Clinical Investigation Protocol for the Demonstration of Safety and Efficacy of VeSTAL Weight Loss Device in Human Subjects. Randomized Study of VeSTAL in Patients Who Are Overweight
Phase: NA
Conditions: Obesity
Sponsor: Neurovalens Ltd.

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Clinical Investigation Protocol for the Demonstration of Safety and Efficacy of VeSTAL 
Weight Loss Device in Human Subjects 
Randomized Study of VeSTAL in Patients who are Overweight  
 
Study Number: 
243973 (NI)_181094 (UCSD USA) 
Protocol Version: 
11 
 
 
This Protocol has been read and approved by: 
 
Name 
Title 
 
 
Date: 
Leigh-Ann McCrum 
Clinical Research Manager 
 
 
January 6th  2021 
 
 
 
 
 

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Table of Contents 
1. 
Chief Investigator and Principal Investigator(s) Signature Page ...................................................... 6 
2. 
Statement of Conformity ............................................................................................................ 11 
3. 
Study Synopsis ........................................................................................................................... 11 
4. 
Purpose and Scope ..................................................................................................................... 21 
5. 
Background ................................................................................................................................ 22 
 
Published Clinical Evaluations to Support Vestibular Stimulation and Weight Loss.................................... 22 
 
Studies on Galvanic Vestibular Stimulation ................................................................................................. 25 
 
Risk Evaluation of Published Literature Vestibular Stimulation ................................................................... 26 
6. 
Overview of Clinical Study .......................................................................................................... 29 
 
Summary of Site Visit 1 Screening / Baseline (0 months) ............................................................................ 31 
 
Summary of Site Visit 2 (3 months) .............................................................................................................. 33 
 
Summary of Site Visit 3 (6 months) .............................................................................................................. 34 
 
Schedule of Events........................................................................................................................................ 36 
 
Summary of Dual Energy X-Ray Absorptiometry (DXA) Scanning Procedure .............................................. 39 
 
Hypocaloric Diet ........................................................................................................................................... 40 
 
Summary of Dietary Questionnaires ............................................................................................................ 41 
 
Assessment of Diet and Activity ................................................................................................................... 41 
 
The Healthy Eating Program and Support .................................................................................................... 43 
 
Exercise ......................................................................................................................................................... 44 
 
Impact of Weight on Quality of Life (IWQOL) .............................................................................................. 45 
 
Hearing Test and Ear Examination ............................................................................................................... 45 
 
Serum Assays ................................................................................................................................................ 46 
 
Active Versus Sham Device........................................................................................................................... 47 
7. 
Rationale of Clinical Study .......................................................................................................... 50 
8. 
Conduct of Investigation to Reduce Bias ..................................................................................... 52 
9. 
Device Description / Intended Use Statement ............................................................................. 52 
10. 
Manufacturer ......................................................................................................................... 52 
11. 
Device Description .................................................................................................................. 53 
 
Headset Device ............................................................................................................................................. 53 
 
Software and Application ............................................................................................................................. 54 
 
Associated Devices, Consumables ................................................................................................................ 56 
12. 
Instructions for Use ................................................................................................................ 57 
13. 
Packaging and Labelling .......................................................................................................... 57 
14. 
Storage and Accountability ..................................................................................................... 59 
 
Accountability ............................................................................................................................................... 59 
 
Storage .......................................................................................................................................................... 59 

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15. 
Device Training ....................................................................................................................... 59 
16. 
Risk Benefit Analysis ............................................................................................................... 60 
 
General Risks ................................................................................................................................................ 61 
 
Risk Management Procedures ...................................................................................................................... 63 
17. 
Scope and Objectives .............................................................................................................. 66 
 
Primary Objective ......................................................................................................................................... 66 
 
Secondary Objective ..................................................................................................................................... 66 
 
Other objectives ........................................................................................................................................... 66 
18. 
Overall Design ........................................................................................................................ 67 
 
Endpoints for USA Regulatory Clearance ..................................................................................................... 67 
Where: ...................................................................................................................................................................... 67 
 
Endpoints for EU Regulatory Clearance ....................................................................................................... 68 
 
Other Endpoints for USA and EU Regulatory Puposes ................................................................................. 68 
19. 
Number of Subjects and Investigational Sites .......................................................................... 70 
20. 
Subject Selection .................................................................................................................... 70 
 
Target Population ......................................................................................................................................... 70 
 
Subject Selection .......................................................................................................................................... 70 
 
Subject Recruitment ..................................................................................................................................... 71 
 
Inclusion Criteria ........................................................................................................................................... 72 
 
Exclusion Criteria .......................................................................................................................................... 72 
 
Withdrawal criteria ....................................................................................................................................... 74 
21. 
Investigation Procedures ........................................................................................................ 76 
 
Informed Consent ......................................................................................................................................... 76 
 
Obtaining Informed Consent ........................................................................................................................ 78 
 
Special Circumstances for Informed Consent .............................................................................................. 80 
22. 
Subject Eligibility .................................................................................................................... 80 
23. 
Subject Identification .............................................................................................................. 81 
24. 
Treatment Procedure.............................................................................................................. 81 
 
Randomization / Assignment of subjects to treatment groups ................................................................... 81 
 
Blinding ......................................................................................................................................................... 81 
 
Independent Data Monitoring Committee (DMC) ....................................................................................... 82 
 
Prior to Initiating Study ................................................................................................................................ 82 
 
Pre-Testing Activities .................................................................................................................................... 82 
 
Hearing Examinations (At baseline and 6 months) ...................................................................................... 82 
25. 
Adverse Events ....................................................................................................................... 83 
 
General ......................................................................................................................................................... 83 
26. 
Recording and Assessment of Adverse Events ......................................................................... 84 
27. 
Causality and Severity Assessment of Adverse Events .............................................................. 85 

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28. 
Reporting UADEs .................................................................................................................... 85 
29. 
Competent Authority Notification ........................................................................................... 86 
30. 
Follow-up of Unresolved Events .............................................................................................. 86 
31. 
Data Collection ....................................................................................................................... 86 
 
Completion of Case Report Form ................................................................................................................. 87 
 
Device Usage Records During Home Use Period.......................................................................................... 88 
 
Review and Return of Completed Documentation ...................................................................................... 88 
 
Retention of Documentation........................................................................................................................ 88 
32. 
Suspension, Termination and Close-Out of Clinical Investigation .............................................. 90 
 
Suspension or Premature Termination of Clinical Investigation .................................................................. 90 
 
Routine Study Termination and Close Out ................................................................................................... 90 
33. 
Data Management Procedures ................................................................................................ 90 
 
Data Archiving .............................................................................................................................................. 91 
34. 
Statistical Plan ........................................................................................................................ 91 
 
Statistical Plan............................................................................................................................................... 91 
 
Primary Endpoints USA Regulatory Clearance: ............................................................................................ 93 
Where: ...................................................................................................................................................................... 94 
 
Primary Endpoints EU Regulatory Clearance: .............................................................................................. 96 
35. 
Analysis of clinical performance .............................................................................................. 99 
36. 
Reports and Publication .......................................................................................................... 99 
 
Interim Report .............................................................................................................................................. 99 
 
Final Report .................................................................................................................................................. 99 
 
Publications .................................................................................................................................................. 99 
37. 
Ethical Considerations .......................................................................................................... 100 
 
Ethics Committee Approval ........................................................................................................................ 100 
 
Subject Confidentiality ............................................................................................................................... 100 
38. 
Declaration of Helsinki .......................................................................................................... 102 
39. 
Indemnity ............................................................................................................................. 102 
40. 
Compensation ...................................................................................................................... 102 
41. 
Regulatory Requirements ..................................................................................................... 103 
 
Regulations and Standards ......................................................................................................................... 103 
42. 
Good clinical practice compliance ......................................................................................... 104 
 
Clinical investigation Personnel and Responsibilities................................................................................. 104 
 
Site Monitoring ........................................................................................................................................... 104 
 
Auditing ...................................................................................................................................................... 105 
 
Modification to the Clinical Study Protocol................................................................................................ 106 
 
Conflict of Interest ...................................................................................................................................... 106 
 
Protocol Violations and Deviations ............................................................................................................ 106 

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43. 
References ........................................................................................................................... 107 
44. 
Appendices and Attachments................................................................................................ 111 
• 
Safety Reporting -see below for safety reporting information and forms to assist in reporting 
requirements................................................................................................................................... 111 
• 
Investigational Device Instructions for Use ................................................................................ 111 
• 
Deviation/Violation Log ............................................................................................................ 111 
• 
EPIC-Norfolk Food Frequency Questionnaire (FFQ) .................................................................... 111 
• 
Modifiable Activity Questionnaire (MAQ) ................................................................................. 111 
• 
Case Report Forms ................................................................................................................... 111 
• 
Example of Quality of Life Survey .............................................................................................. 111 
 

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1. Chief Investigator and Principal Investigator(s) Signature Page 
Chief Investigator Name: Erik Viirre 
  
Chief Investigator Title: Professor Neurosciences Department UCSD  
  
Chief Investigator Address: UC San Diego Health - La Jolla 
9 
500 Gilman Dr #0970 
La Jolla , California 92093 
United States of America  
Chief Investigator Tel No.: (858) 657-8540 
  
Chief Investigator E-mail: eviirre@ucsd.edu 
 
Principal Investigator Name NI Site: Julie Sittlington 
  
Principal Investigator Title: Dr  
  
Principal Investigator Address: University of Ulster 
Room W3010 
Cromore Road 
Coleraine 
Co. Londonderry 
BT52 1SA 
Northern Ireland 
Principal Investigator Tel No.: +44 28 7012 4101 
  
Principal Investigator E-mail: jj.sittlington@ulster.ac.uk 
 
Principal Investigator Name UCSD Site: Erik Viirre 
  
Principal Investigator Title: Professor Neurosciences Department UCSD 

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Principal Investigator Address: UC San Diego Health - La Jolla 
9500 Gilman Dr #0970 
La Jolla , California 92093 
United States of America 
Principal Investigator Tel No.: (858) 657-8540 
Principal Investigator E-mail: 
 
eviirre@ucsd.edu 
Principal Investigator Name TDE Site: Jean Chen  
  
Principal Investigator Title: Dr 
  
Principal Investigator Address: Texas Endocrinology Diabetes (TDE)  
6500 N. MoPac 
Bidg. 3, Ste. 200 
Austin 
Texas  
USA 
 
Principal Investigator Tel No.: +1 512.334.3505 
  
Principal Investigator E-mail: jean.chen@texasdiabetes.com 
  
 
The undersigned have read and understood the Clinical Investigation Plan specified above and 
throughout pages below. In my capacity as Investigator, I understand my duties including ensuring 
safety of study subjects and providing study sponsor complete and timely information as outlined in 
this protocol. It is understood that all information pertaining to the investigational device study will be 
held strictly confidential. I agree to maintain the procedures required to carry out the study in 
accordance with accepted Good Clinical Practice principles and to abide by terms of this protocol. 
 
Chief Investigator Signature:  
  

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Date of Signature:  
 
Principal Investigator Signature  
(NI Site): 
 
  
Date of Signature:  
 
Principal Investigator Signature  
UCSD CCR Site: 
 
  
Date of Signature:  
 
Principal Investigator Signature  
EPARC Site: 
 
  
Date of Signature:  
 
Principal Investigator Signature  
TDE Site: 
 
  
Date of Signature:  

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Abbreviations 
Abbreviation 
Definition 
ABHI 
Association of British Healthcare Industry 
ACTRI 
Altman Clinical and Translational Research Institute 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AgRP 
Agouti-Related Peptide 
BMI 
Body Mass Index 
CA 
Competent Authority 
CFR 
Code of Federal Regulations (United States) 
CIP 
Clinical Investigational Protocol 
CRF 
Case Report Form 
CCR 
Center for Clinical Research (primary trial site at UCSD campus) 
CTM 
Clinical Trial Mentors 
C-TRIC 
Clinical Translational Research and Innovation Centre 
DMC 
Data Monitoring Committee 
DXA 
Dual Energy X-Ray Absorptiometry 
EPARC 
Exercise and Physical Activity Resource Center (second trial site at 
UCSD campus) 
EU 
European Union 
FDA 
Food and Drug Administration (United States) 
FFQ 
Food Frequency Questionnaire 
GCP 
Good Clinical Practice 
GVS 
Galvanic Vestibular Stimulation  
HISU 
Human Intervention Studies Unit 
IC 
Informed Consent 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IFU 
Instruction for Use (Assay/Device Handbook) 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 

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IWQOL 
Impact of Weight on Quality of Life 
MAQ 
Modifiable Activity Questionnaire 
MDD 
Medical Device Directive 
MVe 
Medial Vestibular Nucleus 
NI 
Northern Ireland 
NPY 
Neuropeptide Y 
NSR 
Non-Significant Risk 
NTF 
Note To File 
PI 
Principal Investigator 
POMC 
Pro-opiomelanocortin 
REC/EC 
Research Ethics Committee/Ethics Committee 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
SR 
Significant Risk 
TDE 
Texas Endocrinology and Dibates  
tES 
Transcranial Electrical Stimulation 
TBWL 
Total Body Weight Loss 
TLS 
Transport Layer Security 
TSP 
Test Site Protocol 
UADE 
Unanticipated Adverse Device Effect 
UCSD 
University of California San Diego (refers to primary site CCR and 
EPARC) 
UK 
United Kingdom 
USA 
United States of America 
UU 
University of Ulster 
VeNS 
Vestibular Nerve Stimulation 
WST 
We Slim Together 
 

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2. Statement of Conformity 
Neurovalens’s representatives declare that the device specified for the Clinical Study Investigation Plan for 
Investigational Analysis of patients using the VeSTAL device for weight loss was designed to conform with the 
essential requirements of the Medical Device Directive 92/43EEC (MDD) with the exception of those 
requirements which the Clinical Study is intended to fulfil and that every reasonable precaution has been taken 
to protect the health and safety of the subjects. 
 
3. Study Synopsis 
 
TITLE 
A randomized, double blind sham controlled clinical trial to evaluate the 
efficacy of vestibular nerve stimulation (VeNS), combined with a lifestyle 
modification program, compared to a sham control and a lifestyle 
modification program as a means of reducing excess body weight and body 
fat. 
FACILITIES 
All study visits will be carried out between four sites: 
1. Altman Clinical and Translational Research Institute’s Center for 
Clinical Research, which is part of the La Jolla campus of University 
of California San Diego (CCR) 
2. Exercise and Physical Activity Resource Center (EPARC), CALIT2 
Building, Rooms 3401-3506  which is also part of La Jolla campus of 
UCSD. 
3. Human Intervention Studies Unit (HISU) at University of Ulster (UU) 
Coleraine Campus in Northern Ireland  
4. Texas Diabetes & Endocrinology site in Austin Texas (TDE) 
Trial sites CCR and EPARC at the UCSD campus will be referred to 
collectively as ‘UCSD’ throughout this protocol. 
 
An unfunded collaboration agreement will be established between all sites. 
 

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There is a DXA scanner located at all sites described above, apart from the 
TDE site where an external contractor will be used (see Section 6.5).  
 
NUMBER OF SITES 
4 
STUDY DESIGN 
The aim of this study is to evaluate the efficacy of non-invasive electrical 
vestibular nerve stimulation (VeNS), together with a lifestyle modification 
program, as a method of reducing excess body weight and body fat, as 
compared to a sham control with both study arms incorporating a lifestyle 
modification program. 
• 
Allocation: Randomized 
• 
Endpoint classification: Efficacy Study 
• 
Intervention Model: Parallel Assignment in 1:1 active to control 
allocation  
• 
The aim of the study is to recruit a total (i.e. across all 4 sites) of 200 
participants that pass the screening process and are randomized into 
the treatment protocols. With a dropout allowance of 10% this should 
generate a minimum of 90 active treatment and 90 control subjects.  
• 
Masking: Double Blind (Subject, Nursing staff, Dietician, Co-
coordinators, Outcomes Assessor and any other study staff who 
have contact with the subject) 
• 
Data from all sites will be collated at the end of the studies and 
analysis will be performed on one data set. 
 
This protocol governs the activities at both the USA and NI/UK clinical sites. 
  
PRIMARY OBJECTIVE 
To establish the clinical performance of the VeSTAL device stimulation effect 
in patients who are overweight. 

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SECONDARY 
OBJECTIVES 
To evaluate between baseline and 6 months the safety of the VeSTAL device 
relative to control group, in terms of the occurrence of adverse events, 
changes in vital signs (blood pressure and heart rate), and hearing tests. 
 
A variety of secondary endpoints will also be assessed statistically at the 6-
month timepoint after the primary endpoints. The following of these may form 
the basis of potential future labelling claims: 
• 
Total body fat loss (as measured by whole body DXA scanning); 
• 
Healthy Eating Index (HEI) score (https://epi.grants.cancer.gov/hei/) 
(as measured by the two-day 24-hour dietary recall); 
• 
Total caloric intake (as measured by the two-day 24-hour dietary 
recall); 
• 
Systemic inflammation (as measured by high-sensitivity C-reactive 
protein); 
• 
Atherogenic index (as determined by the ratio of total cholesterol to 
HDL); 
• 
Quality of life (as measured by the IWQoL questionnaire). 
 
The full details of the testing procedures procedure for these endpoints will be 
laid out in the Statistical Analysis Plan. All other secondary endpoints at the 
6-month timepoint will be hypothesis generating only. 
 
NUMBER OF SUBJECTS 
In order to achieve adequate numbers, we estimate that we may have to 
consent (i.e. enrol into the study) up to 120 subjects at the CCR site, 
approximately 80 subjects at the EPARC, up to 40 patients at the TDE site,  
and up to 150 subjects at the UU site. So a total of about 300 across all sites. 
This is because the baseline screening can only take place after the formal 
consent process. The anticipated recruitment across the study sites will be as 
follows:  
o 
CCR: up to a total of 106 subjects who pass through 
screening and are randomized;  

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o 
EPARC: up to a total of 60 subjects who pass through 
screening and are randomized; 
o 
UU: up to a total of 94 total subjects who pass through 
screening and are randomized. 
o 
TDE: up to a total of 40 total subjects who pass through 
screening and are randomized. 
 
SUBJECT SELECTION 
CRITERIA 
Pre-screening of Subjects 
In order to prevent subjects traveling in needlessly to the study site it is 
proposed that the study staff allow prospective subjects to pre-screen 
themselves over the phone.  
 
This pre-screening will involve the study coordinator reading out the inclusion 
and exclusion criteria to prospective subjects during an initial phone call. The 
screening questionnaire will not be completed at this stage. Rather the 
purpose is to make prospective subjects aware as to what the inclusion and 
exclusion criteria are, since there is no point in them wasting their time in 
coming in if they are ineligible. Moreover, this will also allow study 
coordinators to provide prospective subjects with a verbal description of the 
study to the subjects.   
 
For the UU site – this pre-screening activity will be managed by Compliance 
Solutions Life Sciences Ltd. and the UU study team with the names of 
potentially eligible subjects being passed directly to the site. Potentially 
eligible participants who successfully meet the Pre-Screening inclusion 
criteria will be sent a study information pack. This study information pack will 
include the following documents: Informed Consent Form, Food Frequency 
Questionnaire, Modifiable Activity Questionnaire, Two-day 24 Hour Recall, 
Concomitant Medications Form and Inclusion/Exclusion Form. The participant 
will be asked to bring these completed forms with them to their baseline visit 
(Visit 1, 0 Months) and at this visit each form will be reviewed by the study 
staff. 

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Inclusion/ Exclusion Criteria Questionnaire 
Subjects who have signed the Informed Consent Form (ICF) will be asked to 
complete a Screening Questionnaire to ensure that they meet to requisite 
inclusion criteria. Consideration was given to which of the exclusion criteria 
for which it would be appropriate, and practical, to actively screen. 
Consideration was given to harm mitigation as frequently obese subjects have 
mild irregularities of blood tests (e.g. liver function) that are no, or limited, 
clinical relevance, and clearly it would not be desirable to unnecessarily 
exclude subjects, nor cause them undue anxiety, on this basis. As detailed 
below, it was decided that the appropriate conditions to actively screen for are 
diabetes mellitus, hypothyroidism and pregnancy.  
 
Pre-enrollment Screening for Type 2 Diabetes Mellitus 
After being consented but prior to being randomized to a treatment arm, 
potential subjects will be screened for type 2 diabetes mellitus by means of a 
fasting blood glucose test. This will be done via a finger prick sample and 
glucose meter. Testing should be performed in the morning after an overnight 
fast of at least 8 hours.  
 
If a subject is found to possibly have type 2 diabetes [i.e. they have a reading 
of 126 mg/dl (7 mmol/L) or above] during the initial screening, then they will 
be excluded and asked to notify their primary care physician. However, if a 
subject passes the initial screening but then a suspicion of this diagnosis is 
made during one of the study tests, then the subject will be asked to notify 
their primary care physician, though they will still be allowed to complete the 
study, and a note to file will be made. 
 
Screening for Pregnancy 
Female subjects of childbearing potential (i.e. who have not gone through the 
menopause or had a hysterectomy or oophorectomy) will be screened for 
pregnancy by means of a standard urinary pregnancy test. It is important to 

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know in a trial of an investigational device for weight loss if a female subject 
has become pregnant, and especially so at 0 and 6 months when the subjects 
undergo a DXA scan which involves a small dose of ionizing radiation. Thus 
urinary pregnancy tests will be carried out at 0, 3 and 6 months. Female 
subjects will be requested, as part of the consent process, to refrain from 
becoming pregnant for the duration of their participation in the study. Should 
a subject become pregnant after enrollment then they will be withdrawn from 
the study, both because of the use of ionizing radiation in DXA scans and the 
increase in weight that occurs during pregnancy. 
 
Screening for Hypothyroidism 
After being consented but prior to being randomized to a treatment arm, 
potential subjects will be screened at the baseline visit for hypothyroidism. 
This will be done using a finger prick test for hypothyroidism, which is available 
for clinical use in the USA and NI sites as ThyroChek (See: 
http://thyrochek.com). This product has a sensitivity of 98.5% and a specificity 
of 96.9%. It is a qualitative test that takes about 10 minutes to give a result. If 
positive it indicates that the TSH level is > 5 mlU/L. If a subject tests positive, 
then they will be excluded from the study and asked to see their primary care 
physician to be investigated for hypothyroidism. 
 
Subject Eligibility 
Where a subject fails to fulfill the inclusion/ exclusion/ screening criteria, this 
will be documented, and the investigator will retain the signed consent form. 
The subject will not advance any further into this clinical investigation. 
 
TEST 
PRODUCT, 
HOW 
USED 
Study staff will train the subject on how to use their study device. Specifically, 
this will include: how to first prepare the skin over the mastoid processes with 
an alcohol wipe; a demonstration of where to place the 32mm diameter 
hydrogel electrodes (i.e. behind the ears on the skin overlying the mastoid 
processes – see Figure 1); how to access the VeSTAL study app and pair the 
iPod (using Bluetooth Low Energy) to the device; how to operate the device 

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using the app; and how to use the up/down buttons on the device if unable to 
use the study app. Study staff will provide subjects with a printed copy of the 
Instructions for Use (IFU) and also highlight its location as a PDF on the iPod. 
The Device Use Schematic will also be highlighted to the subjects – it will only 
be as a PDF on the iPod. 
 
