
the composite MAE rate is unacceptably high. Furthermore, the study will be terminated early 
if the number of failures to implant the devices exceeds 4 (four) failures.  
The study can be discontinued at the discretion of the Investigator or study Sponsor for reasons 
including, but not limited to, the following: 

 
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• 
Occurrence of adverse events unknown to date in respect to their nature, severity, or 
duration, or the unexpected incidence of known adverse events 
• 
Obtaining new scientific knowledge that shows that the study is no longer valid or 
necessary 
• 
Insufficient recruitment of subjects 
• 
Unanticipated adverse device effect (UADE) presenting an unreasonable risk to 
subjects (Sponsor may terminate the study immediately) 
• 
Persistent non-compliance with the protocol 
• 
Persistent non-compliance with regulatory requirements 
If the study is discontinued or suspended prematurely, the Sponsor shall promptly inform all 
clinical investigator(s) / investigational center(s) of the termination or suspension and the 
reason(s) for this. The national and local regulatory authorities shall also be informed promptly 
and provided with the reason(s) for the termination or suspension by the Sponsor or by the 
clinical Investigator / investigation center(s). 
9.14. 
Criteria for Suspending / Terminating a Study Center 
Sponsor reserves the right to stop the screening of subjects at a study center at any time after 
the study initiation visit if no subjects have been enrolled or if the center has multiple or severe 
protocol violations without justification or fails to follow remedial actions. 
Possible reasons for suspending / terminating a study center include, but are not limited to: 
• 
Repeated failure to complete case report forms prior to scheduled monitoring visits; 
• 
Failure to obtain written Informed Consent; 
• 
Failure to report SAEs / UADEs to Sponsor within 24 hours of knowledge; 
• 
Loss of (or unaccounted for) investigational product inventory. 
9.15. 
Final Report 
A Final Report will be prepared even if the study is prematurely terminated. The Final Report 
will be submitted to each participating Investigator, and regulatory agencies, as required. 
9.16. 
Protocol Deviations 
A protocol deviation is defined as an event where the Investigator or site personnel did not 
conduct the study according to the protocol. 
Investigators shall be required to obtain prior approval from Sponsor or its designated 
representative before knowingly deviating from the protocol, except where necessary to protect 
the life or physical well-being of a subject in an emergency. Such approval shall be documented 
in writing and maintained in clinical study management and Investigator files. Prior approval is 
generally not expected in situations where unforeseen circumstances are beyond the 
Investigator’s control, (e.g., subject was not available for scheduled follow-up office visit, blood 
sample lost by laboratory, etc.); however, the event is still considered a deviation and will be 
reported in the data collection system. 
Deviations must be reported to Sponsor or designated representative regardless of whether 
medically justifiable, pre- approved by Sponsor or designated representative, or taken to 
protect the subject in an emergency. Subject specific deviations will be reported on the Protocol 

 
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Deviation case report form. Non-subject specific deviations, (e.g., unauthorized use of an 
investigational device outside the study, unauthorized use of an investigational device by a 
physician who has not signed an Investigator agreement or not been trained in the use of the 
device, etc.), will be reported to Sponsor or designated representative. Investigators will also 
adhere to procedures for reporting study deviations to their Ethics Committee or Competent 
Authority, where required, in accordance with their specific reporting policies and procedures. 
Regulations require that Investigators maintain accurate, complete and current records, 
including documents showing the dates of and reasons for each deviation from the protocol. 
10. 
Regulatory Considerations 
10.1. 
Maintaining Records 
The Sponsor will maintain copies of critical correspondence, clinical data, shipment of devices, 
serious adverse device effects and other records related to the clinical trial. 
10.2. 
Site Record Retention Policy 
The Sponsor and clinical sites will maintain all records pertaining to this study in accordance 
with local and national regulations. Prior to the destruction of study records the Investigator or 
his representative should contact the Sponsor to ensure that they no longer need to be 
retained. In addition, Sponsor should be contacted if the Investigator plans to leave the 
investigational site so that arrangements can be made for the handling or transfer of study 
records. 
10.3. 
Ethics Committee (EC) and Competent Authority (CA) Approval 
Regulatory approvals must be obtained prior to enrolment of the first patient. The Sponsor or 
its designated representative is responsible for obtaining regulatory and local approvals for the 
study. The Sponsor or its designated representative will require a copy of any Ethics 
Committee and Competent Authority correspondence, as well as the final approval letter from 
the Ethics Committee and Competent Authority, where applicable. The Sponsor confirms and 
is aware that the Competent Authority may contact the Ethics Committee that is assessing or 
has assessed the application. 
An Investigator may not make protocol changes without prior approval by Sponsor. All 
significant protocol changes that may affect the following must be submitted and approved by 
the Ethics Committee and Competent Authority before initiating the change: 
• 
Validity of the data or information resulting from the completion of the approved 
protocol; 
• 
Relationship of the likely subject risk to benefit relied upon to approve the protocol; 
• 
Scientific soundness of the investigational plan; 
• 
Rights, safety, or welfare of the human subjects involved in the investigation. 
The Sponsor may make certain administrative changes to the protocol without prior approval 
of the relevant Ethics Committee and Competent Authority. The Sponsor will notify all 
investigative sites of such changes to ensure the study continues to be conducted consistently 
across all sites. 

