Pilot Evaluation of the Empower Neuromodulation System for Anxiety Treatment
Phase: NA
Conditions: Generalized Anxiety Disorder
Sponsor: Theranova, L.L.C.

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NCT04901481 
THERANOVA, LLC 
Clinical Research Protocol 
PILOT EVALUATION OF THE EMPOWER NEUROMODULATION SYSTEM 
FOR ANXIETY TREATMENT 
Protocol Number: 
CRD-12-1396-01 
Version Date: 
October 26, 2021 
Investigational Product: 
Empower Neuromodulation System 
IND/IDE Number: 
N/A, nonsignificant risk study 
Development Phase: 
Feasibility 
Sponsor: 
TheraNova, LLC 
101 Mississippi St. 
San Francisco, CA 94107 
Funding Organization: 
NIH-NCCIH 
Principal Investigator: 
Name:             Lauren Edwards, MD  
Address: 
985575 Nebraska Medical Center  
Omaha, NE 68198-5575 
Telephone: 
402-552-6002 
E-mail: 
lauren.edwards@unmc.edu 
Coordinating Center: 
Not applicable 
Approval: 
 
PI or Sponsor Signature (Name and Title) 
 
 
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is participant to recall at any time.  The information in this 
document may not be disclosed unless federal or state law or regulations require such disclosure.  
Participant to the foregoing, this information may be disclosed only to those persons involved in the 
study who have a need to know, with the obligation not to further disseminate this information.   
 
 
 
 
 
 
 
 
 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study participants enrolled under my supervision and 
providing TheraNova, LLC with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide 
by the terms of this protocol. 
 
Protocol Number:  CRD-12-1396-01 
 
Protocol Title:  Pilot evaluation of the Empower Neuromodulation System in GAD 
Patients 
 
Protocol Date:  October 26, 2021 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 
 
 
 

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Table of Contents 
1 
BACKGROUND ....................................................................................................... 13 
1.1 Overview of GAD and GAD treatment .................................................................. 13 
1.2 Neuromodulation as a Treatment for GAD ............................................................ 14 
1.3 Prior Investigations with the Empower Neuromodulation System ......................... 15 
2 
Risk / Benefit Assessment ......................................................................................... 16 
2.1 Potential Risks ........................................................................................................ 16 
2.2 Potential Benefits .................................................................................................... 17 
2.3 Conclusion of the Risk-Benefit Assessment ........................................................... 17 
3 
STUDY OBJECTIVES ............................................................................................. 18 
3.1 Primary Objectives .................................................................................................. 18 
3.2 Secondary Objectives .............................................................................................. 18 
4 
STUDY DESIGN ....................................................................................................... 19 
4.1 Sponsor ................................................................................................................... 19 
4.2 Sponsor Contact ...................................................................................................... 19 
4.3 Sites ......................................................................................................................... 19 
4.4 Study Overview ...................................................................................................... 19 
5 
CRITERIA FOR EVALUATION ........................................................................... 22 
5.1 Primary Endpoints .................................................................................................. 22 
5.2 Secondary Endpoints .............................................................................................. 22 
5.3 Safety Evaluations .................................................................................................. 23 
6 
PARTICIPANT SELECTION ................................................................................ 23 
6.1 Study Population ..................................................................................................... 23 
6.2 Inclusion Criteria .................................................................................................... 23 
6.3 Exclusion Criteria ................................................................................................... 23 
7 
CONCURRENT MEDICATIONS .......................................................................... 24 
7.1 Allowed Medications and Treatments .................................................................... 24 
8 
STUDY PROCEDURES .......................................................................................... 24 
8.1 Method of Assigning Participants to Treatment Groups ........................................ 24 
8.2 Investigational Device ............................................................................................ 25 