Also study staff will demonstrate to the subjects: how to charge the device; to 
dispose of used electrodes after a stimulation session; how to store unused 
electrodes in a sealed manner so they do not dry out; how to turn the device 
on and off using the power button; and how to use the app or power button to 
pause a stimulation session.  
 
Subjects will be asked to try and use their allocated device for an hour every 
day, and at least five times a week. Theoretically it is thought that the device 
may be more effective if used while sitting upright (as opposed to lying flat) 
(Macefield & James, 2016), due to the orientation of the otolith organs. As 
such subjects will be encouraged to use the device while sitting upright, and 
also in the evening as sometimes people can feel a bit soporific after 
vestibular stimulation. Subjects will be instructed not to walk around, operate 
machinery or drive while using their device. Most people can tolerate up to 
1.0mA without difficulty and subjects will be encouraged to turn the device up 
as much as they are comfortable with.  
 
DURATION OF SUBJECT 
PARTICIPATION 
AND 
DURATION OF STUDY 
Subjects will be enrolled at a rate of up to 3 subjects per day from the study 
start date. The study will last approximately 6 months.  
 
The final analysis will be conducted at the 6 month timepoint, and this will form 
the basis of a future de novo application.  
 
Participants will be given the headset device to use in the home environment 
for a period of 6 months, the daily use of the device will be recorded 
automatically via the device application. Both the UCSD CCR site (based in 

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USA) and the UU site (based in NI) started in September 2019. The EPARC 
site is expected to start in early 2020.The TDE site (based in the USA) is 
expected to start after September 2020.  
 
OTHER EVALUATIONS 
VeSTAL design has been developed in compliance with the design control 
requirements contained in 21 CFR Part 820.30 and ISO 13485:2016. 
STATISTICS 
Primary 
Analysis 
Plan 
Details  
Two statistical analysis pathways have been identified each separate for the 
EU and USA regulatory clearance purposes. 
STATISTICS 
Primary Analysis Plan for 
Regulatory 
Clearance 
pathway in USA 
The Primary Analysis population will be 200 subjects, from the data collected 
across two sites details as given above. 
 
Primary Endpoints: 
The efficacy of the VeSTAL device within the treatment group will be 
quantified by calculation of two primary endpoints after 6 months. 
1. mean percent weight loss; 
2. proportion of participants who lose at least 5% body weight. 
 
Study Efficacy Acceptance Criteria: 
• 
Mean: There should be at least a 2% total body weight loss (TBWL) 
superiority margin between the active-product and sham-treated 
groups.  
• 
Categorical: The proportion of participants who lose 5% TBWL or 
more in the active-product group is at least 50%, independent of the 
sham control  
 
Both weight loss efficacy acceptance criteria must be met to claim success. 
These criteria can be specified in mathematical formulae as follows:  
Rejection of both the null hypotheses μA – μC ≤ 2% and πA ≤ 50% 
at the 2.5% (1-sided) level 
Where:  

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μA and μC are the underlying population mean percentage weight 
loss on active and control respectively  
πA is the underlying population proportion of subjects who lose ≥5% 
of baseline body weight on active.  
 
Methods: Primary Aims 
For total body weight loss (TBWL) as a continuous measure, we will use a 
linear regression with TBWL as the dependent variable and group and other 
covariates of interest (gender, age, etc.) as independent variables. To assess 
any longitudinal effects, we will use a linear mixed effects model for weight 
over time, with fixed covariates for baseline weight, time, group, and a time / 
group interaction, and a random intercept to account for within-subject 
correlation. We will use these models to generate two-sided 95% confidence 
intervals for the difference in mean percent weight loss.  
 
We will use a one-sided exact binomial test to determine if the response rate 
in the treatment group significantly exceeds 50%, with response defined by a 
loss of at least 5% of their body weight.  
 
We will analyze mean fat loss in the same way as TBWL as a continuous 
measure with linear regression and linear mixed effects models. 
 
Analyses will be conducted at 6 months. 
 
 
STATISTICS 
Primary Analysis Plan for 
Regulatory 
Clearance 
pathway in EU  
The Primary Analysis population will be 200 patients, from the data collected 
across two sites details as given above. 
 
Primary Endpoint: 
The efficacy of the VeSTAL device within the treatment group will be 
quantified based on a single primary endpoint: 
1. Mean percent weight loss 

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Study Efficacy Acceptance Criterion: 
• 
Mean: There should be at least a 2% total body weight loss (TBWL) 
superiority margin between the active-product and sham-treated 
groups.  
 
This criterion can be specified in mathematical formulae as follows:  
mA – mC ≥ 2% and pt ≤ 0.05 
Where:  
mA and mC are the observed mean percentage weight loss on 
active and control respectively  
pt is the p-value (two-sided) from a linear regression comparing 
percentage weight loss between active and control (H0: μA = μC; 
H1: μA ≠ μC)  
μA and μC are the underlying population mean percentage weight 
loss on active and control respectively 
 
This single study efficacy acceptance criterion for the EU regulatory clearance 
pathway will be treated to the same statistical analysis as the mean criterion 
for the USA regulatory clearance pathway. 
 
Rationale for Number of 
Subjects 
The primary outcomes are TBWL from the start of treatment (as a percentage 
of baseline total body weight), and the proportion of subjects who lose at least 
5% of their baseline total body weight. These outcomes will be assessed at 
6-months. 
 
Power calculations are based on simulation with assumptions informed by 
pilot data and the Modius weight-loss device as follows: 
• 
90kg median baseline weight in both groups (log-normal distribution 
with CV=24%) 
• 
6.6% mean percent weight loss in the active group at 6 months (SD 
3.9%), 

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• 
3.1% mean percent weight loss in the control group at 6 months (SD 
3.9%), 
• 
correlation between baseline weight and weight loss at 6 months of -
0.4. 
 
Under these assumptions, with a sample size of 180 participants randomized 
1:1 active: placebo, there is greater than 80% power to demonstrate both the 
weight loss mean and categorical acceptance criteria at the 6 month 
timepoint. 
 
 
4. Purpose and Scope 
This protocol describes the overall device investigation; governs the activities at the site of the device 
investigation and describes the study details, interactions and records to be generated throughout the study. 
This document serves as the lead document and supersedes all other documents. e.g. Instructions for Use 
(IFU). 
 
There is an ongoing and worsening problem with obesity in the developed, and much of the developing world. 
Although it has long been realized that Western diets that are rich in sugar and fat play an important role in 
this, it has only recently been realized that exposure to these diets, particularly in childhood, can damage the 
part of the brain that determines how much fat there is in the body. The result of this damage is that the so-
called “set-point” for fat in this part of the brain is pushed upwards. There is a lot of evidence from animal 
studies that activating the brain’s balance (vestibular) system pushes this set-point for fat downwards to cause 
fat loss, probably because this tricks the brain into thinking that the animal is more physically active. The aim 
of this study is to determine whether the same effect can be triggered in humans by non-invasively stimulating 
the vestibular system with a small electrical current through the skin behind their ears, in order to evaluate the 
efficacy of non-invasive electrical vestibular nerve stimulation (VeNS), together with a lifestyle modification 
program, as a method of reducing excess body weight and fat, as compared to a sham control and lifestyle 
modification program.  
 
This protocol will be applied at the following sites:  

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1. Ulster University, Cromore Road, Coleraine, County Londonderry, BT52 1SA in Northern Ireland, at 
the Human Intervention Study Unit (HISU) 
2. Altman Clinical and Translational Research Institute (CCR) building which is part of the La Jolla 
campus of UCSD 
3. Exercise and Physical Activity Resource Center (EPARC), CALIT2 Building, Rooms 3401-3506  which 
is also part of La Jolla campus of UCSD. 
4. Texas Diabetes & Endocrinology 5000 Davis Lane, Suite 200 Austin, TX 78749 USA 
 
 
All sites will be randomized at 1:1 (active: sham) and an endpoint analysis will be performed at 6 months.  
 
5. Background 
The VeSTAL device utilizes a technology called galvanic vestibular stimulation (GVS) (sometimes termed 
vestibular nerve stimulation (VeNS)). In the envisaged configuration, the device will be placed on the head in 
a manner analogous to headphones and will deliver a small electrical current (1.0mA or less) to the skin behind 
the ears, over the mastoid processes.  
The VeSTAL device can only be used for up to one hour a day, and after being used for this time period, it will 
automatically lock out until the next day. Delivery of electrical current to the skin over the mastoid region is 
known to activate all five components of the vestibular apparatus, but lower level currents (below 3mA) are 
thought to particularly activate the two otolith organs responsible for detecting linear acceleration and gravity 
(Zink, Bucher et al., 1998). It is these otolith organs that, from the animal studies, are particularly associated 
with a reduction in body fat. This technique – known as bilateral bipolar galvanic vestibular stimulation – has 
been known since the 19th century and is thought to be safe (Fitzpatrick and Day, 2004). 
 
 Published Clinical Evaluations to Support Vestibular Stimulation and Weight Loss 
There is growing evidence for a "set-point" in the hypothalamus that acts to regulate body mass composition, 
including body fat (Harris, 1990) (Horvath, 2005) (Yon, Mauger et al., 2013). This feedback control mechanism 
modifies feeding behavior and metabolic rate, in order to maintain body mass composition within predetermined 
parameters and does so in order to optimize energy homeostasis. As such, deviations too far in either direction 

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from the set-point are strenuously resisted (Sims, Horton et al., 1968) (Horvath, 2005), (Yon, Mauger et al., 
2013). Thus, not only is it hard to change body mass composition via diet and exercise, but even if one can, 
maintaining the new leaner composition in the long term is typically doomed to failure, as the brain, in effect, 
fights against the change.  
 
Several nuclei within the hypothalamus are involved in regulating this set-point, but one particularly vital one 
appears to be the arcuate nucleus with its populations of pro-opiomelanocortin (POMC), and agouti-related 
peptide (AgRP) / neuropeptide Y (NPY) co-expressing neurons (Parton, Ye et al., 2007, Belgardt, Okamura et 
al., 2009, Varela and Horvath, 2012) (Wang, He et al., 2015). These neurons together comprise the central 
melanocortin system, which acts to regulate energy homeostasis, by responding to circulating hormones, 
nutrients, and neuronal inputs (Cone, 2005). In the case of the POMC neurons, the response is anorexigenic 
with a decrease in food intake and an increase in energy expenditure. Conversely, the orexigenic AgRP/ NPY 
neurons act in an antagonistic manner (Cone, 2005) . 
 
The set-point for body mass composition that is determined by the central melanocortin system obviously varies 
from person to person, and is influenced by both genetic and epigenetic factors (Herrera, Keildson et al., 2011). 
However, it appears that exposure to Western diets, particularly during childhood and adolescence, with their 
often excessive quantities of sugar and saturated fatty acids, can damage neuronal populations within the 
hypothalamus and push the set-point for body fat upwards (Horvath, 2005) (Parton, Ye et al., 2007, Yon, 
Mauger et al., 2013). This makes the overweight body composition become the normal body composition as 
far as the brain is concerned, and reverting to a leaner set-point once this has occurred can be difficult (Horvath, 
2005). The set-point is not totally immutable though, as there is evidence that it can be lowered by long term 
dietary changes, such as, consuming a lot of polyunsaturated fatty acids (Yon, Mauger et al., 2013). Similarly, 
it is also now thought that bariatric surgery acts by reducing the set-point (presumably via hormone release), 
rather than simply decreasing caloric intake (Hao, Mumphrey et al., 2016). 
 
The clear ability of vestibular stimulation to modify body mass composition (most notably to reduce body fat, 
but also to increase lean muscle mass and bone mineral density), appears to be mediated via an otolith-
vestibulo-hypothalamic pathway (Fuller, Jones et al., 2004) (Fuller, Warden et al., 2000). This reflects the 
vestibular system’s vital role in homeostasis and, indeed, vestibular input is known to project to multiple 
brainstem homeostatic sites (Balaban and Yates, 2004) (McGeoch, 2010). This includes the arcuate nucleus 
of the hypothalamus (Fuller, Jones et al., 2004), which, as stated, sits at the crux of the central melanocortin 
system. Moreover, three further observations confirm an intimate interplay between the vestibular and central 

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melanocortin systems: First, melanocortinergic neurons have been found in the medial vestibular nucleus 
(MVe) (Shang, Xiong et al., 2015); second, an enzyme important in the modulation of melanocortin signaling 
is expressed in vestibular nuclei, in particular MVe (Jeong and Diano, 2014); and third, POMC neurons in the 
nucleus of the solitary tract, which are part of the central melanocortin system that connects to the 
parasympathetic nervous system, also receive input from the MVe (Wang, He et al., 2015). 
 
The prominent role of the MVe here, is noteworthy, as it is the main projection target of the utricle (Newlands, 
Vrabec et al., 2003), which is the otolith organ that detects movement on a horizontal plane. Also, retrograde 
tracer studies have identified the MVe as one of the areas involved in the central control of the sympathetic 
nerves supplying both normal fat (properly termed white adipose tissue) (Bamshad, Aoki et al., 1998), and 
brown adipose tissue (Bamshad, Song et al., 1999), which is a more specialized type of fat extremely rich in 
mitochondria, the organelles of the cell that generate energy. It is believed that activating brown adipose tissue 
could act to reduce the total amount of white adipose tissue, and thus have an anti-obesity potential, and 
moreover, insulin sensitivity and therefore type 2 diabetes mellitus (Scheele and Nielsen, 2017). There are also 
definite but, as yet, somewhat anatomically less well delineated connections between the vestibular nuclei in 
the brainstem and the sympathetic nerves that innervate skeletal muscle and bone (Vignaux, Besnard et al., 
2013) (Bolton, Wardman et al., 2004, Bent, Bolton et al., 2006)  
 
In summary, it thus seems that the central melanocortin system interprets activation of the MVe (by horizontal 
movements stimulating the utricle) to indicate a state of increased physical activity. Homeostatically, in such a 
state of apparent increased activity, it is optimal, from an energy conservation point of view, for the body to 
have a leaner composition, in order to reduce unnecessary energy expenditure from carrying around excess 
fat. Also, under such conditions it would be homeostatically more efficient for the muscles and bones to be 
stronger, as this would facilitate them coping with the state of chronically increased movement. Given its 
described connections to both sides of the autonomic nervous system (i.e. anorexigenic POMC neurons within 
the parasympathetic nervous system (Wang, He et al., 2015), and the sympathetic nerves innervating white 
and brown adipose tissue (Bamshad, Aoki et al., 1998) (Bamshad, Song et al., 1999), bone and muscle (Bolton, 
Wardman et al., 2004, Bent, Bolton et al., 2006) (Vignaux, Besnard et al., 2013), the MVe is also well placed 
to effect these changes in body mass composition – i.e. reduce total body fat and increase lean muscle mass 
and bone mineral density.  
 
Thus GVS, which is known to stimulate the otolith organs (Zink, Steddin et al., 1997) (Fitzpatrick and Day, 
2004), when repeatedly administered over time, will cause recurrent activation of the MVe, which will be taken 

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by the central melanocortin system to indicate a state of chronically increased physical activity, with the 
consequence of altering the set-point for body mass composition to a physically leaner state; with less adipose 
tissue and stronger bones and muscles. 
 
Pilot data collected at UC San Diego (IRB study #110538) demonstrated a reduction in body fat when receiving 
vestibular stimulation over a 4 month period. Total body and truncal fat was measured using DXA scanning. 
The treatment of 3 males and 3 female subjects of median 23 years old, showed a significant reduction in 
truncal fat (t (7) =2.88, p<0.025), the data also suggested a trend towards a significant reduction in total body 
fat (t (7) =2.17, p=0.067). Overall the treatment group showed an 8.3% decrease in truncal fat (cf. an 8.6% 
increase in the control group), and a reduction in total body fat of 6.3% (cf. a 6% increase in the controls). The 
control group participants received a sham device stimulation, the overall comparison was skewed due to a 
subject who gained 3.8kg in truncal fat. However, if this subject is considered as zero weight gain the difference 
in truncal fat between groups remains significant (t(7)=2.53, p=0.039) (McGeoch, McKeown et al., 2017) 
 Studies on Galvanic Vestibular Stimulation 
Krystal et al. (2010) investigated the effect of one hour of GVS, at up to 0.5mA delivered at 0.5Hz, in 101 
healthy volunteers and 97 controls who received sham stimulation. They found that the stimulation was 
“generally well tolerated.” Adverse events occurred in 16.8% of the treatment group compared to 6.2% of sham 
treated subjects. Headache was the commonest side-effect which occurred in 11.9%, with dizziness the second 
most common at 3%. In total 12 of the 17 adverse events were ranked as mild, 4 moderate and 1 episode of 
dizziness and nausea as severe. All of the adverse events resolved spontaneously or, in the case of headache, 
with the use of over the counter medications. The investigators note that “no serious or unanticipated device 
related effects” occurred. It is noteworthy that the total current delivered by the GVS device in this study is 
directly comparable to that delivered by the VeSTAL device, as it has a 50% duty cycle, which means it delivers 
current only half the time (Krystal, Wyatt et al., 2010). 
 
Marshall et al. (2010) described the effect of GVS in a population of 105 individuals with chronic insomnia. The 
device used in their study was similar to the VeSTAL device in that it could deliver between 0.1 and 1.0mA at 
0.5Hz.  However, unlike the VeSTAL device it did not have the 50% duty. The study participants all received 
GVS for an hour a day for 30 days. Only two adverse events (a petit mal seizure and tinnitus) were reported in 
the group, neither of which was thought by the investigators to be attributable to use of the GVS device. 
(Marshall, Jasko et al., 2010) 

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A study in which noisy GVS was delivered to 30 elderly people at between 0.1 and 0.2mA for a continuous 
three-hour session also observed no adverse events (Fujimoto, Yamamoto et al., 2016). The word noisy here 
indicates that the stimulation current is varied randomly. Although this is clearly a different waveform from that 
delivered by VeSTAL, the total current delivered over the three-hour period will, because of the 50% duty cycle 
in VeSTAL’s waveform, be similar. 
 
There is thus a body of literature in the adult population supporting the safe usage of both transcranial electrical 
stimulation (tES) and more specifically GVS devices delivering at least 1mA in stimulation. In conclusion, there 
is not a significant risk of harm from using the device, and as such criteria in the FDA guidance document do 
not apply. Thus, as the device does not meet the criteria of a significant risk (SR) device it is a non-significant 
risk (NSR) device.  
 
  Risk Evaluation of Published Literature Vestibular Stimulation  
The following risk assessment was also carried out for the vestibular nerve stimulation device, and its 
embedded software, that can deliver up to 1mA.  Under the guidance for IRBs from the FDA a device will be 
determined to be non-significant risk (NSR) if it does not meet the definition of a significant risk (SR) device 
(see https://irb.ucsd.edu/device.pdf). A SR device is one which meets at least one of the following criteria: 
a. The device is intended as an implant. 
b. The device supports or sustains human life. 
c. The use of the device is of substantial importance in diagnosing, curing, mitigating, 
or treating disease or preventing impairment of health. 
d. The device could cause significant harm to any subjects. 
e. The subject must undergo a procedure as part of the device study. 
f. The device appears on the FDA list of significant risk devices. 
g. The study or any of the study procedures could cause harm to the subjects which: 
i. could be life threatening; 
ii. could cause permanent impairment of a body function; 
iii. could cause permanent damage to body structure; 
iv. or could necessitate medical or surgical intervention to preclude permanent impairment of 
a body function or preclude permanent damage to body structure. 

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As the device is not implanted, no procedure is required to use it, it does not support or sustain life and it is not 
on the FDA list of significant risk devices, criteria a, b, e and f clearly do not apply. Regarding criterion c, the 
aim of this study is to investigate whether vestibular stimulation can, in conjunction with lifestyle interventions, 
assist with weight and fat loss. It may be the case that VeNS has such a role, but it is unlikely that this will be 
of “substantial importance in … curing, mitigating, or treating disease, or preventing impairment of health.” 
Thus, criterion c does not apply. 
 
This then leaves criteria d and g, which both pertain to users suffering significant harm from the device. When 
the device is turned on it will start at 0mA and the current can then be increased in 0.1mA increments up to 
1.0mA. The waveform is a bipolar rectangular shape with 50% duty cycle and – i.e. half the time no current is 
being delivered. The device is powered via a 3.75V battery and can be recharged through a USB connection. 
There is also a hardware interlock to ensure the device cannot be switched on when the charging cable is being 
used. Note the device is battery, and not mains, powered. 
 
The devices are placed on the head in a manner analogous to headphones, and the VeNS devices will deliver 
a small electrical current (1.0mA or less) to the skin behind the ears over the mastoid processes. The device 
can only be used for up to one hour a day, and after being used for this time period the device will automatically 
lock out for the next 16 hours. Delivery of electrical current to the skin over the mastoid region is known to 
activate all five components of the vestibular apparatus, but lower level currents (below 3mA) are thought to 
particularly activate the two otolith organs responsible for detecting linear acceleration and gravity (Zink et al., 
1998). It is these otolith organs that, from the animal studies, are particularly associated with a reduction in 
body fat. This technique – known as bilateral bipolar vestibular stimulation – has been known about since the 
19th century and is known to be safe, though skin irritation behind the ears can occasionally occur (Fitzpatrick 
& Day, 2004). 
 
In 2015, Paneri et al. (2015) reviewed the safety of repeated sessions of transcranial electrical stimulation 
(tES), a term that they use to encompass both the transdermal electrical modulation of cranial nerves (i.e. as 
in VeNS) and transcranial direct current stimulation (tDCS) of the cerebral cortex. Based on studies of tES on 
patient groups with depression (Brunoni, Valiengo et al., 2013) and migraine (Magis, Sava et al., 2013), and 
an array of studies of tES on normal volunteers (Brunoni, Amadera et al., 2011) (Kessler, Turkeltaub et al., 
2012) (McIntire, McKinley et al., 2014) (Morales-Quezada, Cosmo et al., 2015) (Nitsche, Liebetanz et al., 2003) 
(Poreisz, Boros et al., 2007) (Raimundo, Uribe et al., 2012) (Russo, Wallace et al., 2013) (Tadini, El-Nazer et 

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al., 2011), together with theoretical assessments of tES (Bikson, Datta et al., 2009) (Brunoni, Nitsche et al., 
2012), they commented that the “safety and tolerability profile previously accumulated regarding extended use 
of tES in clinical populations is compelling and supports a low-risk or non-significant risk designation” (Paneri, 
Khadka et al., 2015) 
 
Paneri et al. (2015) also assessed the safety and tolerability of repeated tES across time in a group of 100 
volunteers who were split into three groups. The first group received sham stimulation, the second tES at 2mA, 
and the third pulses of tES at between 5 to 7 mA (this is notably higher than the 1mA maximum we are 
proposing to use). A total of 1905 treatment sessions were carried out in total across the three groups. The 
investigators report no serious adverse events in any treatment condition, and that the common side effects 
were restricted to skin tingling, itching, and mild burning. Moreover, the incidence of these events were not 
statistically higher in the tES groups (Paneri, Khadka et al., 2015). These mild skin sensations were not 
associated with withdrawal from the study and the Investigators reported they became less salient after the first 
few sessions. Other adverse events, such as headache, were rare (<5%) and statistically indistinguishable 
across the three groups. Paneri et al (2015) concluded that the “repeated use of limited output tES across 
extended periods, is well tolerated and poses no significant risks to healthy subjects, as previously observed 
in clinical studies”. 
 