 
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11. 
Publication Policy 
The Sponsor will be responsible for publishing the results of this study in a timely manner. In 
all publications related to this study, credit shall be given to Sponsor for its sponsorship of the 
study, and appropriate recognition of the contribution made by the institutions and principal 
Investigators will be given, as applicable. Sponsor may use, refer to, and disseminate reprints 
of scientific, medical, and other published articles relating to the study, including such reprints 
that disclose the name of Investigators and / or the relevant institution. 
A description of this clinical study will be made available on http://clinicaltrials.gov. 
 
 

 
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12. 
Definitions 
Acute Cardiovascular Surgery 
An immediate transfer from the catheterization lab to the operative room during the initial 
treatment phase due to the need for emergency coronary artery bypass graft surgery, cardiac 
valve surgery, or other vascular surgical intervention. 
Allergic Reaction 
An overreaction of the body’s immune system to a component of an investigational device 
(e.g., nitinol metal, polyester, plastics), contrast agents and / or anesthesia medication given 
to the subject for completion of a study related procedure (e.g., MSCT, angiogram, 
investigational device), which requires medical intervention to treat the allergic reaction. 
Acute Kidney Injury (AKI) 
• 
Stage 1: Increase in serum creatinine to 150–199% (1.5– 1.99 × increase compared 
with baseline) OR increase of ≥0.3 mg / dL (≥26.4 µmol / L) OR Urine output <0.5 ml / 
kg per hour for >6 but <12 hours 
• 
Stage 2: Increase in serum creatinine to 200–299% (2.0– 2.99 × increase compared 
with baseline) OR Urine output <0.5 ml / kg per hour for >12 but <24 hours 
• 
Stage 3: Increase in serum creatinine to ≥300% (>3 × increase compared with baseline) 
OR serum creatinine of ≥4.0 mg / dL (≥354 mmol / L) with an acute increase of at least 
0.5 mg / dL (44 mmol / L) OR Urine output <0.3 ml / kg per hour for ≥24 hours OR 
Anuria for ≥12 hours [Subjects receiving renal replacement therapy are considered to 
meet Stage 3 criteria irrespective of other criteria] 
AV Block 
Atrioventricular block is a type of heart block in which the conduction between the atria and 
ventricles of the heart is impaired. 
Blood Loss 
• 
Major Blood Loss – Defined as transfusion of >2 units packed red blood cells (PRBC)). 
• 
Estimated Procedural Blood Loss – Defined as the total estimated blood loss (mL) 
during the index procedure. Includes blood loss resulting from adjunctive procedures 
performed during the index-procedure. 
Bleeding 
• 
Life-threatening or disabling bleeding: 
o Fatal bleeding (BARC type 5) OR 
o Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or 
pericardial 
necessitating 
pericardiocentesis, 
or 
intramuscular 
with 
compartment syndrome (BARC type 3b and 3c) OR 
o Bleeding causing hypovolemic shock or severe hypotension requiring 
vasopressors or surgery (BARC type 3b) OR 
o Overt source of bleeding with drop in hemoglobin of ≥5 g / dL or whole blood 
or packed red blood cells (RBCs) transfusion ≥4 units* (BARC type 3b) 
o Given one unit of packed RBC typically will raise blood hemoglobin 
concentration by 1 g / dL, an estimated decrease in hemoglobin will be 
calculated; BARC: Bleeding Academic Research Consortium. 