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8.2.1 Device Description .......................................................................................... 25 
8.2.2 Device Description .......................................................................................... 25 
8.2.3 Intended Use ................................................................................................... 26 
8.2.4 Technical Specifications ................................................................................. 26 
8.2.5 User Interface .................................................................................................. 26 
8.2.6 Participant-Contacting Materials .................................................................... 26 
8.2.6.1 
Gel Electrodes ......................................................................................... 26 
8.2.6.2 
Controller ................................................................................................ 27 
8.3 Measures of Compliance ......................................................................................... 27 
9 
STUDY PROCEDURES AND GUIDELINES ....................................................... 27 
9.1 Clinical Assessments .............................................................................................. 27 
9.1.1 Concomitant Medications ............................................................................... 27 
9.1.2 Demographics ................................................................................................. 28 
9.1.3 Medical History .............................................................................................. 28 
9.1.4 Physical Examination...................................................................................... 28 
9.1.5 Psychiatric Examination ................................................................................. 28 
9.1.6 Medical chart review ....................................................................................... 28 
9.1.7 Surveys ............................................................................................................ 28 
9.1.7.1 
Daily Surveys .......................................................................................... 29 
9.1.7.2 
Weekly Surveys ...................................................................................... 29 
9.1.7.3 
Surveys only at Visits 1 and 3................................................................. 29 
9.1.8 Treatment Session ........................................................................................... 29 
9.1.9 Treatment regimen reminders sent to participants via text message .............. 30 
9.1.10 
Contact with participants who are not adhering to the treatment regimen . 31 
9.1.11 
Adverse Events ........................................................................................... 31 
9.1.12 
Suicidality Evaluation ................................................................................. 31 
9.1.13 
Participant Compensation ........................................................................... 31 
9.2 Clinical Laboratory Measurements ......................................................................... 32 
9.2.1 Pregnancy Test ................................................................................................ 32 
10 EVALUATIONS BY VISIT ..................................................................................... 32 
10.1 
Visit 1 (Day 1) .................................................................................................... 32 
10.2 
Visit 2 (Day 15 ± 7) ............................................................................................ 32 
10.3 
Visit 3 (Day 43 ± 7) ............................................................................................ 32 
10.4 
Early Withdrawal Visit ....................................................................................... 33 
11 ADVERSE EXPERIENCE REPORTING, DOCUMENTATION, AND 
Monitoring ......................................................................................................................... 33 
11.1 
Definitions........................................................................................................... 33 
11.1.1 
Adverse Event (AE) .................................................................................... 33 
11.1.2 
Unanticipated Problem (UP) ....................................................................... 33 
11.1.3 
Serious Adverse Event (SAE) ..................................................................... 33 

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11.2 
Time Period and Frequency for Event Assessment and Follow-Up ................... 34 
11.3 
Characteristics of an Adverse Event ................................................................... 34 
11.3.1 
Relationship to Study Intervention ............................................................. 34 
11.3.2 
Expectedness of SAEs ................................................................................ 34 
11.3.3 
Severity of Event ......................................................................................... 34 
11.4 
Reporting Procedures .......................................................................................... 35 
11.4.1 
Unanticipated Problem Reporting ............................................................... 36 
11.4.2 
AE Reporting .............................................................................................. 36 
11.4.3 
Reporting of Pregnancy .............................................................................. 37 
11.5 
Halting Rules ...................................................................................................... 37 
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS............... 37 
12.1 
Early Discontinuation of Study ........................................................................... 37 
12.3 
Withdrawal of Participants from the Study ........................................................ 38 
12.4 
Replacement of Participants ............................................................................... 39 
13 PROTOCOL VIOLATIONS ................................................................................... 39 
14 DATA SAFETY MONITORING ............................................................................ 39 
14.1 
Independent Monitoring Committee ................................................................... 39 
14.2 
Safety Review Plan ............................................................................................. 39 
14.3 
Study Report Outline for the Independent Safety Monitors (Interim or Annual 
Reports) ........................................................................................................................... 40 
14.4 
Submission of On-Site Monitoring/Audit and Inspection Reports ..................... 40 
14.5 
Stopping Rules .................................................................................................... 40 
15 STATISTICAL METHODS AND CONSIDERATIONS ..................................... 40 
15.1 
Data Sets Analyzed ............................................................................................. 40 
15.2 
Demographic and Baseline Characteristics ........................................................ 40 
15.3 
Analysis of Primary Endpoint ............................................................................. 40 
15.4 
Analysis of Secondary Endpoints ....................................................................... 41 
15.5 
Randomization and Sample Size ........................................................................ 42 
16 DATA COLLECTION, RETENTION AND MONITORING ............................. 43 
16.1 
Data Collection Instruments ............................................................................... 43 
16.2 
Data Management Responsibilities..................................................................... 43 
16.3 
Database Protection ............................................................................................ 43 
16.4 
Source Document Protection .............................................................................. 43 