This conclusion is in keeping with the findings of Wilkinson et al. (2009), who reported on a stroke patient who 
received repeated VeNS sessions as part of his rehabilitation therapy. The Investigators observed no adverse 
events during stimulation over 5 consecutive daily sessions of VeNS at 1mA for 30 minutes per day. Utz et al. 
(2011) studied the adverse effects of 255 VeNS sessions at 1.5mA (again higher than the 1mA we propose to 
use) in 55 stroke patients and 30 healthy controls. They found only a few mild adverse effects, with the most 
common being slight itching (mean 10.2%) and tingling (mean 10.7%) underneath the electrodes. They 
concluded that VeNS induces “very few and mild adverse effects in healthy and persons with stroke and [is] 
safe” (Utz, Korluss et al., 2011). There is thus a body of literature supporting the safe usage of both tES and 
specifically VeNS devices delivering at least 1mA in stimulation. 
 
Similarly, in February 2016, Halo Neuroscience, a company based in San Francisco, released additional data 
on the safety of tES; on this occasion for a 2mA tDCS device used on 1010 subjects (HaloNeuroscience, 2016) 
They state that “there were zero reports of burn or seizure activity across all 1010 subjects, zero serious or 
unexpected adverse effects and zero withdrawals due to adverse events other than unpleasant sensation”. 

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They conclude that their tES study showed “a favorable safety profile and [was] associated with a very low 
incidence of adverse events, with no unexpected or serious adverse events”. 
 
The above studies were carried in the adult population, However, there is also a smaller body of work reporting 
the use of VeNS in the under 18 age group. Two studies have been published looking at the effect of VeNS 
(GVS) on adolescent scoliosis (Pialasse, Descarreaux et al., 2015) (Pialasse, Descarreaux et al., 2015). These 
studies both administered VeNS up to 1mA in intensity in several dozen children aged from 10 to 18 years. 
Both children with adolescent scoliosis and healthy controls were recruited. Binaural, bipolar stimulation was 
administered up to 1mA in repeated pulses of 2 seconds in duration. No adverse events were reported by the 
investigators. Similarly, another study involving both children and adults, undergoing vestibular rehabilitation, 
who were repeatedly administered one-minute of VenS up to 2mA in intensity, also did not document any 
adverse events (Carmona, Ferrero et al., 2011). 
 
Specific measures taken by the study device to reduce the incidence of skin irritation are the 50% duty cycle 
(i.e. half the time no current at all is being delivered), and the maximum current of 1.0mA. This means that the 
maximum phase current that can be delivered is only 500μC. It is noteworthy that no duty cycle, with the 
consequent reduction in maximum phase current, was reported as being used in any of the studies describing 
the use of VeNS in the pediatric age group (Carmona, Ferrero et al., 2011) (Pialasse, Descarreaux et al., 2015, 
Pialasse, Descarreaux et al., 2015), and despite, this none of them reported any adverse effects. In conclusion, 
there is not a significant risk of harm from using the device, and as such criteria d and g do not apply. Thus, as 
the device does not meet the criteria of a significant risk (SR) device it is a non-significant risk (NSR) device.  
6. Overview of Clinical Study 
Note: This protocol refers to ‘study staff’ throughout. The study staff role may be filled by clinical trial 
coordinators, or other clinical trial site staff who may be trained technicians, nurses or dieticians qualified to 
perform the various study activities detailed throughout this protocol. Each subject will be assigned a unique 
subject identifier (Subject ID). Individual subjects are allowed to participate in the study only once. 
 
The purpose of this investigational device study is to collect data to support regulatory submissions, primarily 
in the United States of America (USA), but it may also be used to support submissions in other regions, 
including the European Union (EU). 
 

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This double blind randomized controlled trial will be conducted at four clinical trial sites: The University of 
California, San Diego’s Clinical (UCSD) and Ulster University (UU) in Northern Ireland. The study is an 
Investigator Initiated Study and when the term ‘Study Sponsor’ is referenced, it relates to Neurovalens Ltd. (the 
device manufacturer). The study site located in USA will enroll approximately 106 subjects post-randomization. 
The study site in Northern Ireland will enroll approximately 94 subjects post-randomization. Each Subject will 
be assigned a unique Subject identifier (Subject ID). Individual subjects are allowed to participate in the study 
only once. The study will be randomized for a 6 month period with a 1:1 active to sham device allocation. After 
completion of this initial 6 month period, the study will stop.  
 
Screening of subjects will be completed remotely over the telephone with the completion of a study inclusion 
and exclusion criteria Screening Questionnaire and willingness to participate in the study.  This interview will 
be conducted via the clinical sites telephone line which will be detailed on the advertisements associated with 
advertising the study for identification of potential study participants.  Subjects will be given a brief outline of 
the study and asked if they would be interested to continue for potential inclusion by answering inclusion and 
exclusion questions, all interviews will be recorded on the study Pre-Screening questionnaire (telephone 
screening form). Subjects who are deemed eligible on paper will be asked for their contact details and this 
information will be forwarded to the clinical site to arrange the 1st baseline visit activities (Visit 1, 0 months).   
 
At the UU site only: If a particiant has successfully met the inclusion criteria via telephone Pre-Screening, their 
contact information will be sent via email to the study staff at UU to arrange for their baseline visit (Visit 1, 0-
Month).  The participant will be informed that a study information pack will be sent to them for completion prior 
to their baseline visit. This study information pack will include the following documents: Informed Consent Form, 
Food Frequency Questionnaire, Modifiable Activity Questionnaire, Two-day 24 Hour Recall, Concomitant 
Medications Form and Inclusion/Exclusion Form. The participant will be asked to bring these completed forms 
with them to their baseline visit (Visit 1, 0 Months) and at this visit each form will be reviewed by the study staff 
at UU. 
 
The scheduled site visits that each subject will undertake are:  
• 
Site Visit 1 (~3.5 hours; at 0 month timepoint for enrollment) (Subject fasted for at least 8 hours) 
• 
Site Visit 2 (~1.5 hours; at 3 month timepoint) (No fast required) 
• 
Site Visit 3 (final visit: ~3 hours; at 6 month timepoint) (Subject fasted for at least 8 hours) 
 

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The subject will be asked to refrain from exercise during the 24 hours period before each of the visits that 
involve DXA scanning (i.e. Visits 1 and 3). 
 
There is also a scheduled contact (email or telephone call) with the subject at the 1 month timepoint to ask 
subjects to complete the Adverse Event questionnaire and Blinding assessment (gathered by the VeSTAL 
study app).    
 
At the end of Visit 3 (i.e. only after the above actions have been completed), the final analyses will be conducted.  
Subjects will return their devices and cease participation at Visit 3. 
 
 Summary of Site Visit 1 Screening / Baseline (0 months) 
• 
The study staff will provide potential subjects with a description of the study, including 
requirements for participation, specific study activities, and procedures, these procedures 
should focus on the home use of the device and operation of the device. 
• 
Potential subject will read and, if wishing to participate, sign the Informed Consent Form, of 
which they will then receive a signed copy.  
• 
Study staff will enroll the subject by assigning them a Subject ID and then screen the subject 
via: 
o Completing the inclusion / exclusion criteria Screening Questionnaire to ensure 
compliance with inclusion/ exclusion criteria; 
o Carrying out a finger prick blood glucose to exclude diabetes mellitus (subject will 
have attended fasted) (see Subject Selection Criteria);  
o Carrying out a finger prick ThyroChek test for hypothyroidism (see Subject Selection 
Criteria); 
o If a female subject of childbearing potential, then a urinary pregnancy test should be 
carried out. 
• 
Subjects who successfully pass the screening criteria can proceed in the study and study 
staff will record their demographic information (age, gender, race/ethnicity), what medications 
(prescribed and over the counter) they take, and then randomize the subject using the block 
randomization method (1:1 active to control).  
• 
Subjects will undergo measurements and assessments for Visit 1 as specified below. 

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• 
Study staff will provide the subject with the study device that they have been randomized to 
use throughout their home use period and give the subject training in how to use it via the 
reading of the instructions for use for the VeSTAL device (see Section 11 Study Device 
Description for details on device that will be trained to study participants).  
• 
Study staff will also issue the subject with the following: an appropriately labeled box for the 
study device to stay in; sufficient electrodes and alcohol wipes to support daily usage by the 
subject until their next site visit; a charging cable and plug for the device; and an iPod 
supplied by the device sponsor to enable the subjects to use the investigational device. The 
iPod will be pre-installed with the VeSTAL study app that allows the device to be controlled 
via Bluetooth, the Activity Tracker Pedometer app, the Facebook app and a PDF in the 
iBooks app of the Physical Guidelines for Americans from the US Department of Health. IFU 
and Device Use Schematic will also be pre downloaded on supplied ipods.  
• 
Subjects will be informed about the exercise apps that are preloaded on the iPod they are 
being provided with. (See Lifestyle Modification Program details described below).  
• 
Study staff will give the subjects’ registration details on how to join a slimming support group 
called We Slim Together (See Lifestyle Modification Program details described below). 
• 
Dietary counseling and prescription of a hypocaloric diet with counseling on how to achieve 
this will be provided by a dietician. (See Lifestyle Modification Program details described 
below) In total 1 hour and 30 minutes will be spent with the dietician, including the time for 
the assessments described below.  
• 
After completion of the various testing procedures (see below) study participants will be 
instructed to return home and begin using their device on a daily basis for one hour a day. 
 
Measurements and Assessments During Visit 1  
• Screening procedures (Inclusion/Exclusion criteria questionnaire; Glucose finger prick for 
diabetes; ThyroChek for hypothyroidism; and if applicable a urinary pregnancy test) 
• Document demographic details – age, gender, race/ethnicity 
• Document medications (prescribed and over the counter) that the subject takes 
• Weight (Must be conducted with the participants wearing underwear and a hospital gown only 
– this must be consistent throughout the study duration. Weight will be taken on calibrated 
scales at study site, and calibration records will be reviewed during monitoring visits.) 

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• Height (Must be taken with shoes off and can be used to calculate BMI in conjunction with 
weight.) 
• Visual check skin behind ears (inspect to confirm not red or broken) 
• Heart rate and blood pressure 
• Lipid Panel (fasting) 
• Glycated hemoglobin (HbA1c) 
• Fasting blood glucose 
• High sensitivity C-reactive protein (CRP) 
• Quality of life survey (Duke University IWQOL – http://www.qualityoflifeconsulting.com/iwqol-
lite.html). Details on how to complete the questionnaires will be assessed during the SIV 
before study commencement. 
• DXA Scan (whole body scan) 
• Waist and hip measurements (To be taken in the same clothing described above, underwear 
and gown.) This will only be performed at the USA sites. 
• Dietician to assess diet and activity via: two-day 24-hour dietary recall; completion of the EPIC-
Norfolk Food Frequency Questionnaire (FFQ), and completion of the Modifiable Activity 
Questionnaire (MAQ). 
• Hearing test/ otoscope examination of the ear canal conducted. 
• Blinding assessment: As per the FDA guidance 
(https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocum
ents/ucm373766.pdf) the subject will be asked which intervention group (i.e. active or sham) 
they believe they are in and why they believe this. These data will be gathered by the VeSTAL 
study app, and this question will be posed to the subject immediately after they complete their 
first stimulation session. The subject and coordinator will not enter into discussion on this 
matter. These data will be passed to the study statisticians who will collate them for use in the 
final analyses. 
 
Case report forms for each subject must be completed by the study team after each visit. 
  
 Summary of Site Visit 2 (3 months) 
Measurements and Assessments During Visit 2 

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• 
Urine pregnancy test (if applicable) 
• 
Visual check skin behind ears 
• 
Weight (Must be conducted with the participants wearing underwear and a hospital gown 
only – this must be consistent throughout the study duration. They should also have an 
empty bladder. Weight will be taken on calibrated scales at study site, and calibration 
records will be reviewed during monitoring visits.) 
• 
Completion of adverse event questionnaire by subject  
• 
Dietician to assess diet via a two-day 24-hour dietary recall. 
 
Other Activities During Visit 2: 
• 
Dietary counseling from research dietician to optimize compliance with the hypocaloric 
diet (including review of dietary habits as above). In total one hour will be spent with the 
dietician. 
• 
Ensure subject has an adequate supply of electrodes and alcohol wipes to last until next 
visit. 
• 
Pay subject compensation as per compensation schedule 
 
Case report forms for each subject must be completed by the study team after each visit. 
 
 Summary of Site Visit 3 (6 months) 
Measurements and Assessments During Visit 3 
• 
Urine pregnancy test (if applicable) 
• 
Visual check skin behind ears 
• 
Weight (Must be conducted with the participants wearing underwear and a hospital gown 
only – this must be consistent throughout the study duration. They should also have an 
empty bladder. Weight will be taken on calibrated scales at study site, and calibration 
records will be reviewed during monitoring visits.) 
• 
Heart rate and blood pressure 
• 
High sensitivity CRP 
• 
Lipid panel (fasting) 
• 
Fasting glucose (plasma) 

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• 
HbA1c 
• 
Quality of life survey (Duke University IWQOL) 
• 
Completion of adverse event questionnaire by subject  
• 
DXA Scan (whole body) 
• 
Waist and hip measurements (To be taken in the same clothing described above, 
underwear and gown.) This will only be performed at the USA sites. 
• 
Dietician to assess diet and activity via: two-day 24-hour dietary recall; and completion of 
the MAQ. 
• 
Hearing test/ otoscope examination of the ear canal will be completed. 
 
Other Activities During Visit 3: 
• 
Blinding assessment: As per the FDA guidance 
(https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/u
cm373766.pdf) the subject will be asked which intervention group (i.e. active or sham) they believe 
they are in and why they believe this. The subject will be asked to privately write down which type of 
device they believe they were given (i.e. active or sham) and also why they believe this. They subject 
should then fold the paper over, so the coordinator cannot see it, and pass it to the coordinator. The 
subject and coordinator will not enter into discussion on this matter. These data will be passed to the 
study statisticians who will collate them for use in the final analyses. 
• 
Privately (i.e. without telling the subject) the coordinator will also record which group they 
believe the subject to be in. The double blind will remain in place and these data will also 
be passed to the statisicians for analysis. 
• 
Document changes, if any, in medications taken (prescribed and over the counter) 
• 
Dietary counseling from research dietician to optimize compliance with the hypocaloric 
diet (including review of diet and exercise habits as above). In total one hour will be 
spent with the dietician at USA sites and approximately 30 minutes at UU. 
• 
Pay subject compensation as per compensation schedule 
• 
The study participants will return the investigational device and unused consumables – 
i.e. electrodes and alcohol wipes. They can though keep the iPod. 
 
 
Case report forms for each subject must be completed by the study team after each visit. 

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 Schedule of Events 
Visit ID 
Visit 1 
Visit 2 
Visit 3 
Visit Description 
Screening/ 
Baseline 
Month 3 
Month 6 
End of trial 
Visit Window (Months ± 7 Days) 
0 Months 
3 Months 
6 Months 
Informed Consent Form, (HIPAA & 
Experimental Subject’s Bill of Rights for 
USA participants) 
X 
 
 
Inclusion/Exclusion Questionnaire 
X 
 
 
Glucose 
finger 
prick 
(Diabetes 
screening) 
X 
 
 
ThyroChek test for hypothyroidism 
X 
 
 
Urine pregnancy test (if applicable) 
X 
X 
X 
Record demographic details 
X 
 
 
Record 
medications 
or 
change 
in 
medications 
X 
X 
Give registration details for slimming 
support group 
X 
 
 
Randomize into study; give allocated 
device and supplies; train how to use 
device 
X 
 
 
Ensure subject has adequate electrodes/ 
alcohol wipes  
X 
X 
Check skin behind ears 
X 
X 
X 
Weight (underwear and gown) 
X 
X 
X 
Height (no shoes) 
X 
 
 
Waist 
and 
hip 
measurements 
(underwear and gown) 
X* 
X* 
Fasting glucose 
X 
 
X 

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* This measurement will only be performed at the USA sites. 
0 At 1-month timepoint the Adverse Event Questionnaire will be done via telephone or email. At 6-month 
timepoint the Adverse Event Questionnaire will be completed in person.  
Glycated hemoglobin (HbA1c)  
X 
 
X 
High sensitivity CRP 
X 
 
X 
Lipid panel 
X 
 
X 
Heart rate and blood pressure 
X 
X 
Quality of life survey (Duke University 
IWQOL) 
X 
X 
Adverse event questionnaire 
X0 
X 
X 
DXA Scan (whole body scan) 
X 
X 
Hypocaloric diet counseling 
X1 
X1 
Two-day 24-hour dietary recall 
X2 
X2 
X2 
FFQ 
X2 
 
MAQ 
X2 
 
X2 
Hearing test/ otoscope examination  
X 
X 
Blinding assessment: Ask subject to 
indicate which intervention group they 
think they are in 
X3 
 
X3 
Coordinator to privately record which 
intervention group he thinks the subject 
is in 
 
 
X 
UU site: Give subject compensation for 
time (see compensation schedule). 
 
 
X 
TDE and UCSD sites: Give subject 
compensation 
for 
time 
(see 
compensation schedule). 
 
X 
X 
VeSTAL 
device 
and 
unused 
consumables returned to site 
 
 
X4 
Ask if subject wants to be registered for 
a complimentary device if FDA approval 
occurs 
 
 
X5 

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1 Dietary counseling from a research dietician with emphasis on weight loss and healthy eating via a hypocaloric 
diet. 
2 Research dietician will have subject complete this activity. 
3 This will be performed at 0-Month and 1-Month timpoints collected via the VeSTAL app and at 6-Months in 
person at the clinical site. At 0-Month the VeSTAL app notification will be displayed after the first session of 
using the VeSTAL device  
4 If the participant completes the study to Visit 3 at 6 months then they will be given the iPod they used 
throughout as a gift. 
5  Staff at USA sites to ask subject if they wish their email address registered with the Sponsor so they can be 
notified to claim a complimentary device should medical device regulatory approval be granted as a result of 
this study. 
 
Frequency of Follow-Up Appointments  
As shown in the summary of frequency of follow-up appointments for all sites, the subjects will visit in person 
at: enrollment (0 months); 3 months and 6 months.  
 
Telephone or email follow-up are scheduled once for the 1-month post enrollment timepoints. These follow-up 
sessions are estimated to take about 10 minutes each and during them the subjects should complete the 
adverse event questionnaire.  
 
Also, at the 1 month timepoint the subject will be asked which intervention group (i.e. active or sham) they 
believe they are in and why they believe this (also referred to as a Bliniding Assessment). These data will be 
gathered by a pop-up question in the VeSTAL study app. The subject and coordinator will not enter into 
discussion on this matter. These data will be collected and analysed at the end of the study. 
  
Study participants are also free to contact (call or email) study personnel at any time with any issues or inquiries, 
and there is also the facility to bring subjects in on an ad hoc basis should concerns arise. 
 
 
 
Summary of Frequency of Folllow-Up Appointments for sites: 
 
Follow-up for all sites:  

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Clinical Site in Person Visits 
Enrolement (0-Month), 3-Month 
and 6-Month timepoints 
Adverse 
Events 
collected 
in 
Person 
3-Month and 6-Month timepoints 
Adverse Events collected via 
telephone or email 
1-Month timepoint 
Blinding Assessment collected via 
VeSTAL study application  
0-Month and 1-Month timepoints  
(At 0-Month the VeSTAL app 
notification will be displayed after 
the first session of using the 
VeSTAL device.) 
Blinding Assessment collected in 
Person 
6-Month timepoint 
 
 Summary of Dual Energy X-Ray Absorptiometry (DXA) Scanning Procedure 
Dual Energy X-ray Absorptiometry (DXA) is a technique that was originally developed to determine bone 
mineral density and to aid in the management of osteoporosis. More recently, the technique has been expanded 
to include the analysis of fat mass and lean body mass in addition to bone density. The DXA machine emits 
alternating high and low energy X-rays that produce precise, high quality images. A fan beam is now used, and 
this technology allows decreased scan times so that scans are completed within seconds or minutes. 
 
The basic principle of DXA data acquisition is based on the differences between bone and soft tissue 
attenuation at the high and low X-ray levels. As the X-ray beam passes through the subject, detectors register 
the varying levels of X-rays that are absorbed by the anatomical structures of the subject. The raw scan data, 
which includes values of tissue and bone, are captured and sent to a computer. An algorithm interprets each 
pixel and creates an image and quantitative measurement of the bone and body tissues. The amount of 
radiation exposure is very low.  
 
We will acquire a whole body DXA scans in Array mode (using the available DXA scanner at the Clinical Sites) 
at time-points 0 and 6 months. The technique has a precision error (1SD) of 3% for whole body fat, and 
automatically calculates total body fat, truncal fat and visceral adipose tissue. The radiation exposure 

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associated with this protocol is small, and the cumulative total the MPE indicates that the dose is 5 µSv for 
each DXA scan.  This gives total radiation dose of 10 µSv as 2 DXA scans are performed. 
10 microSieverts= 0.01 milliSieverts for the particpants.   
 
In order for the DXA scanner to function properly all metal must be removed from the subjects’ bodies and if 
possible they should change into a hospital gown/ light clothing. There is a DXA subject instruction sheet, this 
will be provided by the clinical research dietician and scanner operator at the Clinical Site, that is being included 
with this submission. It includes instructions like avoiding strenuous exercise and large meals and maintaining 
equivalent states of hydration in the hours immediately before a scan. Also, all female subjects, of child bearing 
potential, must undergo a urinary pregnancy test prior to each DXA scan to ensure that they are not pregnant.   
Due to the suggestion in the literature of a small risk of increased error, subjects will be requested to refrain 
from exercising (e.g. running, swimming or weight-lifting) in the 24 hours before any of the DXA scans. 
 
 Hypocaloric Diet 
All subjects taking part in the study must agree to try to lose weight by participating in a hypocaloric diet for the 
duration of the study – i.e. 6 months. A hypocaloric diet is the standard lifestyle modification program used in 
the trials of all the FDA approved weight loss medications – i.e. orlistat (600kcal per day deficit going to 900kcal 
after 6 months) (Sjöström et al., 1998), lorcaserin (600kcal daily deficit) (Smith et al., 2010), phenteramine-
topiramate (500kcal deficit) (Allison et al., 2011), naltrexone-bupropion (500kcal) (Apovian et al., 2013), and 
liraglutide (500kcal) (Wadden et al., 2013).  
 
The subjects will receive advice and counseling on how to achieve an hypocaloric diet from the research 
dietician who will see the subjects for one hour of counseling and assessment at the 0, 3 and 6 month visits. 
At the baseline visit the dietician will calculate the subject’s basal metabolic rate (BMR) by means of the Harris-
Benedict equation (Harris & Benedict, 1918). The dietician will then calculate that subject’s total daily energy 
expenditure by multiplying the BMR by 1.3 (this is the standard method followed in the weight loss drug trials 
as described in this paper about orlistat (Sjöström et al., 1998). 
 
After doing this calculation the dietician will then prescribe a 600kcal deficit hypocaloric diet for each subject. 
The dietician will review the hypocaloric diet plan with the subject and provide them with sample meal plans 

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together with weight loss and weight maintenance tips. The dietician will review the subject’s weight and 
adherence to their diet plan at the 3 month follow-up visit and provide ongoing advice and counseling. 
 
 Summary of Dietary Questionnaires 
Dietary counselling from a professional dietician will be performed with an emphasis on weight loss and healthy 
eating. These counselling sessions will include the following: 
1. A two-day 24-hour dietary recall at 0, 3 and 6 months 
2. An EPIC-Norfolk Food Frequency Questionnaire (FFQ) at 0 months. 
3. A Modifiable Activity Questionnaire (MAQ) at 0 and 6 months.  
 