 
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• 
Major bleeding: 
o Overt bleeding either associated with a drop in the hemoglobin level of at 
least 3.0 g / dL or requiring transfusion of 2 or 3 units of whole blood / RBC, 
of causing hospitalization or permanent injury, or requiring surgery AND 
o Does not meet criteria of life-threatening or disabling bleeding. 
• 
Minor bleeding: 
o Any bleeding worthy of clinical mention (e.g. access site hematoma) that 
does not qualify as life-threatening, disabling or major. 
Cerebral Infarction 
Evidence of brain cell death from imaging studies or pathological examination. If there are 
clinical symptoms, then it is a stroke; otherwise, it is an asymptomatic cerebral infarction. 
Death 
Death is divided into two categories and will be reported anytime in a subject’s study 
participation: 
• 
Device or procedure related death - Death related to the Study Device or to any 
procedure (index or subsequent) intended to treat the target. 
• 
Non-device or procedure related death – Death NOT related to any procedure (index 
or subsequent) intended to treat the target or death not related to the Study Device. 
Device Deficiency 
Inadequacy of the Study Device with respect to its identity, quality, durability, reliability, safety 
or performance. Device deficiencies include malfunctions, use errors, and inadequate labeling. 
Explant 
Removal of the study device implant for any reason. 
Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) 
MACCE is defined as: 
• 
All-cause mortality 
• 
All strokes (major, minor and TIA) 
• 
Acute kidney injury – Stage 3 (including renal replacement therapy) 
Myocardial Infarction (MI) 
Peri-procedural MI (≤72 h after the index procedure): 
• 
New ischemic symptoms (e.g. chest pain or shortness of breath), or new ischemic signs 
(e.g. ventricular arrhythmias, new or worsening heart failure, new ST-segment 
changes, hemodynamic instability, new pathological Q waves in at least two contiguous 
leads, imaging evidence of new loss of viable myocardium or new wall motion 
abnormality), 
• 
Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index procedure, 
consisting of at least one sample post-procedure with a peak value exceeding 15x 
upper reference limit (troponin) or 5x for CK-MB. If cardiac biomarkers are increased at 
baseline (> 99th percentile), a further increase of at least 50% post-procedure is 
required AND the peak value must exceed the previously stated limit. 

 
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Spontaneous MI (>72 h after the index procedure): 
Any one of the following criteria: 
• 
Detection of rise and / or fall of cardiac biomarkers (preferably troponin) with at least 
one value above the 99th percentile URL, together with evidence of myocardial 
ischemia with at least one of the following: 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia [new ST-T changes or new left 
bundle branch block [LBBB] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion 
abnormality 
• 
Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and / or evidence of fresh thrombus by coronary 
angiography and / or at autopsy, but death occurring before blood samples could 
be obtained, or at a time before the appearance of cardiac biomarkers in the blood. 
• 
Pathological findings of an acute myocardial infarction. 
Post-Procedure Intensive Care Unit Time 
Number of hours a patient is in an intensive care unit prior to discharge or moving to a step 
down or standard care unit. 
Post-Procedure Length of Hospital Stay 
Number of days from the end of the procedure until the patient is discharged from the hospital. 
This does not include time spent in a skilled care facility. 
Procedural Success 
Successful delivery of the investigational baroloop System placed around a vagal nerve 
providing effective stimulation at 14 days post-implantation. 
Procedure Time 
Number of minutes needed to perform the index procedure from time of initial skin incision to 
time of final skin closure and final intra-operative device testing.  
Renal Failure 
Need for dialysis or a laboratory finding of serum creatinine > 3.5 mg / dL. 
Respiratory Failure 
The need for mechanical ventilation beyond the first 24 hours post-index procedure (and / or 
reintervention) or the need for re-intubation or ventilator support after the first 24 hours (unless 
the subject was ventilator dependent pre-procedure). 
Stroke Diagnostic Criteria: 
• 
Acute episode of a focal or global neurological deficit with at least one of the following: 
Change in level of consciousness, hemiplegia, hemiparesis, numbness or sensory loss 
affecting one side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or 
other neurological signs or symptoms consistent with stroke 

 
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• 
Stroke - Duration of a focal or global neurological deficit ≥24 h; OR, <24 h, if available 
neuroimaging documents a new hemorrhage or infarct; OR the neurological deficit results 
in death 
• 
TIA – Duration of a focal or global neurological deficit < 24 h, any variable neuroimaging 
does not demonstrate a new hemorrhage or infarct 
• 
No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain tumor, 
trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences), to be 
determined by or in conjunction with designated neurologist 
• 
Confirmation of the diagnosis by at least one of the following: 
o Neurologist or neurosurgical specialist 
o Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on 
clinical grounds alone 
• 
 