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16.5 
Archival of Data .................................................................................................. 44 
16.6 
Availability and Retention of Investigational Records ....................................... 44 
16.7 
Schedule and Content of Reports ........................................................................ 44 
16.8 
Monitoring .......................................................................................................... 45 
16.9 
Participant Confidentiality .................................................................................. 45 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ........ 46 
17.1 
Non-Significant Risk Determination for the Study ............................................ 46 
17.2 
Protocol Amendments ......................................................................................... 47 
17.3 
Institutional Review Board (IRB) ....................................................................... 47 
17.4 
Informed Consent................................................................................................ 48 
17.5 
Publications ......................................................................................................... 48 
17.6 
Investigator Responsibilities ............................................................................... 48 
APPENDIX 1.  STUDY VISITS ...................................................................................... 50 
APPENDIX 2.  REFERENCES CITED ......................................................................... 51 
 

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PROTOCOL SYNOPSIS 
TITLE 
Pilot evaluation of the Empower Neuromodulation System in GAD 
Patients 
SPONSOR 
TheraNova, LLC 
FUNDING 
ORGANIZATION 
NIH-NCCIH 
NUMBER OF SITES 
One (1) 
STUDY DESIGN 
This is a double-blinded (study participant and clinician assessor), 
sham-controlled pilot study. 
INVESTIGATIONAL 
DEVICE 
Empower Neuromodulation System 
INDICATIONS FOR 
USE/PATIENT 
POPULATION 
The Empower Neuromodulation System is intended to provide 
transcutaneous electrical nerve stimulation to reduce anxiety. 
 
The indicated population is adults who are diagnosed with generalized 
anxiety disorder (GAD). 
PRIMARY 
OBJECTIVES 
The primary study objectives of this pilot study are to evaluate the 
feasibility and acceptability of the Empower Neuromodulation System 
as a daily therapy for GAD. Feasibility will be evaluated via treatment 
adherence (% treatment sessions completed out of the total possible) 
and acceptability will be evaluated via usability as assessed by the 
System Usability Scale (SUS) questionnaire. 
SECONDARY 
OBJECTIVES 
The secondary study objectives are to evaluate additional endpoints for 
feasibility (effective nerve stimulation) and acceptability (overall 
satisfaction with treatment) as well as endpoints for safety (device-
related adverse events), effectiveness (anxiety, medication use, 
depression, PTSD, sleep quality, quality of life) and blinding to 
treatment group (blinding assessment). 
NUMBER OF 
PARTICIPANTS 
Up to 60 (our enrollment target for the intent-to-treat population is 30 
participants total, so n=60 includes up to 50% screen fails). 
PARTICIPANT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
1. ≥19 years old 
2. Current diagnosis of GAD per DSM-5 via M.I.N.I. assessment 
by clinician 
3. HAM-A ≥18 
4. Negative urine pregnancy test at screening (females only) 
5. Able to provide informed consent 
6. Capable and willing to follow all study-related procedures 
 

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Exclusion Criteria: 
1. Has current (past 30 days) psychotic or bipolar disorder, 
homicidal 
ideation, 
psychiatric 
hospitalization, 
or 
moderate/severe SUDs per clinician assessment via M.I.N.I. 
2. HAM-D ≥18 
3. PCL-5 ≥34 
4. Exhibits suicidal intent as confirmed on the Columbia-Suicide 
Severity Rating Scale-Revised (C-SSRS-R) with a “Yes” 
response to question 4 or question 5 or to question 6 in the past 
3 months. 
5. Changes in psychoactive medications in the past 30 days 
(including but not limited to psychotropic medications, thyroid 
hormone medication, steroids), with the exception of 
benzodiazepines 
6. If regularly taking benzodiazepines, has had changes in 
benzodiazepine dosing in the past 30 days or average use >2 
days per week 
7. Psychotherapy was initiated or discontinued in the past 30 days 
or psychotherapy modality was changes in the past 30 days  
8. Has a history of epilepsy or a seizure disorder  
9. Has been diagnosed with peripheral nerve damage of the arm or 
hand or has numbness or tingling in the arm or hand at least 
weekly 
10. Is currently pregnant or breastfeeding, has been pregnant within 
the past 6 months or intends to become pregnant during the 
study period 
11. Currently has an active implant and/or an electrical or 
neurostimulator device, including but not limited to cardiac 
pacemaker or defibrillator, vagal neurostimulator, deep brain 
stimulator, spinal stimulator, sacral stimulator, bone growth 
stimulator, or cochlear implant 
12. Has an electrically conductive metal object (e.g. jewelry) that 
cannot be removed from the palm or biceps and will directly 
contact the gel electrodes of the Empower Neuromodulation 
System at either anatomic location 
13. Has an open incision, wound, scar, active infection or otherwise 
compromised skin at the palm or biceps and will directly 
contact the gel electrodes of the Empower Neuromodulation 
System at either anatomic location 
14. Does not have daily access to an electrical outlet for charging 
the investigational device and associated smartphone 
15. Has used of an investigational drug/device therapy within the 
past four weeks 
16. Unable to provide informed written consent 
17. Has any medical condition that would, in the opinion of the 
investigator, make the participant ineligible 