The EPIC-Norfolk Food Frequency Questionnaire and the Modifiable Activity Questionnaire will be completed 
manually by the participant with the dietician assisting with any questions during the dietician counselling visits 
or remotely were indicated on this protocol as appropriate.  The two-day 24-hour dietary recall data will be 
analyzed via a database application called Nutritics, Nutritics will collate all two-day 24-hour dietary recall data 
across both sites for end analysis.  This software will be trained and released to the clinical site via the sponsor 
at the training and Site Initiation Visit. 
 
 Assessment of Diet and Activity 
The dietician will complete the three following assessments with each subject: 
1. Dietary information will be collected using a slightly adapted version of the USDA multiple-pass 24-hour 
recall method, originally developed by the USDA to limit the extent of underreporting that occurs with self-
reported intake. The method will be adapted to use three distinct passes and will collect information about a 
subject’s food intake during the preceding weekday and weekend day (two-day 24-hour recall) to better reflect 
the overall diet. This will be done at the 0, 3 and 6 month visits. 
 
There is no form for the subject to complete but rather involves the dietician conducting a “sweep” style 
interview with the subject. In brief the steps will be: (1) the quick list, which is an uninterrupted listing by the 
subject of foods and beverages consumed; (2) the forgotten foods list, which queries the subject on categories 
of foods that have been documented as frequently forgotten; and (3) the detail cycle, which elicits descriptions 
of foods and amounts eaten aided by the Portion Photos of Popular Foods guide ("Portion Photos of Popular 

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Foods" by Mary Abbott Hess, MS, RD and published by the American Dietetic Association). If possible step 1 
will be undertaken by the participant at home before each research appointment. Steps 2 & 3 will be undertaken 
by the dietitian within the dietary consultation. 
 
The two-day 24-hour dietary recall data are analyzed by the dietician to provide information on the total energy 
content consumed by the subject during the period, and the breakdown of this total in terms the percentage 
contributed individually by carbohydrate, fat, protein and alcohol. The dietician will use this nutrition analysis 
software to analyse the 24-hour dietary recall (https://www.nutritics.com/p/clinical). These data will be entered 
in an anonymized form into the software and dietician will be trained in advance of the study on how to enter 
the data.  
 
2. EPIC-Norfolk Food Frequency Questionnaire (FFQ) which is a validated dietary research tool composed by 
the University of Cambridge and the UK’s Medical Research Council.  As it is a UK developed instrument some 
of the language used is particular to that country. On the advice of the FDA the FFQ has been adapted to 
additionally explain in American English what type of foods are being referred to. It gives a view of intake 
frequency for specific foods and beverages over the previous year, and so provides a validated means to 
compare the dietary habits of the active and sham groups at baseline. This will be assessed by the dietician at 
the 0 month timepoint. The dietician can also analyze the FFQ using the Nutritics software to provide a 
spreadsheet containing data on energy, nutrient and food group consumption for each subject. 
 
3. Modifiable Activity Questionnaire (MAQ). This will be done at 0 and  6-months for all sites as it assesses 
activity over the previous year. This validated assessment of activity will provide data on: total physical activity 
averaged over the past year in hours per week; and total physical activity averaged over the past year in MET-
hours per week. One Metabolic Equivalent of Task (MET) is a physiological measure set by convention as 3.5 
ml O2·kg−1·min−1 (or 3.5ml of oxygen per kilogram of body mass per minute) and is roughly equivalent to the 
expenditure of 1kcal per kilogram of body weight per hour. MET value multiplied by weight in kilograms tells 
you calories burned per hour (MET*weight in kg = calories/hour).   
 
When the research dietician manually enters the above data into the various assessment tools, correct data 
entry will be verified by the study coordinator. 
 

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 The Healthy Eating Program and Support  
Study staff will give the subjects registration details on how to join a dietary advice support group called We 
Slim Together (WST) (https://wstcommunity.co.uk). This is a commercial weight loss support group based in 
Northern Ireland that has agreed to provide a tailored weight loss support service to the trial subjects in both 
the USA and UK. Specifically, the purpose of this support group is to help and encourage the subjects to adhere 
to the hypocaloric diet prescribed by the dietician. WST follows a similar program style to Weight Watchers with 
dieters eating low calorie conventional foodstuffs (as opposed to shakes). A recent systematic review showed 
that at the one-year point there is evidence to support the efficacy of this type of weight loss program (Gudzune 
et al., 2015). As part of the ICF the subjects are asked to consent to the WST mentoring team being told their 
weight and the daily caloric target that they have been set by the research dietician. This will be done by email, 
and no other subject specific information will be communicated by study staff to the WST team. Moreover, the 
data will be attached to the subject’s ID number rather than their name. 
 
The subjects will have a weekly invitation, at a time convenient to them, for a 10-minute private discussion with 
a named WST mentor. In advance of this session the subject will be asked to weigh themselves and to make 
the mentor aware of this weight, so they can judge the subject’s progress with the weight loss plan. (These 
weights are simply to guide this interaction will not be collected as part of the study data). Three out of every 
four weeks this private discussion will take place over Facebook messenger, and every fourth week it will 
consist of a face-to-face video call via Skype, Facetime or another analogous service. Subjects will be asked 
to try and attend at least 75% of these scheduled discussions with their mentor, and the WST mentors will 
provide the study team with monthly feedback on subject attendance. 
 
The subjects will get access to the general WST community, which is accessed via a private Facebook group. 
The Facebook app will be pre-installed on the iPod.  Subjects will be asked not to discuss their involvement in 
the trial or use of the trial device on this group, and the WST group moderators will also be aware of this 
injunction. Also, as part of the WST community the subjects will get access to: all WST recipes; all WST cooking 
videos; weekly live motivational talks; and access to 24/7 community support.  Although subjects must engage 
with the weekly mentoring sessions if they want to take part in the study, taking part in the other aspects of the 
WST is left to their discretion.  However, once a week the subjects will be asked by the VeSTAL app to estimate 
to the nearest hour what their usage of these other WST support group facilities has been. 
 

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The WST program involves encouraging participants to eat fresh rather than processed foods and educating 
them about low density foods that will keep them fuller for longer. The aim is to help make meals enjoyable 
while sticking to the hypocaloric diet set by the dietician. Thus, for instance, it will be suggested to participants 
that meals made up of the combinations of say 25% lean protein (with less than 5% fat), no more than 25% of 
carbohydrates like pasta, rice or potatoes, and about 50% vegetables.  
 
An alternative company called Clinical Trial Mentors (CTM) may be used in substitute for WST if required i.e. 
if WST are unable to meet the capacity of mentoring support needed for the trial (e.g due to the impact of 
COVID-19). CTM provide the same service as WST and if required will follow an identical setup as described 
above, including the same procedures and privacy considerations.  
 
 
Exercise 
There is no mandatory exercise regimen imposed as part of the study. This is because exercise appears to be 
a less important factor in generating weight loss than diet (Melanson et al., 2013). This observation may in part 
be due to compensatory behavioral adaptations (e.g. eating more), but also the fact that out with the lower 
range of physical activity energy expenditure is constrained, meaning that increasing levels of exercise do not, 
in fact, lead to ever increasing levels of total energy expenditure. Rather, in what is termed the constrained 
model, total energy expenditure plateaus with increasing exercise probably due to a compensatory fall in basal 
metabolism (Pontzer et al., 2016).  
 
Nonetheless, as there are multiple health benefits from being physically active, and so the subjects will be 
encouraged to avail themselves of the guidance and apps that are being provided to them on the iPod. The 
following physical activity resources are on each study iPod: the Activity Tracker Pedometer app which will 
allow subjects to track how many steps they take; and as a PDF in the iBooks app the Physical Activity 
Guidelines 
for 
Americans 
from 
the 
US 
Department 
of 
Health 
(see: 
https://health.gov/paguidelines/pdf/paguide.pdf).  
 
No data gathered by the pedometer app will be utilized in the study. It is being provided as an aide for the 
subjects to use to try and get more exercise. Subjects will be told that chapters 4 to 6 and chapter 8 of the 
Physical Guidelines for Americans are the most informative for them to read. These are the chapters that 

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respectively detail the guidelines for: Active Adults; Active Older Adults; Safe and Active; and Taking Action: 
Increasing Physical Activity Levels of Americans.   
 
Impact of Weight on Quality of Life (IWQOL) 
A Quality of Life Survey (IWQOL) will be done at 0 and 6 and months by the study staff.  This validated 
instrument, developed by Duke University, has been used by a variety of researchers to assess various obesity 
treatment options and their impact on individual patients. The questionnaire is available in a number of 
languages including Spanish. A detailed description is available on this website: https://olv.duke.edu/iwqol. As 
can be seen on this website this instrument has been used extensively in studies relating to weight loss and 
obesity: http://www.qualityoflifeconsulting.com/iwqol-litepublications.html.  
 
Hearing Test and Ear Examination 
It is proposed that study participants should undergo a hearing test and otoscope examination of the ear canal 
at 0 and 6-months “prior to and at the end of the clinical study”. The FDA has allowed a two week window after 
the subjects are seen and commence device usage for these tests to be carried out in. There is no suggestion 
from any of the literature looking at the safety of GVS that hearing, or the ear canal are adversely affected 
(Krystal et al., 2010; Marshall et al., 2010). And that a study specifically looking at the impact of GVS on cochlear 
function showed no effect (Cevette et al., 2012). Nonetheless, although there is no suggestion that hearing is 
adversely affected the FDA are requesting that such tests be carried out before agreeing to approve the device. 
 
An audiogram (hearing) test will be conducted on study participants at baseline and at 6 months for all sites. 
Prior to the audiogram, the outer canals of the study participant’s ears will be examined with an otoscope to 
make sure that the tympanic membrane is intact, and that there is no infection. An audiologist will then place a 
pair of insert headphones (Etymotic, ER-3A) into the subject’s ears and ask them to raise a hand or press a 
button when they hear a soft pure-tone. Bone conduction and air conduction thresholds (dB HL) will be 
measured at 250, 500, 1000, 2000, 3000, 4000, 6000, and 8000 Hz bilaterally. This is a standard hearing test 
to determine if hearing loss is present, and if so how much and of what type. A plot of frequency versus 
amplitude sensitivity threshold for each ear will be generated. The speech recognition threshold and word 
recognition score will also be obtained. All testing will be completed in a sound-treated booth in order to avoid 
extraneous noise.  
 

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The clinical site will contact the hearing test provider used specific for the clinical site during the visits. For the 
UU site the hearing tests will be conducted at Specsavers Opticians and Audiologists, 7-8 The Diamond 
Coleraine, BT52 1DE.  The receptionist there will be contacted by the UU Facility to arrange a suitable 
appointment for a full hearing assessment to be conducted at a time which is suitable for the study participant.  
The time and date of the appointment should be recorded on the appropriate case report from for that visit. UU, 
UCSD and TDE site subjects will receive an audiogram (full hearing) test at 0 and 6 months (Or assessment 
using the AMTAS Flex system).  Prior to the audiogram, the ear canals of the study participant will be examined 
with an otoscope to make sure that the tympanic membrane is intact, and that there is no infection. This hearing 
test will be based on the standard and most common type of hearing test, pure tone audiometry. The result of 
the test is an audiogram diagram which plots a person's hearing sensitivity at the tested frequencies. These 
tests will be performed at the UCSD and the TDE clinical sites. The audiologist will return the hearing 
examination and test results to the clinical site on completion via email, a hard copy of the tests will be retained 
at the hearing clinic and collected by the sponsor monthly and the original copy along with the email filed in the 
patient data pack.  The capture of this appointment should be reviewed by the PI or Sub PI when reviewing the 
patient data packs.   
 
As an alternative to the audiology assessment outlined above it has also been agreed with the FDA that 
subjects’ hearing may be assessed using the Grason Stadler AMTAS Flex device to assess pure tone 
thresholds. This is a patient self-guided device that can be overseen by the study coordinators in the clinic to 
assess air conduction screening and threshold audiometry. This option will only be utilized at the UC San Diego 
and TDE sites. It will be carried out with the subjects wearing the headphones provided with the AMTAS Flex 
device and in a quiet room. If any concern of an abnormal finding is raised during these investigations then the 
subjects will undergo audiology assessment as described above.  
 
 
 
Serum Assays 
Venous blood assays, with the subjects in a fasted condition, will be carried out at 0 and 6 months for glucose, 
HbA1c, lipid profile and high sensitivity CRP (hs-CRP). These are being analyzed as secondary (i.e. hypothesis 
generating) endpoints. The purpose in choosing these specific assays is to screen for change in cardiovascular 
risk factors. Specifically, glycemic control, lipid profile and inflammation are assessed using these tests. There 
is an increasing appreciation of the value of hs-CRP in assessing inflammation as a marker of cardiovascular 

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risk (Fonseca and Izar, 2016). The drug trials for liraglutide (Wadden et al., 2013), lorcaserin (Smith et al., 
2010) and naltrexone/bupropion (Apovian et al., 2013) all demonstrated a statistically significant improvement 
in hs-CRP with treatment. 
 
All subjects are provided with an iPod touch. This contains the following pre-installed applications: the VeSTAL 
study app that allows the device to be controlled via Bluetooth; the Activity Tracker Pedometer app; the 
Facebook app; and as PDFs in the iBooks app the Instructions for Use (IFU) for the study device, a Device 
Use Schematic and the Physical Guidelines for Americans from the US Department of Health (see: 
https://health.gov/paguidelines/pdf/paguide.pdf). 
 
 
Active Versus Sham Device 
Description of Device Function  
 
The design of the sham device was inspired by the sham devices used for studies on transcranial direct current 
stimulation (tDCS). This is appropriate as GVS (VeNS) can be viewed as specialized variant of tDCS that 
targets the vestibular system rather than the cerebral cortex. Careful consideration has been given to generate 
a sham device with an appropriate degree of authenticity, so as to maintain subject blinding, while 
simultaneously not, inadvertently, causing significant vestibular system stimulation in the control subjects.  
 
It has been observed that, due to subjects accommodating to the current, the tingling or itching sensations 
perceived on the skin during tDCS typically last about 30 seconds or so before abating (Nitsche et al., 2003; 
Paulus 2003). Based on this finding Gandiga et al. (2006) carried out a study in which both the tDCS and sham 
were increased in a ramp like fashion over about 10 seconds, however while the tDCS continued for 20 minutes, 
the sham was then turned off at the 30 second timepoint. Thus, the sham device still delivered the initial skin 
sensation, while at the same time not providing prolonged stimulation. The authors found that neither stroke 
patients nor healthy controls could distinguish between genuine tDCS and sham stimulation, even after 
experiencing both conditions.  
 
The VeSTAL sham device follows this pattern by applying some stimulation to a user for a limited period of 
time (30 seconds), before tapering down to zero over a further 20 seconds, thus creating the impression of an 
active device. Moreover, subjects will have been informed in the ICF that it is normal for the sensation to be 

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stronger initially on first turning on the device and then for it to, quite quickly, become less noticeable. It 
elaborates that this is because they “accommodate” to the stimulation. The sham stimulus is applied as a 
positive and negative bias square wave signal to the user (just like the active device), but with a frequency of 
0.8Hz. 
 
The decision for the sham to deliver at a frequency of 0.8Hz during each stimulation session was made to 
reduce the likelihood of a vestibulosympathetic response, specifically as measured by muscle sympathetic 
nerve activity (MSNA). This is because MSNA has been directly linked to weight loss (Straznicky et al., 2012), 
and it would seem likely that any putative vestibular modulation of body mass composition would, at least in 
part, be mediated via the sympathetic nervous system. However, the 0.8Hz delivery in the sham device is less 
likely to affect MSNA than the 0.5Hz delivery in the active device (Grewal et al., 2009; Macefield and James, 
2016).  
 
GVS poses the additional challenge, over tDCS, when designing a sham that subjects may not only be aware 
of skin tingling but also of vestibular stimulation. The sham device addresses this by not only temporarily 
providing the sensation of skin tingling but also vestibular stimulation, without as significantly modulating MSNA 
(as it is at 0.8Hz rather than the 0.5Hz frequency of the active device). This should increase the likelihood that 
sham users believe they have been allocated an active device. Moreover, two other factors are also pertinent 
when considering the verisimilitude of the sham device. First, in a manner analogous to the cutaneous 
sensations, the perceptual salience of the vestibular sensation may decrease with time (Fitzpatrick and Day, 
2004). And second, all the study subjects will be naïve to GVS. 
 
Sham Stimulation Activity 
The sham stimulation is a positive and negative bias square wave with a frequency of 0.8Hz, and (just like the 
active device) a maximum output current of 1mA. The stimulation is only active when the subject starts a 
session and lasts for a total of 50 seconds. 
 
Sham Stimulation Activity 
The sham stimulation is a positive and negative bias square wave with a frequency of 0.8Hz with a max output 
of 1mA. The stimulation is only active when the subject starts a session and lasts for a total of 50 seconds.  
 
Stimulation Control / Power Output 

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The user can increase or decrease of the stimulation level via the mobile app or the buttons on the device. 
Unbeknownst to the subject the power level output is set in bands as follows: 
Level 0  
 
No stimulation applied 0mA 
Level 1 – 3 
 
Stimulation applied 0.5mA 
Level 4 – 7 
 
Stimulation applied 0.7mA 
Level 8 – 10 
 
Stimulation applied 1mA 
 
The user has though a finer level of control when decreasing the stimulation: 
Level 0  
0mA 
Level 1  
0.1mA 
Level 2  
0.2mA 
Level 3  
0.3mA 
Level 4  
0.4mA 
Level 5  
0.5mA 
Level 6  
0.6mA 
Level 7  
0.7mA 
Level 8  
0.8mA 
Level 9  
0.9mA 
Level 10 
1.0mA 
This level of control allows the user to decrease the stimulation if they find it too intense but maintain a level of 
stimulation that will give them the impression that the device is an active one. 
 
Stimulation Time 
The stimulation time is characterized by three time periods: 
• 
Placebo Stimulation Period 
• 
User Control Period 
• 
Stimulation Decrease Period 
The Placebo Stimulation Period is the total period of time that electrical stimulation is delivered by the  device 
– i.e. 50 seconds. This period starts as soon as the subject increases the power level setting above zero. 
 
The User Control Period is the period of time when the user has control over the stimulation that is being applied 
to them. This has a period of 30 seconds.  
 

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The Stimulation Decrease Period is the period of time when the device decreases the stimulation output to 
zero. This is a period of 20 seconds. During this period the rate at which the stimulation is decreased is set at 
one level every 4 seconds. This means that every 4 seconds the stimulation is decreased by 1 until it reaches 
Level 1. The device will remain at Level 1 until the ‘Placebo Stimulation Period’ expires.  
 
After the Placebo Stimulation Period expires the device will no longer output any significant stimulation for the 
duration of the setting. The user will still see activity on the mobile app and will still be able to modify the 
apparent stimulation level via this app, or via the buttons on the device. When doing so the device will appear 
to the user to be operating as normal, including the single beep that acknowledges a change in the stimulation 
level (all beeps and light functions are identical between the sham and active device). However, no stimulation 
is delivered for the remainder of the session.  
 
At the 12, 24, 36 and 48 minute timepoints the sham device will confirm correct electrode attachment. It will do 
so by delivering an imperceptible 0.03mA pulse for 10 seconds. If an issue with electrode attachment is 
detected with this then the app will alert the user to reposition the electrode. Only once the device has been 
power cycled (turned off and on again), or after pausing the delivery for more than 5 minutes, will the Placebo 
Stimulation Period begin again. 
7. Rationale of Clinical Study 
There is a growing realization that obesity can, in many ways, be viewed as a neurological disease triggered 
by lifestyle factors. There is clear evidence that the arcuate nucleus in the hypothalamus regulates a “set-point” 
for how much fat the body should have. It does so by altering appetite and metabolic rate so that deviations 
too far in either direction are strongly resisted. This set-point is determined by genetic, epigenetic and lifestyle 
factors. Thus, excessive exposure to dietary monosaccharides, such as glucose, and saturated fats, especially 
in childhood and adolescence, can damage the neurons of the arcuate nucleus and push the set-point up. This 
then can condemn sufferers to a lifetime of obesity.  
 
Establishing a method of tuning down the set-point for body fat thus has to be a goal if we are to successfully 
combat the current obesity pandemic. A significant amount of animal work suggests that stimulating the 
vestibular system in the inner ear, by means of chronic centrifugation, actually does just that and causes a 
reduction in body fat. This is likely because the chronic vestibular activation is taken by the brain to represent 
a state of increased physical activity, and in order to optimize homeostasis it would be appropriate for the body 
to have a leaner physique, by reducing unnecessary energy expenditure from carrying excess fat. 

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It is possible to stimulate the vestibular nerve in humans by applying a small electrical current to the skin behind 
the ears. This is an established technology that is believed to be safe, but only previously used for research 
purposes. It was found in a pilot study (UCSD IRB #110538) that recurrent stimulation of this kind for two or 
three hours a week over four months led to a statistically significant reduction in truncal fat in the active group 
as opposed to the control group who underwent sham stimulation. 
 
Given the current, and increasing levels of global obesity, it is important to determine whether non-invasive 
electrical vestibular nerve stimulation (VeNS), otherwise known as galvanic vestibular stimulation, is a viable 
treatment option, since if it were this would be of significant scientific importance. The only way to answer this 
question is to use human subjects. 
 
In writing this Research Plan we have consulted the following document from the FDA, which although aimed 
at weight loss medications, does contain pertinent advice.  
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071612.pdf 
 
The current study will contribute to the field of knowledge about the neurological mechanisms that control body 
mass composition. We will also determine whether the relatively inexpensive, and non-invasive technique of 
VeNS is an effective treatment for obesity and fat loss. This is of particular importance given the current obesity 
pandemic and the serious public health challenge that obesity poses. 
 
A potential benefit for participants is that they may experience some degree of weight loss as a result of 
participation.  This is true for both the experimental and control groups, as both will be receiving regular weight 
loss counseling throughout the study from a professional research dietician, who will prescribe them a 
hypocaloric diet. Moreover, they will also be enrolled in a commercial healthy eating and dieting program – We 
Slim Together. This program will assist the subjects in making healthy dietary decisions in order to help them 
follow the hypocaloric diet outlined to them by the dietician, which will help with their weight loss. They will also 
be supplied with an iPod, which will be pre-installed with the Physical Activity Guidelines for Americans from 
the US Department of Health. The aim of giving the subject access to this is to encourage healthy exercise 
habits throughout the study. 
 

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8. Conduct of Investigation to Reduce Bias 
All site staff responsible for recording and reporting results from the investigational device will be blinded to the 
results from previous weigh in or use of the device until the end of the study. The staff will be blinded to all 
previous results collected through the study of the patient records in relation to weight loss and patient records. 
 
9. Device Description / Intended Use Statement 
The proposed device is a transdermal neurostimulation product. It consists of a battery-powered headset 
designed to deliver low-level energy in the form of a neurostimulation waveform that modulates the activity of 
the vestibular cranial nerve. The delivery of this waveform is through two self-adhesive electrode pads. These 
pads are placed on the skin overlaying each mastoid process. When turned on, the product delivers a small 
electrical impulse which can be adjusted up or down by the patient. 
 