• 
Ischemic Stroke: 
o An acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction 
caused by an infarction of central nervous system tissue. 
• 
Hemorrhagic Stroke: 
o An acute symptomatic episode of focal or global cerebral or spinal dysfunction 
caused by an intraparenchymal, intraventricular, or subarachnoid hemorrhage. 
(A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or hemorrhagic) 
Transient Ischemic Attack (TIA) 
A transient (<24 hours) episode of neurological dysfunction caused by focal brain, spinal cord, 
or retinal ischemia, without acute infarction. No evidence of infarction if imaging performed. 
Surgical Access Site and Access-related Complications 
• 
Major Surgical Complications: 
o Access site or access-related injury (bleeding, hematoma, irreversible nerve 
injury, or vascular injury) leading to either death, need for significant blood 
transfusions (≥4 U), unplanned percutaneous or surgical intervention, or 
irreversible end-organ damage 
• 
Minor Surgical Complications: 
o Access site injury (bleeding or hematomas requiring transfusion of ≥2 but 
not more than 4 U) not requiring unplanned percutaneous or surgical 
intervention and not resulting in irreversible end-organ damage 
 
 

 
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13. 
Acronyms 
AADE 
Anticipated adverse device effect 
ABPM 
Ambulatory blood pressure monitoring 
ACC 
American College of Cardiology 
ACE 
Angiotensin converting enzyme 
ADN 
Aortic depressor nerve 
AE 
Adverse Event 
AHA 
American Heart Association 
AHI 
Apnea hypopnea index 
AKI 
Acute kidney injury 
AMI 
Acute myocardial infarction 
ASADE 
Anticipated serious adverse device effect 
ARB 
Angiotensin receptor blocker 
ASA 
Acetylsalicylic acid 
AV 
Atrioventricular 
BARC 
Bleeding academic research consortium 
BAT 
Baroreflex activation therapy 
BMI 
Body mass index 
CA 
Competent Authority 
CCB 
Calcium channel blocker 
CE 
Conformité Européene 
CEA 
Carotid endarterectomy 
CEC 
Clinical Events Committee 
CIP 
Clinical Investigation Protocol 
CK 
Creatine kinase 
CK-MB 
Creatine kinase-MB fraction 

 
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CPAP 
Continuous positive airway pressure 
CRO 
Contract Research Organization 
CT 
Computed tomography 
CVA 
Cerebrovascular accident 
DBP 
Diastolic blood pressure 
DBS 
Deep brain stimulation 
DSMB 
Data Safety Management Board 
EACTS 
European Association for Cardio-Thoracic Surgery 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECoG 
Electrocorticogram 
EDC 
Electronic Data Capture 
EDS 
Electronic Data System 
eGFR 
Estimated Glomerular Filtration Rate 
ESC 
European Society of Cardiology 
ESH 
European Society of Hypertension 
EU 
European Union 
F 
Frequency 
GDPR 
General Data Protection Regulation 
FIH 
First in Human 
GCP 
Good Clinical Practices 
HGB 
Hemoglobin 
HTN 
Hypertension 
IFU 
Instructions for Use 
IPG 
Impulse generator 
ITT 
Intention to treat 

 
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IV 
Intravenous 
MACCE 
Major Adverse Cardiac and Cerebrovascular Events 
MAE 
Major adverse event 
MDD 
Medical Device Directive 
MDR 
Medical Device Regulation 
MI 
Myocardial Infarction 
MRI 
Magnetic resonance imaging 
MSCT 
Multi-Slice Computed Tomography 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association 
OBP 
Office blood pressure 
PCI 
Percutaneous coronary intervention 
PHI 
Protected health information 
PRBC 
Packed red blood cells 
PW 
Pulse width 
RBC 
Red blood cells 
RCT 
Randomized controlled trial 
SADE 
Serious adverse device effect 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
TIA 
Transient ischemic attack 
UADE 
Unanticipated adverse device effect 
USADE 
Unanticipated serious adverse device effect 
USB 
Universal serial bus 
VARC 
Valve Academic Research Consortium 
VNS 
Vagal nerve stimulation 

 
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WHO 
World Health Organization 
 
 
 

 
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