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TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Transcutaneous electrical nerve stimulation with the Empower 
Neuromodulation System. The active stimulation is applied to the palm 
of the hand. For the duration of the 6-week study, the participant will 
self-administer a stimulation session twice per day. Each stimulation 
session consists of a total of 30 minutes of stimulation, with 15 minutes 
of stimulation on one hand followed by 15 minutes on the other hand.  
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Transcutaneous electrical nerve stimulation with the Empower 
Neuromodulation System. The control/sham stimulation is applied to 
the skin superficial to the biceps muscle. For the duration of the 6-week 
study, the participant will self-administer a stimulation session twice 
per day. Each stimulation session consists of a total of 30 minutes of 
stimulation, with 15 minutes of stimulation on one arm followed by 15 
minutes on the other arm. 
DURATION OF 
PARTICIPANT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Each participant will be in the study for up to 57 days: 
Screening:  up to 7 days 
Study participation: up to 50 days 
The total duration of the study is expected to be 9 months. 
STUDY 
PROCEDURES 
The study will include three clinic visits and twice daily self-
administered treatment sessions at home over the 6-week study. All 
visits can be conducted by secure video call if the COVID-19 pandemic 
prevents in-person visits and Visit 2 can be conducted by phone. The 
visits are the following:  
1) Enrollment clinic visit (Day 1),  
2) Mid-study clinic visit or phone/video call (Day 15 ± 7 days), and  
3) Study completion clinic visit (Day 43 ± 7 days).  
At Visit 1 (enrollment), the participant will first provide informed 
consent and be screened (screening includes clinician-administered 
M.I.N.I., C-SSRS-R, HAM-A, and HAM-D and participant-reported 
PCL-5). The warnings and contraindications as noted in the Instructions 
for Use (IFU) will also be discussed with the participant. If the 
participant meets all enrollment criteria, the participant will complete 
surveys (GAD-Q-IV, PHQ-9, PSQI, and SF-12). The participant will 
then be randomized to the active or sham treatment group (1:1, block 
size of 6) and trained on device and app use, which includes training on 
how to self-administer a treatment session with the Empower 
Neuromodulation System. The participant will then self-administer a 
treatment session and answer all pre- and post-treatment session survey 
questions on the Empower app. During this initial treatment session, 
the participant will, under investigator supervision, adjust the 

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stimulation intensity to a perceptible, yet comfortable level. After the 
session is completed, the clinical research staff will ask the participant 
about potential adverse events (AEs) through open-ended questioning. 
The participant will then be given an Empower system, supplies (skin 
electrodes, batteries, chargers), and the IFU to take home with him/her 
for self-administering treatment sessions at home.  
At Visit 2 (mid-study visit), the participant will be asked about potential 
AEs through open-ended questioning and will be assessed for suicidal 
intent via the C-SSRS-R. The participant will also complete the 
blinding assessment. This visit may be conducted by phone. 
At Visit 3 (study completion), the participant will undergo clinician-
administered assessments (C-SSRS-R, HAM-A, and HAM-D, and 
complete surveys (PCL-5, GAD-Q-IV, PHQ-9, PSQI, and SF-12). The 
clinical research staff will ask about potential AEs that may have 
occurred during the study through open-ended questioning. The 
participant will also complete the blinding assessment, usability survey 
(system usability scale (SUS) questionnaire), and Study Completion 
Questionnaire. 
PRIMARY 
ENDPOINTS 
• 
Feasibility:  Treatment adherence (% of treatment sessions 
completed out of the total possible) for each treatment group 
• 
Acceptability:  System usability scale (SUS) score for each 
treatment group 
SECONDARY 
ENDPOINTS 
• 
Feasibility: For each treatment group, the percentage of treatment 
sessions that provide effective nerve stimulation as assessed via 
participant-reported confirmation of tingling sensation 
• 
Acceptability: For each treatment group, the overall satisfaction 
with treatment (via 100-mm VAS) 
• 
Effectiveness: 
• 
Effect of treatment group on change in clinician-assessed 
anxiety severity (via Hamilton Anxiety Rating Scale 
(HAM-A)) 
• 
Effect of treatment group on change in weekly participant-
reported anxiety severity (via Beck Anxiety Inventory 
(BAI)  
• 
Effect of treatment group on change in participant-reported 
GAD symptoms (via GAD-Q-IV) 
• 
Effect of treatment group on change in daily self-reports 
for anxiety severity (via 100-mm VAS) 
• 
Effect of treatment group on change in self-reports of 
anxiety severity immediately after vs. before treatment (via 
100-mm VAS) 
• 
Effect of treatment group on change in daily self-reports 
for anxiety interference with daily living (via (100-mm 
VAS) 