Once adjusted to a level where the patient is aware of a tolerable, comfortable gentle swaying sensation, the 
stimulation delivered by the VeSTAL device should ideally remain at this level for the duration of the session, 
although further adjustments may be made using via a Bluetooth app or via the fixed up and down buttons on 
the headset or via a Bluetooth app., located just above the power button. The device can also be paused 
using the app by pressing the pause icon, or alternatively paused by pressing the power button on the 
headset twice in quick succession. When finished the patient removes the headset and disposes of the 
electrode pads after each use. When the product is not being used it can be charged through a micro-USB 
cable. For safety reasons, there are software controls in place to prevent the device delivering electrical 
stimulation when it is plugged into the micro-USB cable to charge the battery. When powered on, the product 
can be connected to an iOS or Android app via a Bluetooth Low Energy connection, which will allow fine 
adjustments of the neurostimulation amplitude.  
 
The recommended use is 1 hour per day, the VeSTAL device will automatically stop stimulation if the patient 
reaches one hour of usage per day. The patient cannot use the device again within a 16-hour period, this is to 
allow some flexibility of stimulation routines if required.  
 
10. Manufacturer 
Neurovalens Ltd. 

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The Warehouse  
7 James Street South, BT2 8DN 
Belfast, U.K.  
 
11. Device Description 
 
Headset Device 
Study staff will train the subject on how to use their study device. Specifically this will include: how to first 
prepare the skin over the mastoid processes with an alcohol wipe; a demonstration of where to place the 32mm 
diameter hydrogel electrodes (i.e. behind the ears on the skin overlying the mastoid processes – see Figure 
1); how to access the VeSTAL study app and pair the iPod (using Bluetooth Low Energy) to the device; how to 
operate the device using the app; and how to use the up/down buttons on the device if unable to use the study 
app. Study staff will provide subjects with a printed copy of the IFU and also highlight its location as a PDF on 
the iPod. The Device Use Schematic will also be highlighted to the subjects – it will only be as a PDF on the 
iPod. 
 
Although the 32mm diameter hydrogel electrodes are the first line electrodes to be used with the device, other 
stud electrodes approved for human use, can be used with the device so long as they meet the safety criterion 
specified by the FDA that their “maximum average power density should be less than 0.25 watts per square 
centimeter of electrode conductive surface area”. 
 
Also study staff will demonstrate to the subjects: how to charge the device; to dispose of used electrodes after 
a stimulation session; how to store unused electrodes in a sealed manner so they do not dry out; how to turn 
the device on and off using the power button; and how to use the app or power button to pause a stimulation 
session.  
 
Subjects will be asked to try and use their allocated device for an hour every day, and at least five times a 
week. Theoretically it is thought that the device may be more effective if used while sitting upright (as opposed 
to lying flat) (Macefield & James, 2016), due to the orientation of the otolith organs. As such subjects will be 
encouraged to use the device while sitting upright, and also in the evening as sometimes people can feel a bit 
soporific after vestibular stimulation. Subjects will be instructed not to walk around, operate machinery or drive 

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while using their device. Most people can tolerate up to 1.0mA without difficulty and subjects will be encouraged 
to turn the device up as much as they are comfortable with. 
 
 
 
  
Figure 1 Trial Device Placement 
Illustration of the trial device, showing the headset-style design and mastoid electrode placement. 
 
 
Software and Application 
The device incorporates embedded software and mobile application software, that is classified as a moderate 
level of concern according to FDA document “Guidance for the Content of Premarket Submissions for Software 
contained in Medical Devices” issued May 11, 2005. 
Additionally, risk management information applicable to this product supports a software classification of Class 
A according to standard IEC 62304.  

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In summary, a failure of device software, resulting in hazards to which the software system can contribute, 
would not result in injury or damage to the health of the user or other persons. IEC 62304 requirement: to fall 
within Class A, this status must be valid, with or without the need for implementation of risk control measures 
(i.e. the SW failure may result in hazards that would not cause injury or damage; or the SW failure may result 
in hazards that, following implementation of risk controls, would not result in injury or damage). 
The validation of software requirements will be addressed by system level testing. Test acceptance criteria and 
a summary of test results, along with other software and design details as required for submissions 
incorporating software of minor level of concern, as outlined in the FDA guidance referenced above, will be 
included in the future submissions for the VeSTAL device. 
 
Within the system there are a number of stages that define how data gets from the VeSTAL device to the cloud 
service and subsequently the database: 
1. 
Data logs are recorded by the study device; 
2. 
The data logs are read from the device by the mobile application using Bluetooth Low Energy; 
3. 
The data logs are stored by the mobile application; 
4. 
When a full session is recorded the data logs for that session are sent to the cloud service using TLS 
(Transport Layer Security); 
5. 
The cloud service parses the session data and stores it and the raw logs in the database. 
These steps apply to both the active and sham devices. Along with this every record is date and time stamped 
at various points within the process. At point 1 a date/time stamp is generated on each log entry by the device, 
this is stored by the mobile application at point 3. At point 4 a start and end date/time stamp is generated for 
the entire session by the mobile application. At point 5 the session data is date/time stamped again to show 
when it was initially added to the cloud database. If any edits are performed after the data has reached the 
cloud service, the audit log will maintain a list of the following for each edit: 
• 
A date/time stamp of when the change happened; 
• 
The user that made the change; 
• 
A snapshot of the data before the change; 
• 
A snapshot of the data after the change. 
 
The data recorded in this manner for each session are: duration of usage; average intensity; and average 
resistance encountered. During the study, study staff will only have access to duration of usage data. The app 
will upload these data when connected to Wi-Fi. The trial devices have storage capacity to record a few week’s 

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worth of usage too, which they will store pending retrieval when the subjects next connect the device to the 
app. 
In order to help the study team monitor compliance the duration of usage data will periodically be automatically 
assessed. This will occur once subjects have been in the trial for at least 2 weeks, and happen on a weekly 
basis each Monday. If a subject’s usage over the previous two weeks is below 9 hours then an email alert, 
containing the subject’s ID code and total use figure, will be sent to the study coordinators and PI. (The figure 
of 9 hours every 2 weeks was chosen to allow a clear margin below what the subjects are asked to achieve as 
a minimum). The study team can then monitor the situation and judge how to proceed to optimize compliance. 
This may include contacting the subject to encourage device usage and asking if anything can be done to help 
with the process. 
 
Subjects have the option, if they so wish, to input their weight into the study app, which will display to the 
subjects a record of the entered values over time. This is purely for the subject’s own information, and to assist 
their We Slim Together (WST) mentor in best advising them how to follow their prescribed hypocaloric diet to 
lose weight. The WST mentor will be able to view the entered weight values (attached to the subject’s ID 
number and devoid of any subject identifiable data) via a password-accessible database. No other information 
from the app, other than the weight that the subject chooses to enter, will be made available to the WST team. 
Conversely, weight values entered into the app by the subjects will not be accessible at any point by the study 
staff and have no role in any of the endpoint analyses. 
 
 
Associated Devices, Consumables 
The VeSTAL device as part of a system, using consumable electrode pads and wipes, Neurovalens should be 
contacted to provide additional consumables if required throughout the trial. 
 
All subjects are provided with an iPod touch. This contains the following pre-installed applications: the VeSTAL 
study app that allows the device to be controlled via Bluetooth; the Activity Tracker Pedometer app; the 
Facebook app; and as a PDF in the iBooks app the Physical Guidelines for Americans from the US Department 
of Health (see: https://health.gov/paguidelines/pdf/paguide.pdf). 
 
Any other material/equipment required for testing are provided/sourced by the investigation site directly. 
 

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12. Instructions for Use 
IFU is included as a supporting document to this protocol. 
 
13. Packaging and Labelling 
 
The VeSTAL Device is delivered with the following components: 
• 
Alcohol wipes  
• 
Electrode pads  
• 
USB charging cable 
 
Each of these components is labelled with the following information: 
 
• 
Title 
• 
Date of Manufacture 
• 
Stated volume 
• 
Lot number 
• 
Storage conditions 
 
The Headset Labelling is as follows: 
 
 
 

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The Headset Labelling is as follows for the USA: 
“Caution: Investigational device. Limited by Federal (or US) law to investigational use” 
Batch Number: 
Serial Number: 
 
Outer packaging USA: 
 
CAUTION--Investigational device. Limited by Federal (or United States) law to investigational use. Vestibular 
Stimulation to Trigger Weight Loss (VESTAL) Clinical Trial. Clinical trial number: NCT03640286. 
 
Manufacturer: Neurovalens Ltd, Floor 4 The Warehouse, Belfast, BT2 8DN 
 
Outer packaging EU: 
 
Manufacturer: Neurovalens Ltd, Floor 4 The Warehouse, Belfast, BT2 8DN 
 
Warnings and Precautions: 
• Discontinue use and contact study personnel if unexpected reactions occur.  
• Possible adverse effects include: skin irritation; discomfort from the stimulation; sensation of feeling off-
balance; occasional nausea; headache; and rarely vomiting.  
• Only apply to the mastoids (the hard-bony area behind your ear). 
• Use only while seated or lying down. 
• Do not use while mobile (moving), as it can affect your sense of balance. 
• Do not use while driving, or operating machinery of any kind.  
• Do not use if you have been diagnosed with epilepsy. 
• Do not use in the presence of a pacemaker, implanted defibrillator or neurological stimulation device (e.g. 
deep brain stimulation or vagal nerve stimulation device). 
• Do not use in wet environments. 
• Do not share your headset with anyone else. 
• Do not try to remove the batteries. They are non-user replaceable. 
• Keep away from children. Small items such as electrode pads are choking hazards. 
• If you feel discomfort during use, pause and reduce intensity before resuming. 
 

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Contents: 1 VeSTAL device; 1 micro USB charger; 1 USB plug; 180 x hydrogel electrodes; and 200 alcohol 
wipes. 
 
Made in UK. Neurovalens, Belfast, UK. 
Contains 1 x VeSTAL headset, 1 x charging USB cable, 1 x box of alcohol wipes (100), 2 x bags of electrode 
pads (100) 
 
“Must not be used while driving or operating machinery of any kind. Should not be used in the 
presence of an implanted cardiac pacemaker, defibrillator or neurological stimulation device. 
Possible hazards or adverse effects include: skin irritation; discomfort from the stimulation; 
sensation of feeling off-balance; occasional nausea; and rarely vomiting. 
Warnings and precautions: it is recommended that you use this device only while seated or lying 
down.” 
 
14. Storage and Accountability 
 
Accountability 
Investigational devices will be supplied by Neurovalens. Study Staff will be required to record all material 
received, used and destroyed to ensure full accountability. Returned devices will be evaluated for operational 
compliance at the end of the study. 
 
Storage 
The information supplied with the VeSTAL devices state to keep them dry and out of direct sunlight. There is 
no other special storage instruction which accompany the VeSTAL device.  
15. Device Training 
All investigation site staff will be trained to the relevant level of investigation conduct in device usage. Training will 
include: 
• 
Instructions on the use of the device 
• 
Health and Safety aspects 
• 
Clinical Investigation Plan and procedures there-in 

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• 
Completion of investigation documentation 
• 
Handling/reporting complaints and adverse events 
 
Training records will be maintained for all site staff involved in the study for audit purposes. 
 
16. Risk Benefit Analysis 
The risks to participants in this study are relatively small (skin irritation, mild discomfort, possible nausea, 
headache and, compared to background, a very small dose of radiation), as well as transient in nature; the 
discomfort and nausea will stop soon after stopping VeNS. And headaches have been observed to be mild and 
self-limiting or relieved by simple analgesia. Conversely, in terms of the importance of the knowledge that a 
positive study would yield, the potential benefits are significant. The global obesity pandemic poses significant 
public health challenges and developing novel strategies to combat it are of paramount importance. 
 
The current study explores the possibility that the non-invasive and relatively inexpensive technique of VeNS 
may be useful as a weight loss adjunct. Given the importance of the knowledge that may be gained, we believe 
the small risks to the subjects are reasonable. 
 
In the line with ISO 14971 a risk analysis has been conducted. The majority of risk has been mitigated through 
product design and manufacturing e.g. consideration was given to the risks associated with biocompatibility 
and safety etc. and therefore materials such as phthalates have been eliminated from the devices manufacture. 
The residual risk to patients who are administered this intervention is low. A list of potential risks associated 
with the device, procedures undertaken to minimize them, and methods used for their management are shown 
below. 
 

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General Risks 
1. 
Information of a personal nature will be collected in order to determine eligibility for the study, and 
therefore there is a risk of loss confidentiality.  
2. 
Subjects may experience some degree of distress or anxiety due to confusion, the personal nature 
of the questions, the usage of the trial devices, or their disqualification based on the exclusion 
criteria.  
 
Risks Relating to Screening Tests 
1. A diagnosis of diabetes mellitus may be suggested.  
2. A diagnosis of hypothyroidism may be suggested. 
3. A diagnosis of pregnancy may be suggested. 
 
Risks Relating to Phlebotomy 
1. Pain 
2. Fainting 
3. Bruising  
4. Rarely, a small hematoma or infection where the needle punctures the skin 
5. The tourniquet may cause discomfort or bruising of the upper arm 
 
Risks related to VeNS 
A risk assessment for the device has been carried out in accordance with ISO: 14971: 2012 and is held on site 
at Neurovalens, Neurovalens have submitted a risk request for the VeSTAL device for the study site located in 
USA, which indicates that it is a non-significant risk device determination. Due to the low current (1mA) and 
voltage (4.25 V), the VeNS stimulator being used in the study is safe. However, the following specific risks do 
exist: 
1. Skin irritation at the electrode sites. 
2. That the stimulation sites may be uncomfortable at the time of stimulation – an electrical tingling 
sensation may occur and also VeNS may induce the sensation of being pushed towards the side of 
the cathode. 
3. A sensation of disequilibrium, analogous to being on a boat, may occur during the test that some 
subjects find uncomfortable.  
4. VeNS may induce nausea. 

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5. VeNS may occasionally induce vomiting. 
6. Headache 
 
Risks Related to Being Weighed 
Subjects must change into a hospital gown prior to being weighed, which some subjects may find embarrassing 
or uncomfortable. 
 
Risks related to DXA Scanning 
1. For the site based in the USA it has been calculated that subjects will be exposed to a combined total 
radiation dose of 0.09000mSv from the two whole body scans they will receive over the course of 
participating in the study. The scanner used at the clinical sites in the USA is a Hologic Horizon W DXA 
scanner, and the scans administered will be whole body scans in Array mode. Ionizing radiation is 
known to carry a dose related increased risk of cancer. 
2. For the site based in Northern Ireland it has been calculated that subjects will be exposed to a combined 
total radiation dose of GE Lunar iDXA system (approx. 0.0025mSv from 2 whole body scans). The 
MPE indicates that the dose is 5 µSv for each DXA scan.  This gives total radiation dose of 10 µSv as 
2 DXA scans are performed. 
10 microSieverts= 0.01 milliSieverts 
The scan sequences we are proposing to use were selected to provide the greatest possible information about 
body mass composition while exposing the subjects to the lowest possible dose of ionizing radiation.  
 
3. In order for the DXA scanner to function properly all metal must be removed from the subjects’ bodies 
and they must change into a hospital gown. Some subjects may find doing so to be embarrassing or 
uncomfortable. 
 
Risks relating to Weight Loss Programs 
1. Subjects will have to discuss their dietary habits and weight loss aspirations with a professional 
dietician and some subjects may find doing so to be embarrassing or awkward. Also, as with any 
personal data there is a risk of loss of confidentiality. 
2. Data pertaining to the subjects’ diet and physical activity will be collected via interview with the dietician 
at the baseline, 3 and 6 month visit. As with any personal data there is a risk of loss of confidentiality. 
3. Subjects will also liaise with mentors from the dieting group We Slim Together, and some may be 
uncomfortable about doing so. 

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Risks Relating to Audiograms 
1. Some subjects may find the process of otoscope examination of the ear canal prior to the audiogram 
to be uncomfortable. 
2. It is theoretically possible that the otoscope examination could cause some local trauma to the ear 
canal. 
3. It is possible that the audiogram test may reveal some hearing loss that the subject was not previously 
aware of and that this could cause them psychological distress.  
4. Minor discomfort or pressure may be experienced from headphones. 
 
Risk of Loss of Confidentiality 
This is a general risk that applies to all of the data gathered as part of the study. The processes for managing 
the risk of loss of confidentiality are described in Section 39.   
 
 
Risk Management Procedures 
The risks to subjects participating in this clinical investigation are further reduced by the following factors: 
• 
Subjects will only be enrolled if they meet inclusion criteria 
• 
Investigators will be selected based upon their knowledge and expertise in the field and will be trained 
to use the device. 
• 
Clear instructional material will be provided with each device. 
• 
Subjects will be closely followed by trained investigators and their clinical research staff to monitor 
safety. 
• 
Procedures performed in the study are established and will be administered by trained and qualified 
clinical research staff. 
 
Risks relating to Screen Visit 
1. If a diagnosis of diabetes mellitus is suggested during screening, then the subject will not be able to 
continue in the study. Instead the subject will be advised that this is a possibility and that they should 
see their primary care physician for further assessment regarding this possible diagnosis. Some 
subjects may not be aware that they have diabetes, but if it is diagnosed it allows treatment to be 
undertaken which can significantly reduce the risk of the various ill effects that diabetes can cause. 

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2. If a diagnosis of hypothyroidism is suggested during screening, then the subject will not be able to 
continue in the study. Instead the subject will be advised that this is a possibility and that they should 
see their primary care physician for further assessment regarding this possible diagnosis. Some 
subjects may not be aware that they have hypothyroidism, but if it is diagnosed it allows treatment to 
mitigate its adverse effects.  
3. If a diagnosis of pregnancy is suggested during any of the pregnancy screening tests, then the subject 
will not be able to continue in the study. Instead the subject will be advised that this is a possibility and 
that they should see their primary care physician for further assessment. Some subjects may not be 
aware that they are pregnant, but if so then it is important that this is something they are made aware 
of. 
 
Risks Relating to Phlebotomy 
1. Phlebotomy will only be carried out by clinical site staff who are trained in the procedure. 
2. Subjects will be seated at the time of the procedure to mitigate risk in case they faint. 
3. The phlebotomist will apply local pressure to the site after the blood draw. 
4. It will be confirmed that bleeding has stopped and then an appropriate bandage will be applied.  
 
Risks Related to Vestibular Nerve Stimulation (VeNS) 
 
1. The devices being used have been judged to be non-significant risk devices in the risk assessment, 
carried out according to FDA criteria. 
2. Any potential subjects a history of irritation to the skin behind the ear will be excluded (See Criterion 3 
in Exclusion Criteria).  
3. Hypoallergenic hydrogel electrodes of 32mm diameter will be used in order to minimize the likelihood 
of skin irritation. If the subjects try these electrodes and do not like them then any alternative electrode 
they are offered will comply with the stipulation from the FDA that the “maximum average power density 
should be less than 0.25 watts per square centimeter of electrode conductive surface area”.  
4. If skin irritation occurs after using the device the subjects will be advised to apply aloe vera or other 
moisturizing gel, and they will also be given a contact number at for the appropriate clinical site, UU, 
TDE or UCSD and they can call in order to arrange a review.  
5. Prior to the beginning of the study the possible discomforts of VeNS will be described to the participant 
in lay language, and the investigator will make sure that the subject understands what will happen 
when using the device.  

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6. The usage of the device is electronically limited to just 60 minutes per day.  
7. Usage is voluntary, and subjects will be informed at the beginning of the study that they may withdraw 
at any time, for any reason, with no negative repercussions. 
8. Subjects will be warned about the sensation of disequilibrium and will be advised that the device should 
be used only while seated.  
9. The maximum current the device can deliver is 1mA but there is no requirement for the subjects to use 
it as this level. Instead they will be asked to increase the current (using buttons on the device) to a level 
that is comfortable. The minimum setting is 0.1mA and the current can be increased in 0.1mA 
increments. 
10. If subjects find the sensation invoked at the level they have the current set, to be uncomfortable (e.g. 
in terms of nausea or disequilibrium) then they can lower the stimulation level to a more comfortable 
setting. 
11. The subjects can always take off the devices at any point they wish.  
 
Risks Relating to Being Weighed 
A private area will be provided for the subjects to change into a hospital gown. 
 
Risks Related to DXA Scan 
1. All female participants will have to provide a negative urinary pregnancy test prior to DXA scanning 
due to the very small amount of ionizing radiation involved in DXA scanning. 
2. If participants become claustrophobic during the scanning process, the scan will be stopped, and the 
participant will be able to leave the room. Given the scans can be conducted in around 5 minutes this 
risk should be minimal. 
3. Thorough prescreening of all patients prior to the DXA scan to make sure they have no metal on their 
bodies or clothing. Participants will also be asked to wear a hospital gown, which will be available to 
them at the clinical site. 
4. They will be provided with a private area to change back and forth from their clothes into the gown. 
5. The dose of ionizing radiation from these scans is very small (it has been calculated that it will add up 
to a total of 0.09000mSv for the two whole body scans in the USA and the MPE indicates that the 
dose is 5 µSv for each DXA scan.  This gives total radiation dose of 10 µSv as 2 DXA scans are 
performed, 10 microSieverts= 0.01 milliSieverts in the UK.  Exposure to this small dose of radiation 
will be explicitly mentioned in the consent document. 

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Risks pertaining to Weight Loss Programs 
1. The Dietician at the clinical investigation sites who will administer the weight loss advice will be a 
qualified professional, employed by the clinical site with experience of such studies in the past.  
2. We Slim Together is a professional weight loss group. The only data that will be shared with them will 
be done with each subject’s consent and will consist of the hypocaloric dietary target set by the study 
dietician, the subject’s weight and an ID number for the subject. 
3. Subjects will be free, if they so wish, to use a pseudonym while interacting with WST. 
 
Risks Relating to Audiograms 
1. The examinations will only be carried out by trained clinical professionals.  
2. Participants will be free at any time to indicate that they wish to stop the procedure. 
3. The risk of revealing a previously unknown hearing impairment will be described in the Informed 
Consent Form. 
4. If headphones are not tolerated, then a different type of ear phone will be employed, which consist of 
a soft foam which is placed at the entrance to the ear canal. 
 
17. Scope and Objectives 
 
Primary Objective 
To establish the clinical performance of the VeSTAL Device stimulation effect in patients who are overweight. 
 
 
Secondary Objective  
To evaluate the safety of the VeSTAL device relative to control group, in terms of the occurrence of adverse 
events, changes from baseline in vital signs (blood pressure and heart rate), and safety laboratory results 
(chemistry and haematology), in patients who are overweight. 
 
Other objectives 
Evaluate the representativeness of the study population in terms of the balance in demographic and disease 

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state covariates. 
 
18. Overall Design  
 
Endpoints for USA Regulatory Clearance 
Primary Endpoints USA: 
The efficacy of the VeSTAL device within the treatment group will be quantified by calculation of two primary 
endpoints after 6 months of treatment: 
• 
mean percent weight loss; 
• 
proportion of participants who lose at least 5% body weight. 
 
Study Acceptance Criteria USA: 
• 
Mean: There should be at least a 2% total body weight loss (TBWL) superiority margin between the 
active-product and sham-treated groups.  
• 
Categorical: The proportion of participants who lose 5% TBWL or more in the active-product group is 
at least 50%, independent of the sham control  
 
Both weight loss efficacy acceptance criteria must be met to claim success. These criteria can be specified in 
mathematical formulae as follows:  
 
Rejection of both the null hypotheses μA – μC ≤ 2% and πA ≤ 50% at the 2.5% (1-sided) level 
Where:  
μA and μC are the underlying population mean percentage weight loss on active and control 
respectively  
πA is the underlying population proportion of subjects who lose ≥5% of baseline body weight on 
active.  
 