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• 
Effect of treatment group on medication use (via self-
reports) 
• 
Effect of treatment group on change in clinician-assessed 
depression severity (via HAM-D) 
• 
Effect of treatment group on change in participant-reported 
depression severity (via PHQ-9) 
• 
Effect of treatment group on change in participant-reported 
PTSD severity (via PCL-5) 
• 
Effect of treatment group on change in sleep quality (via 
PSQI survey) 
• 
Effect of treatment group on change in quality of life (via 
SF-12 survey) 
• 
Blinding:  For each treatment group, the blinding index and 95% 
confidence interval (via Bang et al.26 blinding assessment method) 
SAFETY 
EVALUATIONS 
Incidence of adverse events and device-related adverse events 
STATISTICS 
 
The primary endpoints are feasibility and acceptability of the Empower 
Neuromodulation System as a daily therapy for GAD. Feasibility will 
be evaluated via treatment adherence, and acceptability will be 
evaluated via usability as assessed by the SUS questionnaire.  
 
Feasibility: We will calculate adherence (treatment sessions 
administered as a percentage of total possible) for each participant. We 
will consider a treatment session to be completed if at least 20 minutes 
of the session was administered. We will also compare adherence 
between the active and sham treatment groups (t-test). 
 
Acceptability: We will compare SUS scores for the active and sham 
treatment groups (t-test), and compare each against the average 
(SUS≥68) and excellent (SUS≥80) benchmarks.27 
RATIONALE FOR 
NUMBER OF 
PARTICIPANTS 
As a pilot study, our primary goal is to demonstrate feasibility for GAD 
treatment. Accordingly, the study sample size is based on similar pilot 
GAD studies in the literature. For two rTMS studies, each treatment 
arm had 12-25 participants, with an average of 15 participants.28, 29 To 
be consistent with these studies, we will enroll 15 participants per 
treatment arm, for a total of 30 participants.  
 

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1 
BACKGROUND 
TheraNova has developed the Empower Neuromodulation System, a portable, safe, easy-
to-use neuromodulation device that stimulates the ulnar and median nerve to enable a 
convenient and non-pharmaceutical therapy for generalized anxiety disorder (GAD). The 
overall goal of this study is to conduct a 6-week pilot investigation into the feasibility and 
acceptability of the Empower Neuromodulation System in GAD patients. Safety and 
effectiveness endpoints will also be evaluated as secondary endpoints. 
1.1 
Overview of GAD and GAD treatment 
Anxiety disorders are the most common type of psychiatric disorder.30 Approximately 32% 
of Americans experience an anxiety disorder at some point in their lives.2 With this high 
prevalence, it is no surprise that the estimated annual economic burden of anxiety disorders 
in 1998 was $63 billion,31 and the cost is likely higher today. Characterized by excessive 
anxiety and worry for at least 6 months, generalized anxiety disorder (GAD) is one of the 
most common anxiety disorders,1, 2 affecting 2.9% (~6.4 million) of American adults each 
year.2 GAD is often a chronic, recurring condition3-5 that is associated with decreased 
psychosocial functioning and quality of life as well as increased disability days.1, 6 GAD is 
also costly to treat, with medical costs that are 33% higher than other anxiety disorders.1, 6 
Furthermore, GAD is often comorbid with major depressive disorder (MDD), which, in 
turn, negatively affects remission from both GAD and MDD.4, 5 Importantly, recent weekly 
GAD-2 surveys by the U.S. Census Bureau have indicated that the prevalence of GAD may 
be sharply increasing as a result of the COVID-19 pandemic. In July 2020 surveys, 36% of 
American adults had symptoms of GAD vs. 8% before the pandemic.32 Taken together, 
there is an urgent need for comprehensive therapies that effectively treat anxiety disorders, 
in general, and GAD, in particular. 
 