 
 
 

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Endpoints for EU Regulatory Clearance 
Primary Endpoint EU: 
The efficacy of the VeSTAL device within the treatment group will be quantified by calculation of the following 
endpoint: 
1. Mean percent weight loss  
 
Study Acceptance Criterion EU: 
• 
Mean: There should be at least a 2% total body weight loss (TBWL) superiority margin between the 
active-product and sham-treated groups.  
 
This weight loss efficacy acceptance criterion must be met to claim success. This criterion can be specified in 
mathematical formulae as follows:  
mA – mC ≥ 2% and pt ≤ 0.05  
Where:  
mA and mC are the observed mean percentage weight loss on active and control respectively  
pt is the p-value (two-sided) from a linear regression comparing percentage weight loss between 
active and control (H0: μA = μC; H1: μA ≠ μC)  
μA and μC are the underlying population mean percentage weight loss on active and control 
respectively 
 
 
Other Endpoints for USA and EU Regulatory Puposes 
 
Secondary Endpoints which may become the basis of claims in USA and EU (At 6 months): 
Total body fat loss (as measured by whole body DXA scanning), dietary outcomes (as measured by the two-
day 24-hour dietary recall), quality of life measures (as measured by the IWQoL questionnaire) and blood 
parameters are secondary endpoints which may become the basis of labelling claims. As such they will be 
tested hierarchically after the primary endpoints (full details of the hierarchical testing procedure will be detailed 
in the Statistical Analysis Plan).  
 
Secondary Outcome Measures USA and EU (At 6 months): 

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• 
The difference in mean fat mass loss (in grams) between the active-product and sham-treated 
groups is statistically significant. (As measured by means of a whole body DXA scan).  
• 
The difference in mean trunk fat loss (in grams) between the active-product and sham-treated groups 
is statistically significant. (As measured by means of a whole body DXA scan). 
• 
The difference in mean visceral adipose tissue (VAT) mass loss (in grams) between the active-
produce and sham-treated groups is statistically significant. (As measured by the whole body DXA 
scan). 
• 
Difference in mean lean mass gain (in grams) between the active-product and sham-treated groups 
is statistically significant. (As measured by means of a whole body DXA scan). 
• 
Difference in mean bone mineral content (BMC) gain (in grams) between the active-product and 
sham-treated groups is statistically significant. (As measured by means of a whole body DXA scan). 
• 
Fasting glucose 
• 
Lipid profile (Assess total non-HDL cholesterol, and HDL to total cholesterol ratio) 
• 
High-sensitivity C-reactive protein 
• 
Glycated hemoglobin (HbA1c) 
• 
Two-day 24-hour dietary recall 
• 
Modifiable activity questionnaire 
• 
Blood pressure 
• 
Heart rate 
• 
Waist and hip circumferences (This will only be performed at the USA sites.) 
• 
Body Mass Index (BMI) 
• 
Quality of life – IWQOL-Lite questionnaire.  
• 
Dose response analysis: it is likely that some subjects will not utilize their device for the mandated 7 
hours per week. Usage data will be available from the devices permitting a dose response analysis, 
which will done be in an intention to treat manner. 
• 
Adjustment of medication – both reduction and new medications. 
• 
Mentor support group usage (total hours). 
 
Safety Endpoints 
 
Adverse Event Monitoring Questionnaire (At 1, 3, and 6-months) 

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Based on the survey of adverse events devised by Utz et al. (2011) occurrence of the following adverse events 
will be specifically enquired about by having the subjects complete the Adverse Event questionnaire: headache; 
pain/irritation behind the ears; vertigo/ dizziness; blurred vision; nausea; fatigue/ tiredness; seizures; tinnitus; 
and other symptoms. This will be done in person during the 3 and 6 months in person and at the 1-month 
timepoint, this questionnaire will be conducted via telephone or by email. It will also be completed on an ad hoc 
basis should the need arise. The questionnaire will ascertain if any of these symptoms occur during or after 
use of the device, and if so how frequently. 
 
We will monitor each instance of an adverse event causing a dropout from the study. The dropouts, together 
with causes, will be recorded and reviewed at the end of the study. This guidance from the FDA will be followed: 
https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf. If it becomes evident that 
the proportion of subjects who drop out due to safety concerns/ adverse events convincingly exceeds 30%, the 
study will be halted. 
 
19. Number of Subjects and Investigational Sites 
An anticipated number of 200 patients shall participate in the device investigation. Subject enrollment will 
take place across two sites: 
1. University of California San Diego (UCSD) 
2. University of Ulster (UU) 
3. Texas Diabetes and Endocrinology (TDE) site  
20. Subject Selection 
 
Target Population 
Patients who are overweight. 
 
Subject Selection 
Pre-enrollment Screening  
 
Prior to being allowed to start the study proper, potential subjects with type 2 diabetes should be excluded by 
means of a fasting blood glucose test. This can be via a finger prick sample and glucose meter. Testing should 

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be done in the morning after an overnight fast of at least 8 hours. If the reading is 126 mg/dl or above, then the 
potential subject will be excluded from the study and asked to see their primary care physician in order to be 
investigated for type 2 diabetes mellitus. At the same Screen Visit subjects will complete a questionnaire about 
their medical history and medications to ensure that they fulfil the inclusion and exclusion criteria for the study. 
Any concomitant medications taken by the subject will be captured via the Concomitant Medication Form. The 
questionnaire will be identified using an alphanumeric code and will not have any identifiable subject data on 
them. The source documents will be securely stored at the Clinical Site. 
 
The following procedures will also be performed during the Screening process:  
• 
Obtain Informed Consent  
• 
Obtain demographic data, including gender, date of birth/age, race, and ethnicity;  
• 
Screening questionniare to confirm conformity with inclusion and exclusion criteria – access to medical 
records not required, medical history collected via questionnaire. 
• 
Measurement of height and weight to allow BMI to be calculated 
• 
Pregnancy test on urine (for women of childbearing potential only) 
• 
Hypothyroidism screening test  
• 
Fingerprick blood glucose 
 
 
 
Subject Recruitment 
The clinical sites at UCSD) will recruit subjects via Research Match (see: 
https://actri.ucsd.edu/clinical/Pages/using-ResearchMatch.aspx). This is a “is a NIH-sponsored national 
registry of volunteers who have indicated a willingness to learn more about research studies.” The aim of this 
registry is to connect “researchers with appropriate potential subjects.” The UCSD and TDE sites will also 
recruit via social media advertizing (e.g. Facebook), social networking advertizing (e.g. Craigslist), newspaper 
adverts, posters, leaflets, tabling events, use of volunteer databases and potentially radio advertizing.  
 
For the TDE site, as they are a clinical practice with an internal research centre, they will also recruit subjects 
via their patient database. Existing patients may be called or sent emails with the relevant study information or 
through social media or network advetrtising as well.  
 

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For the clinical trial site based in Northern Ireland potential subjects will be targeted via social media campaigns 
such as Facebook, Twitter and Instagram as well as radio and local news advertising. 
 
In order to improve recruitment numbers, we also plan to post recruitment flyers in the hospitals and universities 
associated to where the clinical trial is taking place. The advertisement to Facebook groups relating to weight 
loss that operate in the local areas where the clinical sites are located; if necessary Neurovalens may ask 
Facebook to promote this statement via a paid advertisement.  
Neurovalens shall be responsible for recruitment and shall follow best practice for the management of bias in 
subject recruitment. 
 
Inclusion Criteria 
1. 
Signed informed consent 
2.  
Body mass index BMI ≥ 27 kg/m2. 
3. 
Males or Females. Note females of child-bearing potential must have a negative urine pregnancy test 
at screen and also just before each DXA scan. (As DXA involves a small dose of ionizing radiation). 
They should agree to follow a physician-approved contraceptive regimen for the duration of the study 
period (other than DMPA injections as this causes weight gain). 
4. 
22-80 years of age inclusive on starting the study. (In order to comply with FDA guidance: 
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm08974
0.htm#s6)  
5. 
Ability and willingness to complete all study visits and procedures; in particular an agreement to engage 
with: trying to use the device on a daily basis; the hypocaloric diet weight loss program; and this 
provided weight loss support and mentoring. 
6. 
Agreement not to use of prescription, or over-the-counter, weight loss preparations for the duration of 
the trial. 
7. 
Agreement not to start smoking tobacco or marijuana for the duration of the study. 
8. 
Access to Wi-Fi (to connect iPod to internet) 
 
 
Exclusion Criteria 
1. History of vestibular dysfunction or other inner ear disease as indicated by the screening questions. 
2. History of bariatric surgery, or gastric resection. 

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3. History of skin breakdown, eczema or other dermatological condition (e.g. psoriasis) affecting the skin 
behind the ears. 
4. History of weight loss device implantation (e.g. VBloc Maestro or Abiliti). 
5. Use of a non-invasive weight loss device (e.g. Modius) 
6. Hypothyroidism requiring current treatment with levothyroxine (e.g. Levo-T, Synthroid, Thyroxine) 
(Other thyroid disorder patients on stable treatment for at least 3 months are acceptable). 
7. Other endocrinological causes of weight gain (e.g. Cushing’s disease, Cushing’s syndrome or 
acromegaly) 
8. Previous diagnosis of HIV infection or AIDS (HIV is known to cause a vestibular neuropathy which 
would prevent VeNS from working). 
9. Diagnosis of cirrhosis, chronic pancreatitis, or liver, kidney or heart failure. 
10. Treatment with prescription weight-loss drug therapy in the 6 months before starting the study.  
11. Tobacco smoking (including vaping) in the six months prior to starting and for the duration of the study. 
12. Use of marijuana (smoking, vaping or in edible form) more than twice a month on average. 
13. Known genetic cause of obesity (e.g., Prader-Willi Syndrome). 
14. Body weight change of more than 20% in either direction within the previous year. 
15. Physician-prescribed diet, and/ or current, active member of an organized weight loss program.  
16. Diabetes mellitus (Types 1 & 2).  
17. Diagnosis of epilepsy or use of anti-epileptic medication within six months of starting the study (e.g. for 
the treatment of peripheral neuropathy) 
18. Chronic (more than a month of daily use) treatment with opioid analgesic drugs within the last 6 months. 
19. Regular use (more than twice a month) of anti-histamine medication within the last 6 months. 
20. Use of oral or intravenous corticosteroid medication within 6 months of starting the study. 
21. Use of the beta-blockers atenolol, metoprolol or propranolol within 3 months of starting the study. 
22. Current alterations in treatment regimens of anti-depressant medication for whatever reason (including 
tricyclic antidepressants) (Note: stable treatment regimen for prior 6 months acceptable). 
23. An active diagnosis of cancer.  
24. A myocardial infarction within the preceding year. 
25. A history of stroke or severe head injury (as defined by a head injury that required craniotomy or 
endotracheal intubation). (In case this damaged the neurological pathways involved in vestibular 
stimulation).  
26. Presence of permanently implanted battery powered medical device or stimulator (e.g., pacemaker, 
implanted defibrillator, deep brain stimulator, vagal nerve stimulator etc.). 

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27. Psychiatric disorders (including untreated severe depression, schizophrenia, substance abuse, eating 
disorder etc.) 
28. Current participant in another weight loss study or other clinical trial. 
29. Have a family member who is currently participating or is planning to participate in this study. 
30. Weight over 350 pounds at UU, TDE and CTRI site (as this is the weight limit of the DXA scanner) or 
a weight over 500 pounds at the EPARC site (as this is the weight limit of the DXA scanner) 
31. Pregnancy 
 
The decision to exclude participants with type 2 diabetes mellitus was made after reading the FDA’s draft 
guidance 
(see: 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071612.pdf). 
This 
notes 
that, 
“[c]compared with nondiabetic patients, overweight and obese patients with type 2 diabetes often respond less 
favorably to weight-management products and may face unique safety issues such as risk for sulfonylurea-
induced hypoglycemia following weight loss (if the dose of sulfonylurea is not appropriately lowered or the drug 
discontinued).”  
 
The FDA then go on to advise “examining the efficacy and safety of weight-management products in trials 
dedicated to patients with type 2 diabetes.” On the basis of this advice we made the decision to exclude patients 
with type 2 diabetes. This is an important patient group of course, and our intention is to investigate type 2 
diabetics in due course.  
 
If a subject is found to possibly have type 2 diabetes during the initial screening, then they will be excluded and 
asked to notify their primary care physician. However, if a subject passes the initial screening but a suspicion 
of this diagnosis arises during one of the study tests, then the subject will be asked to notify their primary care 
physician, though they will still be allowed to complete the study.  
 
 
Withdrawal criteria 
These processes are to be implemented at both study sites. 
 
Subjects who do not meet the screening criteria will be considered screen failures and will be replaced. 
 

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Subjects may withdraw from the investigation for any reason, at any time. Subjects are free to participate or 
not participate as they wish.  
 
During the course of the study, subjects may be withdrawn from further involvement. Reasons for withdrawal 
may include: 
 
• 
Subject removal of consent 
• 
Any adverse event (related or not) that in the opinion of the investigator will endanger the well-being of 
the subject if they continued in the study. 
• 
Poor compliance with the study requirements (protocol violation) 
• 
Subjects lost to follow-up  
 
All subjects withdrawn from the study due to unexpected device effect, directly related to the clinical 
investigation, will be followed-up and treated until the effect resolves. 
 
Subjects who are withdrawn will not be replaced. All discontinuations will be documented along with the reason 
for withdrawal. Reasonable efforts will be made to contact any subject lost to follow-up during the course of the 
investigation in order to complete assessments and retrieve data. Should a subject be lost to follow-up the data 
available will be used in the final report, all uses of partial data will be documented. Ethics Committees and 
regulatory authorities will be notified of withdrawal as required by the regulations. 
 
If possible, when a subject withdraws, or is withdrawn, a final visit should be conducted to allow a withdrawal 
discussion with the subject. At this visit the study device, iPod and any unused consumables should be 
collected. Also, at this visit it will be requested in a non-coercive manner if the subject will permit their weight 
to be taken, and if they are willing to complete the Adverse Event monitoring questionnaire. Moreover, if the 
subject had reached the point where they were due a follow-up appointment (i.e. at 3 and 6 months), then they 
be asked, again in a non-coercive manner, whether they are willing to have the scheduled tests and 
measurements for that appointment. It will though be made clear to the subject that these activities are optional 
on their part. 
 
If the subject does not wish to return for a final visit, then a withdrawal discussion on the telephone will be 
attempted. In this discussion factual information may be provided to the subject and arrangements made for 
end-of-study activities like return of study investigational device, payment of any outstanding compensation 

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and whether the subject will complete the adverse event questionnaire over the phone. There will be no attempt 
to coerce or unduly influence the subject. 
 
A list will be assembled of all subjects who withdrew, or were withdrawn, from the study after enrollment. This 
will be broken down by center and treatment group and contain the following information: subject ID; specific 
reason for discontinuation; duration of treatment and last day of study adherence before discontinuation; 
whether or not the blind for the subject was broken at the time of discontinuation; if the subject returned the 
study device; and, after conclusion of the study and unblinding, what that subject’s treatment allocation was – 
i.e. active device or sham. 
 
21. Investigation Procedures 
 
Informed Consent 
In order to facilitate the identification of prospective research participants who meet the eligibility criteria for 
enrollment review it is proposed that pre-screening by telephone take place. In order to allow this to take place 
over the telephone it is requested that a waiver of consent documentation is allowed.  
 
As this pre-screening process will collect identifiable information that includes Protected Health Information 
(PHI) prior to obtaining consent to participate in the study, we wish to request a waiver of individual HIPAA 
authorization. Below we describe how each of the following criteria for granting the waiver will be satisfied: 
 
a) 
Why the disclosure of PHI involves no more than minimal risk. 
 
This process is considered minimal risk to the potential subjects as all data gathered via this process will be 
treated in the same confidential manner as data gathered at any other part of the study. Moreover, all data for 
subjects deemed ineligible to participate will be destroyed at the end of the phone call to pre-screen them.  
 
b) 
Why granting the waiver will not adversely affect privacy rights and welfare of the individuals whose 
records will be used. 
 
It is not believed that this process will adversely affect the privacy rights and welfare of potential subjects that 
are pre-screened as the telephone script still includes the Elements of Consent. Potential subjects are thus 

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requested to give verbal consent to undergo the pre-screening process. Other than the data provided over the 
phone by potential subjects undergoing the pre-screening process no hospital records or other PHI will be 
accessed as part of the telephone pre-screening process. 
 
c) 
Why the project could not practically be conducted without a waiver. 
 
The pre-screening process takes place over the phone it is not possible to obtain signed consent.   
 
Without the waivers of documented consent and individual HIPAA authorization in place the recruitment 
process would be much more cumbersome, a lot less practical and potentially significantly inconvenient for the 
potential subjects, as there are multiple inclusion and exclusion criteria. Thus, many potential subjects would 
attend in person at Clinical Site despite being clearly ineligible to participate in the study.  
 
d) 
Why the project could not practically be conducted without the use of PHI. 
 
There are over 30 inclusion and exclusion criteria, many of which pertain to aspects of PHI, and several of 
which relate to various relatively common health conditions and medications. Thus, without the use of PHI it 
would be impossible to inadequately screen potential subjects properly, and many would attend in person at 
the Clinical Site despite being obviously ineligible to participate in the study. 
 
e) 
An adequate plan to protect identifiers from improper use and disclosure. 
No identifiers will be attached to the pre-screening documentation, and no identifiers will be collected during 
the pre-screening process. At the end of the phone call to pre-screen subjects it will be determined whether 
the subject appears likely to be eligible or ineligible to pass the study’s screening process. Eligible subjects will 
be invited to attend the Clinical Site to be consented and enrolled into the study. Once this determination 
regarding eligibility is made the pre-screening questionnaires will be destroyed for all subjects. 
 
A separate document detailing the potential subjects who have been contacted via the pre-screening process 
will be kept in a locked data cabinet in the Clinical Site. (If this information is stored on a computer, then it will 
be on a Clinical Site computer assigned to study staff by the Clinical Site for research purposes, and it will 
require a password for access, which only personnel directly involved in the study will have.) No PHI will be on 
this document. Rather, all that will be recorded is whether the potential subject was found eligible or ineligible 

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via the pre-screening process. (It is necessary to keep a record of the names of the potential subjects found 
ineligible to proceed to avoid accidentally contacting the same person twice during the recruitment period). 
 
Access to these data in any format will only be available for study staff on the protocol. All data gathered via 
this process will be treated in the same confidential manner as data gathered at any other part of the study. 
Once recruitment to the study is complete (i.e. 200 subjects have successfully passed the screening process 
after giving informed consent) then this list of subjects who underwent the pre-screening process will also be 
destroyed.  
 
f) 
An adequate plan for destroying the identifiers at the earliest opportunity, or justification for retaining 
identifiers. 
No identifiers will be collected as part of the pre-screening process and no identifiers will be marked on the pre-
screening documentation, which will be destroyed at the end of the pre-screening call after determining likely 
eligibility. Once recruitment to the study is complete (i.e. 200 subjects have successfully passed the screening 
process after giving informed consent) then the list of subjects who underwent the pre-screening process will 
also be destroyed. (See Section (e) above). 
 
g) 
Written assurance that the PHI will not be re-used or disclosed for other purposes. 
We provide assurance that the protected health information (PHI) will not be re-used or disclosed for other 
purposes except as required by law, or for authorized oversight of this research study.  
 
h) 
Whether it is appropriate to provide the subjects with additional pertinent information after participation 
and, if so, how this will be accomplished. 
As identifiers will not be collected during the pre-screening it is not appropriate for all the potential subjects pre-
screened to be provided with additional information.  Those subjects judged eligible to proceed on the basis of 
the phone pre-screening will be invited to a face-to-face meeting at the clinical site. There they will be provided 
with a copy of the Informed Consent Form, which the research coordinator will then talk through with them.  
 
 
Obtaining Informed Consent 
Informed consent will be taken by clinical trial coordinators at the clinical site. This will be done in a private 
room at the clinical site in a manner that is non-coercive and using language that is understandable to the 

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potential participants. No exculpatory language will be used, and the participants will not be asked to waive any 
of their legal rights. The subjects will be informed about the purpose and the duration of the current study, and 
the Informed Consent Form will be talked through with the subject. The procedures and objectives will be 
described. As will all investigations, potential discomforts, risks and benefits of participation. Sufficient time will 
be given to subjects to decide whether they wish to participate. Informed consent will be obtained, once the 
subject has been informed and wants to participate in this investigation, using the attached informed consent 
form. 
 
In all cases of informed consent detailed below, the principal investigator (or approved designee) will sign the 
same consent form, on the same occasion as the subject. Three copies of the consent form will be made at 
UCSD and UU sites. The original copy of the signed consent documents will be kept in the Investigator site file 
at the investigation site. A copy will then be filed in the subject’s medical notes at the clinical site, and a further 
copied provided to the subject. Where sites utilize electronic medical notes, a note of the patient’s participation 
in this clinical investigation should also be made in the system. Two copies of the consent form will be made at 
the TDE site. The original copy of the signed consent documents will be kept in the Investigator site file at the 
investigation site and a scanned copy will be provided to the subject. Written informed consent from the subject 
must be obtained before any investigation related procedures (including screening procedures) are performed. 
 
The investigator or another member of the investigative team should appropriately address all and any queries 
that a patient may have regarding the clinical investigation.  
 
The investigator will return to the subject after sufficient time has elapsed and provide a recap of the clinical 
investigation. The approved consent form will then be provided to the subject in order to obtain written consent. 
In order that consent provided by the patient is voluntary and fully informed the subject should: 
• 
Understand the purpose and nature of the investigation 
• 
Understand what the investigation involves, its benefits (or lack of benefits), risks and burdens 
• 
Understand the alternatives to taking part 
• 
Be able to retain the information long enough to make an effective decision 
• 
Be able to make a free choice and free form coercion 
• 
Be capable of making this particular decision at the time it needs to be made. 
 

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Special Circumstances for Informed Consent 
 
In accordance with the European Standard EN ISO 14155:2011, informed consent may be given by a legally 
authorized representative only if a patient is unable to make the decision to participate in the clinical 
investigation. In such cases, the subject will be informed about the clinical investigation within his/her ability to 
understand. 
 
A consultee is a career or an individual who is concerned with the welfare of the named patient who lacks the 
capacity to give consent. The consultee will be consulted by the investigator as to whether the patient should 
take part in the clinical investigation and, in his/her opinion, what the patients’ wishes would be in regard to 
participating if they had capacity in relation to the matter. The consultee will be enlisted to attempt explaining 
the key facts about the investigation in language that would likely be understood by the patient. Communication 
with the consultee may take place by face-to-face interview, telephone or correspondence by letter. Consultees 
will be provided with a detailed information sheet regarding the investigation and will be asked to sign a 
declaration form, ‘Consultee Declaration Form’ stating that the patient would not object to taking part in the 
clinical investigation. 
 
For subjects or legally authorized representatives that are unable to read or write consent will be obtained 
through a supervised oral process. An independent witness shall be present throughout the process. The 
written informed consent form and any other information will be read aloud and explained to the prospective 
subject or his/her legal authorized representative and, wherever possible, either shall sign and personally date 
the informed consent form. The witness will also sign and personally dates the consent form attesting that the 
information was accurately explained, and the informed consent was freely given. 
22. Subject Eligibility 
Where a subject fails to fulfil the screening or randomization inclusion or exclusion criteria, this will be 
documented, and the investigator will retain the signed consent form. The subject will not advance any further 
into this clinical investigation. 