Current guidelines for treatment of GAD include medication, cognitive behavioral therapy 
(CBT), or both.5, 7-10 Most medications show moderate initial efficacy, but benefits often 
decrease over time.9 Benzodiazepines (BZs), which are GABAA receptor agonists,11 are the 
most effective for treating GAD (Hedges’ g (effect size) of ~0.50; where g=0.2, 0.5, and 
0.8 are generally considered small, moderate, and large effect sizes, respectively).5, 7-10 
However, guidelines recommend only prescribing BZs for short-term use due to the 
potential to develop tolerance and dependence.7, 8 Recommended medications for long-term 
use include antidepressants (selective serotonin reuptake inhibitors (SSRIs) and serotonin-
norepinephrine reuptake inhibitors (SNRIs)), which are also recommended for other anxiety 
disorders.7 However, SSRIs and SNRIs have only modest effectiveness for treating GAD 
(Hedges’ g=0.33-0.36).3-5 Also, these medications take several weeks to reach maximum 
efficacy and have common, undesirable side effects, including headaches, nausea, agitation, 
difficulty sleeping, and sexual dysfunction, which substantially impact medication 
adherence and discontinuation.5 As a non-pharmaceutical treatment, CBT has distinct 
advantages for patient acceptability, but CBT also has modest effectiveness (Hedges’ 
g=0.3-0.5).12-14 Taken together, GAD remission rates are relatively low for current first-line 
therapies.  
 

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1.2 
Neuromodulation as a Treatment for GAD 
Neuromodulation has recently shown great promise for treating GAD. Repetitive 
transcranial magnetic stimulation (rTMS), in which magnetic pulses stimulate the left 
dorsolateral prefrontal cortex, is now FDA-cleared for the treatment of MDD and obsessive-
compulsive disorder. Recently, pilot studies (n=10-40 participants per study) have shown 
impressive results for treating GAD with rTMS.28, 29, 33-35 With daily-to-weekly treatments 
for 3-6 weeks, studies have shown Hedges’ g up to 2.1 and responder rates of 64-100% for 
the active treatment vs. 0-20% for the sham treatment, where a responder is usually defined 
as having ≥50% improvement in the anxiety scale used.28, 29, 33-35 However, rTMS has 
several key limitations. First, the safety profile for GAD treatment has not been established. 
In one study, a patient experienced a tonic-clonic seizure during treatment, which may be 
due to the use of rTMS parameters outside of safety guidelines.36 Other less severe side 
effects include face twitching, pain at the stimulation site, headache, and dizziness.28, 29 
Second, the treatment is expensive ($6,000-$12,000 for a 20-30 treatment course),37 which 
may prohibit widespread use. Third, the therapy requires patients to travel to a clinic daily 
for treatment, which is burdensome and reduces adherence.28, 29 Nonetheless, the promising 
results for rTMS show the potential of non-invasive neuromodulation for the treatment of 
GAD. 
 
For many years, acupuncture has been used in Asia to treat psychiatric disorders.15, 16 Two 
acupoints that have been shown to be effective for treating anxiety are on the wrist: HT7 
(along the ulnar nerve) and PC6 (along the median nerve). For example, in a study with 
GAD patients (n=13), 10 weekly acupuncture sessions (at HT7, PC6, and several other 
acupoints) provided an 86% responder rate (i.e. 86% of participants had ≥50% reduction in 
anxiety scores).17 In a separate study of chronic, non-responding anxiety patients (n=40), 
10 weekly acupuncture sessions, which included HT7, PC6, and LR3 (top of foot)) in each 
session, provided a 33-34% decrease in State and Trait anxiety scores (vs. 1-2% changes 
for the non-treatment control; p<0.001).38 While human acupuncture studies have used 
multiple acupoints concurrently, animal studies have more clearly implicated the ulnar 
nerve (HT7)18-22 and the median nerve (PC6)23-25 for anxiety reduction. For example, in a 
rat model of morphine withdrawal, a 60-second session of ulnar nerve acupuncture reduced 
anxiety-like behavior by 220% vs. the sham acupuncture (p<0.05).21 In this study, the 
anxiolytic effects of ulnar nerve acupuncture were blocked by injection of a GABAA 
receptor antagonist. Importantly, brain imaging studies in humans have shown that GAD is 
correlated with increased activity of neurons in the amygdala,39-41 and GABA infusion in 
the amygdala has been shown to reduce anxiety and fear in animal models.39 Taken together, 
these results suggest that ulnar and median nerve stimulation may enhance GABAergic 
activity, which, in turn, inhibits over-active neurons in the amygdala. Additional work has 
implicated the dorsal column of the spinal cord and lateral habenula neurons projecting to 
the midbrain as the pathway for this circuit.42 Regardless of the precise pathway, these 
results demonstrate the anxiolytic effects of stimulating the ulnar and median nerves. 
However, while acupuncture can be an effective therapy, it has the key limitation that 
treatment must be provided by an acupuncturist in the clinic or at home.  
 