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23. Subject Identification 
When a subject is considered eligible for entry into this clinical investigation, the subject will be allocated firstly 
an individual screening number, and should they meet the randomization criteria they will be allocated an 
individual number at randomization (subject ID number). 
 
Subject number will consist of a unique numeral. These numbers will be unique identifiers of the subject and 
documented on each page of the Case Report Form or Requisition Form and all other documentation relating 
to the subject. 
 
The Subject ID number will be assigned to participants at the UU site starting at U1001, at the UCSD CCR site 
starting at C1001, the UCSD EPARC site as E1001 and at the TDE site as T1001. They will then continue in a 
sequential order for each subsequent subject. 
 
Logs relating to screening, enrolment and identification must be completed. However, the later log will only be 
held and the investigational site.  
24. Treatment Procedure 
 
Randomization / Assignment of subjects to treatment groups 
Treatment assignments, investigation or sham devices will be generated via a randomized procedure, with 
participants randomly chosen in permuted blocks. At baseline, subjects will be assigned 1:1 between treatment 
(investigational device) and control groups (sham device). Stratification will be performed by gender and center.  
 
Blinding 
Externally the active and sham devices appear identical. They can only be distinguished by a unique serial 
number that is known only to the manufacturing team at Neurovalens. The master code will be emailed to the 
study statisticians, who have no direct subject contact. The statisticians developed an envelope based subject 
randomization system for the study coordinators, so as to maintain double blinding. 
 
As per the FDA guidance the effectiveness of the blinding will be assessed at the 0 and 6 month timepoints. 
After using the device at the 1-month timepoint this will be via by a pop-up question in the study app asking the 
subjects to indicate which intervention group they believe they are in, and also why they believe this. The 

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coordinators will not be made privy to this information which will be passed to the study statisticians. The 
coordinators will be asked to provide the same information at 6 months (i.e. which group they believe the 
subject is in and why). At 6 months the coordinators will also ask the subjects to privately write down on a piece 
of paper what group they believe they are in and why. The coordinator should not look at the subject’s answer 
until after the unblinding process has taken place by asking the subjects to indicate which intervention group 
they believe they are in, and also why they believe this. The coordinators will be asked to provide the same 
information at 6  months.   
 
Independent Data Monitoring Committee (DMC) 
There are no safety issues with the device that require a DMC for safety monitoring in this study. 
 
Prior to Initiating Study  
• 
The Sponsor and Investigator complete a Clinical Study Agreement 
• 
The Investigator obtains Institutional Review Board (or other necessary regulatory/ ethical) approval 
of the protocol, any advertisements for the study, any information or other sheets to be given to 
participants and the Informed Consent Form. 
• 
The Investigator signs the Investigator Agreement form. 
 
 
Pre-Testing Activities  
• 
Neurovalens will arrange delivery of the study materials required  
• 
The study site staff will be trained on the IFU and how to connect the app on the iPod to the VeSTAL 
device. Training records shall be maintained in the Investigator Site File (ISF). 
• 
The study site staff on this Clinical Study Protocol and any amendments. The training records shall 
be stored in the ISF. 
 
Hearing Examinations (At baseline and 6 months) 
The FDA provided feedback that study subjects should undergo a hearing test and otoscope examination of 
the ear canal. There is no suggestion from any of the literature looking at the safety of GVS that hearing, or the 
ear canal are adversely affected (Krystal et al., 2010; Marshall et al., 2010). And a study specifically looking at 
the impact of GVS on cochlear function showed no effect (Cevette et al., 2012). It is intended that an audiogram 

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(hearing) test be conducted on study participants at baseline and at 6 months. Prior to the audiogram, the outer 
canals of the study participant’s ears will be examined with an otoscope to make sure that the tympanic 
membrane is intact, and that there is no infection. More details on this test are outlined below. Any change over 
the course of the study in a subject’s hearing, or the condition of the external canal of their ear, will thus be 
determined.  
 
Prior to the audiogram, the ear canals of the study participant will be examined with an otoscope to make sure 
they are free of wax, that the tympanic membrane is intact, and that there is no infection. This hearing test will 
be based on the standard and most common type of hearing test, pure tone audiometry. The result of the test 
is an audiogram diagram which plots a person's hearing sensitivity at the tested frequencies.  
 
As described above the GSI AMTAS Flex system and video-otoscopy alternative may be deployed at the UCSD 
sites. This has been agreed with the FDA and will be carried out in a suitably quiet room. The PI at the UCSD 
sites, Dr Erik Viirre MD PhD, who is a clinical neuro-otologist will review the results of these assessments and 
decide if whether subsequent formal audiometry assessment is required. 
 
25. Adverse Events 
 
General 
In accordance with the European Standard BS ES ISO 14155:2011 the following definitions apply in relation to 
adverse events. 
 
Adverse Event (AE). Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether related to the 
investigational medical device. For subjects this definition relates to all study procedures and comparators, for 
users and other persons it relates only to the investigational medical device. 
 
Adverse Device Effect (ADE). Adverse event related to the use of an investigational medical device. This 
includes adverse events resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction and events resulting from intentional misuse of the investigational 
medical device. 
 

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Serious Adverse Event (SAE). An adverse event that 
a) Led to death, 
b) Led to serious deterioration in the health of the subject, that either resulted in 
1) A life-threatening illness or injury, or 
2) A permanent impairment of a body structure or a body function, or 
3) In-patient or prolonged hospitalization, or 
4) Medical or surgical intervention to prevent life-threatening illness, injury or permanent 
impairment to a body structure or function. 
Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event. 
 
Serious Adverse Device Effect (SADE). Adverse device effect that resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Adverse Device Effect (UADE). This is defined by 21 CFR 812.3(s) as “any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of subjects.” 
26. Recording and Assessment of Adverse Events 
All observed or volunteered adverse events (serious or non-serious) and abnormal laboratory findings, 
regardless of treatment group will be recorded in the subjects Case Report Form. For all adverse events, 
sufficient information will be obtained to permit 1) an adequate determination of the outcome of the event (i.e. 
whether the effect should be classified as a serious adverse event) and; 2) an assessment of the causal 
relationship between the adverse event and the investigational medical device or, if applicable, the other study 
treatment. 
 
Adverse events or abnormal laboratory results felt to be associated with the investigational device or, if 
applicable, other study treatment or diagnostic products(s) will be followed until the event (or its sequelae) or 
the abnormal laboratory finding resolves or stabilizes at a level acceptable to the investigator-sponsor. 
 

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Abnormal laboratory results will be assessed by the Chief Investigator and in the event these results require 
additional follow-up, the subject will be contacted by the Chief Investigator (via email) advising the subject to 
contact their General Practitioner (GP). 
 
In accordance with the standard operating procedures and policies of the local Independent Ethics Committee/ 
Institutional Review Board the site investigator will report SAE’s to the IRB/IEC. 
 
27. Causality and Severity Assessment of Adverse Events 
The investigator-sponsor will promptly review documented adverse events and abnormal laboratory results to 
determine 1) if the abnormal laboratory finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the investigational medical device or, if applicable, 
other study treatment or diagnostic product(s); and 3) if the adverse event meets the criteria for a serious 
adverse event. 
 
If the final determination of causality is unknown and of questionable relationship to the investigation medical 
device or, if applicable, other study treatment or diagnostic products(s), the adverse event will be classified as 
associated with the use of the investigation medical device or, if applicable, other study treatment or diagnostic 
products(s) for reporting purposes. If the final determination of causality is unknown but not related to the 
investigational medical device or, if applicable, other study treatment or diagnostic products(s), this 
determination and the rationale for the determination will be documented in the respective subject’s case report 
form. 
 
28. Reporting UADEs 
As per the FDA guidance in this matter 
(https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf): UADEs must be 
reported by the clinical investigator to the sponsor and the reviewing IRB, as described below:  
 
• For device studies, investigators are required to submit a report of a UADE to the reviewing IRB and the 
sponsor [Neurovalens] as soon as possible, but in no event later than 10 working days after the investigator 
first learns of the event (CFR 812.150(a)(1)).  

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• Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation 
to FDA, all reviewing IRBs/ equivalent competent authorities, and participating investigators within 10 working 
days after the sponsor first receives notice of the effect (CFR 812.46(b), 812.150(b)(1)). 
 
29. Competent Authority Notification 
It is the obligation and responsibility of the Sponsor to report to the Competent Authority all serious adverse 
events, serious adverse device effects and/or unexpected adverse device effects received from an investigator 
in a timely manner. 
 
The sponsor will also inform all other participating principal investigators of all serious adverse events, serious 
adverse device effects and/or unexpected adverse device effects that are reported. 
 
30. Follow-up of Unresolved Events 
All serious adverse events, serious adverse device effects and/or unexpected adverse device effects will be 
followed up until they are resolved or for 30 days after the subject’s participation in the clinical investigation 
ends. 
 
31. Data Collection 
All records generated as part of, or in relation to, this study shall be maintained or referenced in a study binder. 
These records will be maintained as required by applicable regulations and or guidelines after completion of 
the study. 
 
Study site staff will be trained on the components of the study binder and the required documents which must 
be entered and documented in the study binder.  
 
In response to a suggestion from the FDA that a site outside California be opened for the study, the sponsor 
opened a second site at the Ulster University in Northern Ireland, United Kingdom. This second site is at the 
Ulster 
University 
in 
Northern 
Ireland, 
at 
its 
Human 
Intervention 
Study 
Unit 
(See: 

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https://www.ulster.ac.uk/research/institutes/biomedical-sciences/core-facility-units/human-intervention-
studies-unit). In order to increase the rate of rectuiment caused by the COVID19 pandemic, the TDE site were 
brought on board. Anonymized data from both all sites regarding the primary endpoints and safety endpoints 
will be sent to the statistical analysts. A poolability analysis will be carried out to assess the comparability of 
the non-US data and the US data. 
 
The UCSD Office of Contract and Grant Administration have been asked to establish an unfunded collaboration 
agreement with the Ulster University All sites will act in accordance with GCP guidance and study monitoring 
will be in place. The Research Plan as executed at CCR UCSD will also be executed at the EPARC UCSD and 
Ulster University sites.  
 
Data will be transferred in an encrypted PDF format. Trial staff will be given direction on how to share the trial 
data and given access to one specific section of a controlled cloud service which is controlled via role based 
access. Once they have authenticated with the service and the service verifies that they have the correct role 
to access the system they will be directed to a single webpage within the application where they will be able to 
upload the encrypted PDF. This PDF is generated on the fly and is therefore not stored in another location that 
could become compromised. Generating the PDF on the fly means that the source data is extracted from the 
database, processed and delivered in the context of a single request. This is an important factor as this means 
that after the request finishes the data in the PDF will not be held in application memory once the request is 
finished and the data relating to the request is freed. After the PDF is generated it is delivered to the assigned 
statistician using TLS 1.2 (a strong protocol), ECDHE_ECDSA with X25519 (a strong key exchange), and 
AES_128_GCM (a strong cipher). These data will be transferred for each subject when they complete 
participation in the study. If they complete the study protocol this will be at the six month mark, however, if they 
drop out early then data accrued up until that point will be sent. 
 
Completion of Case Report Form 
A Case Report Form may be in paper or an electronic format, details and procedures for completing Case 
Report Forms are provided in a separate document. All relevant investigation personnel are trained in the 
requirements of data collection and the method of collection prior to the first subject being recruited at that site. 
It is the responsibility of the PI to ensure that data is timely, accurate and complete. 
 

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Device Usage Records During Home Use Period 
Within the system there are a number of stages that define how data gets from the VeSTAL wearable to the 
cloud service and subsequently the database: 
1. Data logs are recorded by the VeSTAL wearable 
2. The data logs are read from the wearable by the mobile application using Bluetooth Low Energy 
3. The data logs are stored by the mobile application 
4. When a full session is recorded the data logs for that session are sent to the cloud service using TLS 
5. The cloud service parses the session data and stores it and the raw logs in the database 
Along with this every record is date and time stamped at various points within the process. At point 1 a date/time 
stamp is generated on each log entry by the wearable, this is stored by the mobile application at point 3. At 
point 4 a start and end date/time stamp is generated for the entire session by the mobile application. At point 
5 the session data is date/time stamped again to show when it was initially added to the cloud database. If any 
edits are performed after the data has reached the cloud service, the audit log will maintain a list of the following 
for each edit: 
• 
A date/time stamp of when the change happened 
• 
The user that made the change 
• 
A snapshot of the data before the change 
• 
A snapshot of the data after the change 
 
 
Review and Return of Completed Documentation 
The PI will make the original case report forms, where applicable, available to the monitor at each visit. 
Procedures for the return of completed documentation are provided in a separate document.  
 
Retention of Documentation 
The Principal Investigator, or designee, will retain all copies of the records for a period of 7 years from the 
completion of the clinical investigation. A list of essential documents to be maintained will be provided to each 
site at initiation. 
 
•  
Clinical Investigation Plan (CIP - this document) and revisions 
• 
Deviation Records 

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• 
Clinical site project-specific SOPs/protocols including any revisions 
• 
Notes to File (NTF) (for clarifications only – not to be used for any deviation from this TSP) 
• 
Financial disclosures 
• 
Any Investigator Agreement(s) 
• 
IRB/ethics approval: approval (including revisions), roster and annual reports/ final IRB report 
if applicable.  
• 
Clinical site certification 
• 
Training: Device-specific training and proficiency records 
• 
Training records for all operators involved in receipt of the device, testing with the device and/or 
reporting of results, including review 
• 
Equipment: maintenance records 
• 
Records for device: 
o 
Device shipping records, receipt, use, disposal and/or return records  
o 
Records of exposure to device (test records) 
o 
Source records  
• 
Clinical site monitoring records: 
o 
Monitoring log and monitoring attendance log supplied by Neurovalens at each monitoring 
visit 
o 
Site Initiation Visit report, monitor updates if applicable and memo from monitor to start 
testing 
o 
Routine monitoring visit reports 
o 
Site Close Out Visit report 
• 
Device adverse events  
• 
Correspondence relating to the device and this plan: 
o 
Key emails 
o 
Key conversation phone records  
 
Note: It is likely that multiple binders/files will comprise the “regulatory binder”. Assessment of maintenance of 
the study binder will be conducted at test site monitoring visits. 
 

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32. Suspension, Termination and Close-Out of Clinical Investigation 
 
Suspension or Premature Termination of Clinical Investigation 
Reasons for suspension or premature termination at an investigation site may include incidences where 
monitoring or auditing identifies serious or repeated deviations on the part of an investigator. The FDA and IRB 
will be notified of any suspension or early termination of the clinical investigation, together with all other principal 
investigators, in the event that the suspension or termination was due to safety issues. A principal investigator 
may suspend or prematurely terminate participation in the clinical investigation at the investigation sites for 
which they are responsible. 
 
If suspicion of an unacceptable risk to subjects arises during the clinical investigation, or when so instructed by 
the IRB or regulatory authorities, the clinical investigation will be suspended while the risk is assessed. The 
clinical investigation will be terminated if an unacceptable risk is confirmed. Should the risk not be confirmed 
justification and data supporting the decision to resume the clinical investigation will be provided to the relevant 
persons. 
 
Routine Study Termination and Close Out 
Routine close-out procedures will be conducted ensuring that the PI’s records are complete, all documents 
needed for the sponsor files are retrieved, remaining clinical investigation materials are disposed of, previously 
identified issues have been resolved. 
 
33. Data Management Procedures 
The investigator will prepare and maintain adequate and accurate source documents designed to record all 
observations and other pertinent data for each enrolled subject. Study Staff at each site will enter data from 
source documents corresponding to a subject into the protocol- specific Case Report Form. Subjects shall not 
be identified by name in the study database or on any study documents but will be identified by a site subject 
number. The handling of all data on the Case Report Form will be the responsibility of the PI. 
 
The de-identified data will be entered into a validated database. Once all the quality assurance steps have 
been completed and the data integrity verified the database shall be locked. Analysis of these anonymized data 
will be conducted according to a pre-determined statistical analysis plan.  

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Data from subjects who received treatment, who withdraw voluntarily or who are withdrawn from the clinical 
investigation, will be used in the final analysis. The inclusion of partial data will be documented in the final 
report. 
 
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting FDA guidelines for the handling and analysis of data for clinical trials. 
 
Data Archiving 
The database is safeguarded against unauthorized access by established security procedures; appropriate 
backup copies of the database and related software files will be maintained. Databases are backed up by the 
database administrator in conjunction with any updates or changes to the database.  
At critical junctures of the protocol (e.g., production of final reports), data for analysis is locked and cleaned per 
established procedures. 
34. Statistical Plan 
Prior to analysis of the final study data a detailed statistical analysis plan will be written describing all analyses 
that will be performed. 
 
Statistical Plan 
Analysis Populations  
The Primary Analysis population will be the 200 subjects included in the study. The primary analysis population 
is defined to include all randomized subjects (i.e. an intention-to-treat population). 
 
Representativeness Analysis 
To evaluate the representativeness of the population the following analysis will be conducted on the:  
 
Primary Analysis Population: 
As per the guidance from the FDA relating to the representativeness of the study population 
(https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM5
07278.pdf.source=govdelivery&utm_medium=email&utm_source=govdelivery) the following analyses will be 
conducted: 

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For each demographic characteristic an appropriate statistical test will be conducted to flag any differences 
between the two respective subgroups (active and sham devices). For categorical data either a Chi-square test 
(if n ≥ 5 in each table cell) or Fisher’s exact test (if n < 5 in any single table cell), will be used, and for continuous 
a 2-sample t-test will be used to compare the respective subgroups.  
 
Missing data will be clearly reported and included in tables, tests for representativeness will be conducted only 
on the data actually present. 
 
 
Randomization 
Treatment assignments, investigation or sham devices will be generated via a randomized procedure, with 
participants randomly chosen in the permuted blocks.  At baseline subjects will be assigned 1:1 between the 
treatment (investigational device) and control groups (sham device). Stratification will be performed by gender 
and center.  
 
Methods: Primary Aims 
For total body weight loss (TBWL) as a continuous measure, we will use a linear regression with TBWL at each 
time period as the dependent variable and group and other covariates of interest (baseline total body weight, 
gender, age, study site) as independent variables.  As a supportive analysis, we will also a two-sample t-test 
to examine the differences between the control and active treatment groups at each time period.  To assess 
any longitudinal effects, we will use a linear mixed effects model for weight over time, with fixed covariates for 
baseline weight, time, group, and a time / group interaction, and a random intercept to account for within-subject 
correlation. We will use these models to generate two-sided 95% confidence intervals for the difference in 
mean percent weight loss.  
 
We will calculate exact binomial confidence intervals (95%, two-sided) to determine if the response rate in the 
treatment group significantly exceeds 50%, with response defined by a loss of at least 5% of their body weight 
at the 6-month follow-up. As supportive analyses we will also use Fisher’s exact test to compare the response 
rates in each group, and, will consider the use of a logistic regression to control for any other covariates of 
interest. To investigate possible longitudinal trends, we will fit a logistic mixed effects model, similar to the linear 
mixed effects model described above. 
 
Methods: Secondary Aims 

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For each continuous and categorical variable at each time point, we will use a two-sample t-test and Fisher's 
exact test, respectively. Summary statistics (mean, standard deviation, quantiles, counts, and percentages) 
and plots will be produced for all demographic and study outcomes. We will investigate the effectiveness of the 
device by usage by including usage time as a continuous covariate in a linear model for total fat loss. Statistical 
personnel will conduct all analyses using the latest version of R (R Foundation for Statistical Computing, 
Vienna, Austria. http://www.R-project.org/).  
 
We will analyze mean fat loss in the same way as TBWL as a continuous measure with t-tests, linear regression 
and linear mixed effects models. 
 
Missing Data 
The primary hypotheses will be tested on the intent-to-treat population. Missing data will be clearly reported 
and included in tables. We will assess the assumption that the data is missing completely at random. For the 
primary effectiveness analysis of total body weight loss (TBWL) as a continuous measure we will perform a 
multiple imputation analysis. We will include the same covariates in the multiple imputation model as in the 
linear regression, i.e. group, baseline total body weight, gender, age, study site. Two supportive sensitivity 
analyses with different approaches to imputing missing data will also be performed: last observation carried 
forward (LOCF) and baseline value carried forward (ie assuming no weight loss). 
A sensitivity analysis will be performed with the binary weight loss endpoint. This analysis will include a best-
case scenario (assuming subjects with missing values have all lost over 5% body weight), a worst-case 
scenario (assuming no subjects with missing values have lost over 5% body weight), and a tipping point 
analysis (as described in Yan et al., 2009).  
 
Interim Analysis 
 
There is no planned interim analysis.  
 
Primary Endpoints USA Regulatory Clearance: 
The efficacy of the VeSTAL device within the treatment group will be quantified by calculation of two primary 
endpoints after 6 months treatment: 
• 
mean percent weight loss; 
• 
proportion of participants who lose at least 5% body weight. 

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Study Acceptance Criteria USA: 
 
• 
Mean: There should be at least a 2% total body weight loss (TBWL) superiority margin between the 
active-product and sham-treated groups.  
• 
Categorical: The proportion of participants who lose 5% TBWL or more in the active-product group is 
at least 50%, independent of the sham control  
 
 
Primary Outcome Measures USA (6 months) 
- 
Mean: There should be at least a 2% total body weight loss (TBWL) superiority margin 
between the active-product and sham-treated groups.  
- 
Categorical: The proportion of participants who lose 5% TBWL or more in the active-
product group is at least 50%, independent of the sham control. 
 
 
Both weight loss efficacy acceptance criteria must be met to claim success. These criteria can be 
specified in mathematical formulae as follows:  
Rejection of both the null hypotheses μA – μC ≤ 2% and πA ≤ 50% at the 2.5% (1-sided) level 
Where:  
μA and μC are the underlying population mean percentage weight loss on active and control 
respectively  
πA is the underlying population proportion of subjects who lose ≥5% of baseline body weight on 
active.  
 
Secondary Endpoints USA 
A variety of secondary endpoints will also be assessed statistically at the 6-month timepoint after the primary 
endpoints. The following of these may form the basis of potential future labelling claims: 
• 
Total body fat loss (as measured by whole body DXA scanning); 
• 
Healthy Eating Index (HEI) score (https://epi.grants.cancer.gov/hei/) (as measured by the two-day 24-
hour dietary recall); 
• 
Total caloric intake (as measured by the two-day 24-hour dietary recall); 
• 
Systemic inflammation (as measured by high-sensitivity C-reactive protein); 

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• 
Atherogenic index (as determined by the ratio of total cholesterol to HDL); 
• 
Quality of life (as measured by the IWQoL questionnaire). 
 
The full details of the testing procedures procedure for these endpoints will be laid out in the Statistical Analysis 
Plan. All other secondary endpoints at the 6-month timepoint will be hypothesis generating only. 
 
Secondary Outcome Measures USA (At 6  months) 
- 
The difference in mean fat mass loss (in grams) between the active-product and sham-
treated groups is statistically significant. (As measured by means of a whole body DXA 
scan).  
- 
The difference in mean trunk fat loss (in grams) between the active-product and sham-
treated groups is statistically significant. (As measured by means of a whole body DXA 
scan). 
- 
The difference in mean visceral adipose tissue (VAT) mass loss (in grams) between the 
active-produce and sham-treated groups is statistically significant. (As measured by the 
whole body DXA scan). 
- 
Difference in mean lean mass gain (in grams) between the active-product and sham-
treated groups is statistically significant. (As measured by means of a whole body DXA 
scan). 
- 
Difference in mean bone mineral content (BMC) gain (in grams) between the active-
product and sham-treated groups is statistically significant. (As measured by means of a 
whole body DXA scan). 
- 
Fasting glucose 
- 
Lipid profile (Assess total non-HDL cholesterol, and HDL to total cholesterol ratio) 
- 
High-sensitivity C-reactive protein 
- 
Glycated hemoglobin (HbA1c) 
- 
Two-day 24-hour dietary recall 
- 
Modifiable activity questionnaire 
- 
Blood pressure 
- 
Heart rate 
- 
Waist and hip circumferences (This will only be performed at the USA sites.) 
- 
Body Mass Index (BMI) 
- 
Quality of life – IWQOL-Lite questionnaire.  

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- 
Dose response analysis: it is likely that some subjects will not utilize their device for the 
mandated 7 hours per week. Usage data will be available from the devices permitting a 
dose response analysis, which will done be in an intention to treat manner. 
- 
Adjustment of medication – both reduction and new medications. 
- 
Mentor support group usage (total hours). 
 
 
Primary Endpoints EU Regulatory Clearance: 
The efficacy of the VeSTAL device within the treatment group will be quantified by calculation of one endpoint: 
1. Mean percent weight loss 
 
Study Acceptance Criterion EU: 
1. Mean: There should be at least a 2% total body weight loss (TBWL) superiority margin between the 
active-product and sham-treated groups.  
 
Primary Outcome Measure EU (At 6 months) 
1. Mean: There should be at least a 2% total body weight loss (TBWL) superiority margin between the 
active-product and sham-treated groups.  
 
This criterion can be specified in formulae as follows: 
mA – mC ≥ 2% and pt ≤ 0.05  
Where:  
mA and mC are the observed mean percentage weight loss on active and control respectively  
pt is the p-value (two-sided) from a linear regression comparing percentage weight loss between 
active and control (H0: μA = μC; H1: μA ≠ μC)  
μA and μC are the underlying population mean percentage weight loss on active and control 
respectively 
 
Secondary endpoints which may become the basis of claims in EU: 
A variety of secondary endpoints will also be assessed statistically at the 6-month timepoint after the primary 
endpoints. The following of these may form the basis of potential future labelling claims: 
• 
Total body fat loss (as measured by whole body DXA scanning); 

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• 
Healthy Eating Index (HEI) score (https://epi.grants.cancer.gov/hei/) (as measured by the two-day 24-
hour dietary recall); 
• 
Total caloric intake (as measured by the two-day 24-hour dietary recall); 
• 
Systemic inflammation (as measured by high-sensitivity C-reactive protein); 
• 
Atherogenic index (as determined by the ratio of total cholesterol to HDL); 
• 
Quality of life (as measured by the IWQoL questionnaire). 
 
The full details of the testing procedures procedure for these endpoints will be laid out in the Statistical Analysis 
Plan. All other secondary endpoints at the 6-month timepoint will be hypothesis generating only. 
 
Other Secondary Outcome Measures EU (At 6 months) 
- 
The difference in mean fat mass loss (in grams) between the active-product and sham-
treated groups is statistically significant. (As measured by means of a whole body DXA 
scan).  
- 
The difference in mean trunk fat loss (in grams) between the active-product and sham-
treated groups is statistically significant. (As measured by means of a whole body DXA 
scan). 
- 
The difference in mean visceral adipose tissue (VAT) mass loss (in grams) between the 
active-produce and sham-treated groups is statistically significant. (As measured by the 
whole body DXA scan). 
- 
Difference in mean lean mass gain (in grams) between the active-product and sham-
treated groups is statistically significant. (As measured by means of a whole body DXA 
scan). 
- 
Difference in mean bone mineral content (BMC) gain (in grams) between the active-
product and sham-treated groups is statistically significant. (As measured by means of a 
whole body DXA scan). 
- 
Fasting glucose 
- 
Lipid profile (Assess total non-HDL cholesterol, and HDL to total cholesterol ratio) 
- 
High-sensitivity C-reactive protein 
- 
Glycated hemoglobin (HbA1c) 
- 
Two-day 24-hour dietary recall 
- 
Modifiable activity questionnaire 
- 
Blood pressure 

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- 
Heart rate 
- 
Waist and hip circumferences (This will only be performed at the USA sites.) 
- 
Body Mass Index (BMI) 
- 
Quality of life – IWQOL-Lite questionnaire.  
- 
Dose response analysis: it is likely that some subjects will not utilize their device for the 
mandated 7 hours per week. Usage data will be available from the devices permitting a 
dose response analysis, which will done be in an intention to treat manner. 
- 
Adjustment of medication – both reduction and new medications. 
- 
Mentor support group usage (total hours). 
 
Power Calculation 
The statistical plan was developed in conjunction with the biostatistics and trial design optimization company 
Exploristics (https://exploristics.com). Multiple simulation scenarios (each with 1000 iterations) were conducted 
in their KerusCloud platform to determine an appropriate study size for this evaluation. KerusCloud is a cloud-
based, virtual simulation environment for optimizing clinical study design and analysis. 
 
The primary outcomes are mean TBWL from the start of treatment (as a percentage of baseline total body 
weight), and the proportion of subjects who lose at least 5% of their baseline total body weight. These outcomes 
will be assessed at the 6-month timepoint. 
Power calculations are based on simulation with assumptions informed by pilot data and the Modius weight-
loss device as follows: 
90kg median baseline weight in both groups (log-normal distribution with CV=24%) 
6.6% mean percent weight loss in the active group at 6 months (SD 3.9%), 
3.1% mean percent weight loss in the control group at 6 months (SD 3.9%), 
correlations between baseline weight and weight loss at 6 months of -0.4. 
 
Under these assumptions, with a sample size of 180 participants randomized 1:1 active: placebo, there is a 
greater than 80% power to demonstrate both the mean and categorical weight loss acceptance criteria at the 
6-month timepoint. 
 
Under an assumption of no difference between active and control but the same assumptions around SDs and 
correlations there is ≤2% probability of a type-I error with this sample-size. 
 

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Anticipating a drop out rate of 10%, we will plan to recruit n = 200 total subjects overall in the study across both 
sites.  
35. Analysis of clinical performance 
A Statistical Analysis Plan (SAP) will be written and finalized prior to any lock of the study database. The SAP 
will give a detailed description of the summaries and analyses that will be performed.  The SAP is being 
prepared by the specialist statistical consultancy company Exploristics.  
36. Reports and Publication 
 
Interim Report 
There is no planned interim analysis. 
 
 
Final Report 
Following enrollment completion and data monitoring of the clinical investigation a final report will be compiled 
in accordance with applicable regulations, even if the clinical investigation is terminated prematurely. The 
coordinating investigator will review, approve and sign off the final report.  
 
Publications 
Details for the preparation and submission for publication manuscripts containing the study results shall be 
determined by mutual written agreement OR documented in each Investigator Agreement. The publication or 
presentation of any study results shall comply with all applicable privacy laws. 
 
As agreed in the Clinical Research Agreement (negotiated by OCGA) between UCSD and Neurovalens, 
“University shall have the right to publish the results of the work conducted by University under this Agreement, 
to the extent such results do not contain Confidential Information of Company, provided Company has the 
opportunity to review and comment on any proposed manuscripts describing said work thirty (30) days prior to 
their submission for publication.  The Parties agree that the research and clinical investigation under this 
Agreement is part of a multicenter study, no publication or presentation shall be submitted or given by the 
University or Investigator until the study has been completed at all participating centers, or twelve (12) months 
has passed since the termination of the Agreement or completion of the Project, whichever is earlier University 

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agrees to reasonably consider Company’s comments prior to publication. However, if such proposed 
manuscript contains patentable information, University will, at its option, either delete the patentable information 
and publish immediately, or withhold publication for up to an additional sixty (60) days to allow for the filing of 
patent applications.” 
37. Ethical Considerations 
 
Ethics Committee Approval  
Prior to the initiation of this clinical investigation, the Principal Investigator must ensure that the relevant 
research ethics committee approval is in place for his/her site. The following documents, along with any specific 
country or locally required documents, must be submitted; Clinical Evaluation Plan, Patient Information Sheet, 
Patient Consent Form must be submitted for approval.  
 
 
Subject Confidentiality 
Confidentiality of data shall be observed by all parties involved at all times throughout the clinical investigation. 
All data will be secured against unauthorized access. All subject data that appears in reports and publications 
will be anonymized such that the privacy and confidentiality of each subject is maintained. 
 
In order to fulfil the requirements of the PI to allow access to source data, including where required, medical 
notes and meet confidentiality requirements the PI will be required to obtain consent from each subject stating 
that they agree for their medical records to be accessed where relevant to the clinical investigation (this will 
form part of the consent process). 
 
1. Subject’s information will be kept strictly confidential to the extent provided by law. An alphanumeric 
code will be assigned to each subject, and this code will be used in place of a name when reporting 
data. The hardcopy corresponding subjects with codes will be kept in a locked data cabinet in the study 
site, along with all results of all screening inventories, assays, and questionnaires. The computer to be 
used for data collection and analysis will require a password for access, which only personnel directly 
involved in the study will have. Data in any format will only be available for those on the protocol. 
Information collected in the study will not be reused or disclosed for other purposes. Data collected in 
the study will be destroyed after seven years. 

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2. All aspects of the study will be explained to the subject in lay language, and the experimenter will make 
sure that the subject understands what will happen prior to his/her participation. The experimenters will 
inform the subject of the precautions that will be taken with regard to personal information collected 
during the course of the study. The study will be as short as possible. Participation is voluntary, and 
subjects will be informed at the beginning of the study that they may withdraw at any time, for any 
reason, with no negative repercussions. The research should in no way result in social stigmatization 
or any other long-term distress to the subjects.  
 
3. Once successfully passing the screening process we will share the follow subject details by email with 
the team at We Slim Together (WST): the subject’s email address so they can be contacted by WST 
to enroll them in their program; details of the subject’s hypocaloric diet plan; the subject’s initial weight; 
and an ID number so we can identify the subject when liaising with WST. The subject’s consent will be 
taken as part of the ICF in order to share these details. 
 
4. If a subject enters their weight into the study app then this information (attached to the ID number WST 
have for that subject and devoid of any subject identifiable data) will be accessible by the subject’s 
mentor at WST. This will be done by granting the mentor password-controlled access to login to a 
database. No other information from the application, other than the weight that the subject chooses to 
enter, will be made available to the WST team. This is only being done to help the mentor properly 
support the subject in their weight loss journey. This feature is detailed explicitly in the ICF and it is 
made clear to the subject that entering their weight into the VeSTAL application is optional. However, 
the subject is asked in the ICF to engage with their WST mentor and so, if they do not want to put their 
weight into the VeSTAL application, then they are asked to tell their mentor what their current weight 
is when they speak to them. Weight values entered into the app will not be accessible by any of the 
study personnel at the clinical site. And nor will any of these weight values be collected or used for any 
purpose in the study other than as stated above. 
 
5. Once a month WST will email the study coordinator with a register as to how often the subjects are 
attending their weekly check in sessions with their mentor. This information will be linked to the 
subjects’ ID numbers and not to their names or any other identifiable information. The subjects are 
notified in the ICF that WST will send us this information and are asked to consent to it and to agree to 
try to attend at least 75% of the mentoring sessions as part of taking part in the study. 

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6. No other data will be collected by the study staff from, or sent by the study staff to, any other social 
media sites or platforms – e.g. Facebook. 
 
7. In order to minimize the risk of coercing subjects to participate, no attempts to recruit subjects during 
undergraduate classes will be made. 
 
8. Similarly, due to the risk of coercion the following will be excluded from participating: graduate students 
in Psychology; undergraduate students working as research assistants at any of the study sites 
associated universities. 
38. Declaration of Helsinki 
This clinical investigation will be conducted in accordance with the relevant articles of the Declaration of Helsinki 
as adopted by the 18th World Medical Assembly in 1964 and as revised in Tokyo (1975), Venice (1983), Hong 
Kong (1989), South Africa (1996), Edinburgh (2000), Washington (2002), Tokyo (2004) and Seoul (2008). 
39. Indemnity 
Sponsor recognizes its liability in law to compensate for any injury sustained by a subject participating in this 
clinical investigation in accordance with the guidelines of the Association of the British Healthcare Industry 
(ABHI) for any subjects entered into the clinical investigation in the United Kingdom. 
40. Compensation 
There will be no monetary expense to the subject for participation in the study. All study visits will take place at 
the clinical sites, either the UU site, the CCR and EPARC at UCSD or the TDE site, and parking and reasonable 
traveling costs will be reimbursed. Scheduling of the sessions will be made to avoid inconvenience. The VeNS 
devices used in the study will be provided to the subjects free of charge, and the same applies to access to 
dietetic advice. 
 
Participants in the study will receive £/$200 for their complete participation in this study. At both sites if they 
terminate their involvement early, then they will receive £/$50 for their baseline visit and £/$75 each for their 3 
month and 6 month visits that they have completed. If a participant ends their involvement before completing 
the three-month visit, they will be asked to return their device and in return receive £/$15. The compensation 

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schedule below outlines the payments to be made to the participant at the UCSD, TDE and UU sites. This 
compensation is payment for the participants’ time and not any type of coercion to participate. If subjects are 
excluded during the Screen Visit, then they will receive travel/parking expenses but no additional 
compensation.  
 
Participants at UU and UCSD, TDE sites who complete the study for the 6 months duration will be given the 
supplied iPod used during the study as a gift. 
 
Compensation Schedule: 
Visit Details  
EPARC 
CCR 
UU  
TDE 
Visit 1 (0 months) 
 
$50 
$50 
0 
$50 
Visit 2 (3 months) 
 
$75 
$75 
0 
$75 
Visit 3 (6 months) 
 
$75 
$75 
£200 
$75 
 
 
41. Regulatory Requirements 
This investigational device study has been designated as a non-significant risk study and subject to the 
abbreviated requirements of the Investigational Device Exemption regulation in the US in accordance with 21 
CFR part 812.  
Appropriate risk assessment shall be completed prior to shipping investigational materials. All appropriate 
labelling shall be attached to this protocol and where required, applied to the investigational components of the 
investigational system.  
 
Regulations and Standards 
US CFR Regulation 
Description 
21 CFR 820 
Quality System Regulation (GMP) 
21 CFR 814 
Premarket Approval of medical devices 
21 CFR 54 
Financial Disclosure by Clinical Investigators 

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21 CFR 809.10 
Labeling 
21 CFR 812 
Investigational Device Exemptions 
21 CFR 50 
Protection of Human Subjects 
21 CFR 56 
Institutional Review Boards 
21 CFR 58 
Good Laboratory Practice for Nonclinical Laboratory Studies 
ISO Standards 
Description 
ISO 13485 
Quality Management System 
ISO 14971 
Risk Management 
ISO 14155 
Clinical investigation of medical devices for human subjects. Good clinical 
practice 
ISO 15223 
Medical Devices - Symbols to be used with medical device labels, labelling and 
information to be supplied 
42. Good clinical practice compliance 
This Clinical Investigation will be conducted in accordance with the European Standard BS EN ISO 14155:2011 
Clinical investigation of medical devices for human subjects – Good Clinical Practice and Note for Guidance 
on Good Clinical Practice: CPMP/ICH/135/1995, January 1997 (where applicable to medical devices). Parts of 
the Code of Federal Regulation (CFR21) will also be applied where applicable. 
 
 
Clinical investigation Personnel and Responsibilities 
Prior to initiation of this clinical investigation, each Principal Investigator will approve this CIP by signing the 
signature page. This signature confirms that the clinical investigation will be performed in compliance with the 
CIP. In addition, each investigator (including sub-investigators) will provide Financial Disclosure as laid out in 
21CFR part 54. 
 
The funding support for this investigator-initiated protocol will be from a gift to the Center for Brain and Cognition 
from Neurovalens.  
 
Site Monitoring 
The monitor will be responsible for securing the compliance of the clinical investigators to the signed 
agreement, the clinical protocol, the requirements of European Standard BS EN ISO 14155:2011, ICH GCP, 

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Relevant sections US CFR Title 21 Parts 50,56, and 312 and ICH Guidelines for GCP (E6) or conditions of 
approval imposed by the reviewing competent authorities or ethics committee. 
 
The principal investigator will permit a representative from or on behalf of Sponsor to inspect all Case Report 
Forms and corresponding portions of the subject’s clinic records and/or original hospital medical records to 
ensure accuracy, at regular intervals throughout the clinical investigation. These inspections are for the purpose 
of verifying adherence to the protocol and the completeness and accuracy of the data being entered on the 
Case Report Forms. 
 
The planned extent of source data verification is as follows:  
• 
Subjects screened but not randomized will have initial inclusion and exclusion criteria verified; 
• 
Randomized subjects will have all applicable data verified (20% Source Data Verification); 
• 
All subject consent form will be verified. 
 
An Investigator found not to comply will receive written notification of the deficiency, which will include a request 
that the deviation be corrected immediately. If the corrections are not made, shipments of products to the 
institution will be suspended and a request will be made to the Principal Investigator to return any products still 
in his/her possession to Sponsor. 
 
Auditing 
The relevant Regulatory Authority also has the right to conduct an audit of the clinical investigation, to determine 
that the investigation was, in fact, performed at stated investigation sites and that the data reported to the 
authority in support of a marketing application accurately reflects the data in the records of the clinical 
investigator. The authority also inspects such studies to verify that the clinical investigations were conducted in 
accordance with government regulations relating to the ethics committee and informed consent. It is the joint 
responsibility of the Sponsor and the Investigator to ensure that the clinical investigation has been completed 
in line with all government regulations for the relevant country. 
 
In the event that the regulatory authority desires to inspect this clinical investigation, the investigator will permit 
authorized inspectors to inspect all facilities and records relating to the clinical investigation and aid the 
Inspector to perform the audit in a timely fashion. 

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Modification to the Clinical Study Protocol 
Except in emergency situations, prior approval by the IRB is required for changes to, or deviations from, the 
protocol. In the event of such a situation, the PI must update the IRB expeditiously. 
 
Conflict of Interest 
Dr Ramachandran and Dr McGeoch are named as co-inventors on patent held by the Regents of the University 
of California that pertain to using electrical stimulation of the vestibular nerve as a means of altering body mass 
composition. Dr McGeoch was involved in co-founding Neurovalens, which has licensed the right to 
commercially exploit this technology from the University of California.  
 
Neurovalens is funding the research as a grant via a Clinical Research Agreement negotiated with OCGA. 
Requisite forms have been filed for both Dr McGeoch and Dr Ramachandran with the CoI office at UCSD. The 
CoI forms have been reviewed by the IRC, which has outlined a CoI management strategy, which Drs 
Ramachandran and McGeoch have agreed to follow. 
 
 
Protocol Violations and Deviations 
A protocol violation or deviation occurs when the subject, investigator or Sponsor fails to adhere to protocol 
requirements affecting the inclusion, exclusion, subject safety, device testing, and any primary endpoint criteria. 
Any violation or deviation to this protocol must be communicated to Neurovalens within two working days. 
Deviations must be recorded on the form provided as part of the study documentation pack. Description of the 
deviation shall include all study participants who are affected by the deviation.  
 
 Deviation: Any change, divergence, or departure from the approved study design or procedures of a research 
protocol that is under the investigator’s control and that has not been approved by the IRB, and does not affect 
the participant’s safety, rights, or welfare and/or the completeness, accuracy and integrity of the study data. 
This term though sometimes used interchangeably with the term “violation,” is (i) most often used when the 
variance is intended for the safety of one or more research participants or is an unintended change that is not 
considered as serious as a violation, (ii) is considered minor or administrative, and (iii) may involve no more 
than minimal risk to participants or others. 
 

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Noncompliance: Failure to comply with federal regulations, state laws, institutional policies, requirements or 
determinations of the IRB, and/or provisions of the approved research study. It is not considered noncompliance 
when there is a need to deviate from the approved protocol in order to protect the welfare of research 
participants. 
 
Protocol Violation: Any deviation that may affect the subject’s rights, safety, or welfare, and/or the 
completeness, accuracy and integrity of the study data. This term though sometimes used interchangeably with 
“deviation” is often considered a major, more serious, variance from an approved protocol than a deviation. 
 
Serious Noncompliance: Failure to comply with federal regulations, state laws, institutional policies, 
requirements or determinations of the IRB, and/or provisions of the approved research study, where the 
occurrence involves substantive potential or actual increased risk to the safety, rights and welfare of research 
subjects. 
 
Failure to comply with Good Clinical Practice guidelines will also result in a protocol violation.  
 
The Principal Investigator will determine if a protocol violation will result in withdrawal of a subject or reporting 
to the site IRB/IEC. 
 
A deviation is considered a minor or administrative divergence from approved design and procedures when 
the deviation does not affect the subject’s rights, safety, or welfare, and/or the completeness, accuracy and 
integrity of the study data. If a deviation occurs and meets this definition, then the deviation should be reported 
to the IRB on the Deviation Summary Log and submitted at the time of continuing review. At the time of 
continuing review, the Deviation Log will be reviewed to determine if continuing noncompliance has occurred. 
 
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movements and perceived vertical." Electroencephalography and Clinical Neurophysiology 107: 200–205. 
Zink, R., et al. (1997). "Galvanic vestibular stimulation in humans: effects on otolith function in roll." 
Neuroscience Letters 232: 171-174. 
 

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Clinical Trial 
111 of 112 
Project Name 
Clinical Protocol for VeSTAL 
Document Title 
 
243973(NI)_181094(UCSD 
USA) 
Protocol 
01 
11 
 
Study Reference Number 
Document Type 
Document Number 
Revision Number 
 
 
111/112 
44. Appendices and Attachments 
• 
Safety Reporting -see below for safety reporting information and forms to assist in 
reporting requirements 
• 
Investigational Device Instructions for Use 
• 
Deviation/Violation Log  
• 
EPIC-Norfolk Food Frequency Questionnaire (FFQ) 
• 
Modifiable Activity Questionnaire (MAQ) 
• 
Case Report Forms 
• 
Example of Quality of Life Survey 
 
 
Safety Reporting 
 
 
Safety reporting responsibilities to Sponsor as follows 
 
 
Who 
When 
How 
To Whom 
SAE 
Investigator or 
Sponsor 
Within 15 days of 
becoming aware 
of the event 
SAE report form 
Main IEC/REC for the 
investigation 
Urgent Safety 
Measures 
Investigator or 
Sponsor 
Immediately 
By Telephone, follow 
up written 
communication 
Main IEC/REC for the 
investigation 
Urgent Safety 
Measures 
Exceptionally 
by local 
investigator 
Within three days 
In writing reason for 
the urgent safety 
measures and plan for 
further action/follow up 
Main REC for the 
investigation 
 
 
 
 
 

Vestibular Stimulation to Trigger Adipose Loss (VeSTAL) 
Clinical Trial 
112 of 112 
Project Name 
Clinical Protocol for VeSTAL 
Document Title 
 
243973(NI)_181094(UCSD 
USA) 
Protocol 
01 
11 
 
Study Reference Number 
Document Type 
Document Number 
Revision Number 
 
 
112/112