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Because the ulnar and median nerves are superficial at the hand, they can be electrically 
stimulated via transcutaneous electrical nerve stimulation (TENS). TENS is attractive 
because it is safe, non-invasive, and can be self-administered at home. While the direct 
effects of ulnar and median nerve stimulation on anxiety have been demonstrated via 
manual acupuncture, it has been shown in animal models that both manual and 
electroacupuncture (EA) provide activation of all four types of sensory nerve fibers.43 Both 
EA and TENS, which is also called transcutaneous EA, apply an electrical stimulus, with 
the difference being that it is applied percutaneously and transcutaneously, respectively. 
Therefore, we have developed the Empower Neuromodulation System, a portable, safe, 
easy-to-use neuromodulation device that stimulates the ulnar and median nerves to enable 
a convenient and acceptable therapy to treat GAD. The Empower Neuromodulation System 
uses conductive gel electrodes on the palmar surface of the hand. Placing the electrodes at 
these locations enables comfortable delivery of stimulation to the ulnar and median nerves 
(Fig. 1). 
 
1.3 
Prior Investigations with the Empower Neuromodulation System 
The Empower Neuromodulation System has been used in four prior investigations. All 
studies have been designated nonsignificant risk (NSR) or minimal risk by the approving 
IRB, and no device-related adverse events have been reported in any of the studies:  
1. “Study to optimize and validate the treatment parameters for the Empower 
Neuromodulation System” (CRD-12-1154; approved by Salus IRB; study has been 
completed). In this usability study, the Empower Neuromodulation System was used 
to apply transcutaneous electrical nerve stimulation to the palm of the hand and 
biceps. The primary study objectives were to optimize the gel electrode design and 
to evaluate nerve stimulation in an in-office study. Seventeen participants completed 
this study, and no device-related adverse events occurred. In this study, we 
confirmed that the active treatment site (palm of the hand) provides effective nerve 
stimulation, as intended, while the sham treatment site (skin superficial to the biceps 
muscle on the upper arm) does not provide nerve stimulation, as intended. 
Furthermore, through a blinding assessment of the sham treatment, we demonstrated 
that the sham treatment is well blinded. The study was conducted at the TheraNova 
office, and the study PI was Daniel Burnett, MD. 
2. “Pilot evaluation of the Empower Neuromodulation System in AUD Patients” (#18-
26539; approved by the University of California San Francisco (UCSF) IRB; study 
has been completed). In this pilot effectiveness study, the Empower 
Neuromodulation System was used to apply transcutaneous electrical nerve 
stimulation to the palm of the hand to evaluate the effect on alcohol-related and 
anxiety metrics in alcohol use disorder (AUD) patients. Study participants self-
administered two 30-minute treatment sessions (15 minutes per hand in each 
treatment session) with the Empower Neuromodulation System for a 2-week 
treatment phase. The primary study objectives were to evaluate treatment 
effectiveness for reducing alcohol craving and consumption. A total of 25 
participants were enrolled in the study and 20 completed the study. Over two weeks 
of treatment, the Empower device significantly reduced alcohol consumption by a 

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mean of 29% (p=0.026), alcohol craving intensity by a mean of 21% (p=0.001), and 
anxiety by a mean of 31% (p<0.001). No device-related adverse events occurred. 
The study was conducted at the San Francisco Veterans Affairs Healthcare System, 
and the study PI was Steven Batki, MD. 
3. “Use of a wearable neuromodulation device to reduce opioid craving in Veterans 
with chronic pain” (IRB # 19-27491; approved by the UCSF IRB; study is ongoing). 
In this randomized, sham-controlled pilot study, the Empower Neuromodulation 
System is being used to apply transcutaneous electrical nerve stimulation to evaluate 
the effects on pain and opioid cravings in chronic pain patients who are taking 
prescription opioids. The active treatment location is the palm of the hand and the 
sham treatment location is the skin superficial to the biceps muscle. Study 
participants are self-administering two 30-minute treatment sessions (15 minutes 
per hand in each treatment session) with the Empower Neuromodulation System for 
a 2-week treatment phase. To date, a total of 6 participants have enrolled and 
completed the study. We plan to enroll an additional 24 participants. To date no 
device-related adverse events have occurred. The study is being conducted at the 
San Francisco Veterans Affairs Healthcare System, and the study PI is Ellen Herbst, 
MD. 
4. “Pilot evaluation of the Empower Neuromodulation System in OUD patients” (IRB 
# 19-28297; approved by the UCSF IRB; study is ongoing). In this randomized, 
sham-controlled pilot study, the Empower Neuromodulation System is being used 
to apply transcutaneous electrical nerve stimulation to evaluate the effects on opioid 
withdrawal and opioid cravings in opioid use disorder (OUD) patients who are 
initiating treatment with buprenorphine/naloxone. The active treatment location is 
the palm of the hand and the sham treatment location is the skin superficial to the 
biceps muscle. Study participants are self-administering one 30-minute treatment 
session (15 minutes per hand in each treatment session) with the Empower 
Neuromodulation System for a 3-week treatment phase. To date, one participant has 
enrolled and completed the study. We plan to enroll an additional 39 participants. 
To date no device-related adverse events have occurred. The study is being 
conducted at the San Francisco Veterans Affairs Healthcare System, and the study 
PI is Ellen Herbst, MD. 
 
2 
RISK / BENEFIT ASSESSMENT 
Transcutaneous electrical nerve stimulation (TENS) devices, such as the Empower 
Neuromodulation System, are non-invasive, generally considered safe (non-significant 
risk), and are commonly used to relieve neuropathic pain or achieve neuromodulation. 
Many TENS devices are available over-the-counter, demonstrating their established safety 
profile.  
2.1 
Potential Risks 
Most of the potential risks to the participant are generally low. Risks include, but are not 
limited to: 
Likely 

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• A sensation of tickling, tingling, burning, pricking or numbness of the skin along 
the stimulated nerve (paresthesia, generally known as the feeling of "pins and 
needles" or of a limb "falling asleep") 
• Spasms/twitching of arm and hand muscles 
• Involuntary contraction of muscles (tetany) during stimulation on the hand or arm 
of stimulation application 
• Mild discomfort or pain at or near the stimulation site or along the course of the 
stimulated nerve 
Less Likely 
• Skin irritation, redness or inflammation at or near the stimulation site (temporary) 
• Skin reaction or hypersensitivity to the electrode gel 
• Moderate-to-high discomfort or pain (including a throbbing pain) at or near the 
stimulation site or along the course of the stimulated nerve 
• Numbness of fingers (temporary) 
• Nausea 
• Headache 
 
Rare 
• Possible interactions with other electrical and/or neurostimulator device, including 
but not limited to cardiac pacemaker or defibrillator, vagal neurostimulator, deep 
brain stimulator, spinal stimulator, sacral stimulator, bone growth stimulator, or 
cochlear implant. 
The likely and less likely risks are considered to be minimal and are addressed in the 
protocol and consent form. Per the exclusion criteria, to reduce participant risks, we will 
exclude all participants who have an implanted electrical or neurostimulator device.  
2.2 
Potential Benefits 
As discussed above in Sections 1.2 and 1.3, based on previous acupuncture studies in the 
literature and our preliminary study in AUD patients, stimulation of the ulnar and median 
nerves has the potential to provide anxiolytic effects. This potential benefit from a non-
pharmaceutical treatment could provide a valuable therapy option to improve outcomes in 
the treatment of anxiety disorders, in general, and GAD, in particular.   
2.3 
Conclusion of the Risk-Benefit Assessment 
Based on the established safety profile of TENS devices and the potential benefits to 
reducing anxiety for GAD patients, we believe that the benefits outweigh the risks in this 
study. 

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3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary study objectives of this pilot study are to evaluate the feasibility and 
acceptability of the Empower Neuromodulation System as a daily therapy for GAD. 
Feasibility will be evaluated via treatment adherence (% treatment sessions completed out 
of the total possible) and acceptability will be evaluated via usability as assessed by the 
System Usability Scale (SUS) questionnaire. 
3.2 
Secondary Objectives 
The secondary study objectives are the following: 
• Feasibility: Evaluate the feasibility of the Empower Neuromodulation System 
treatment via its ability to provide effective nerve stimulation (via participant-
reported tingling sensation, a direct indication of effective nerve stimulation) 
• Acceptability: Evaluate the acceptability of the Empower Neuromodulation System 
treatment via overall satisfaction with treatment (via 100-mm VAS) 
• Safety: Evaluate the safety of the Empower Neuromodulation System treatment via 
device-related adverse events  
• Effectiveness: Evaluate the effectiveness of the Empower Neuromodulation System 
treatment for (all endpoints assessed for active vs. sham groups): 
o Reducing clinician-assessed anxiety severity (via Hamilton Anxiety Rating 
Scale (HAM-A)) 
o Reducing participant-reported anxiety severity (via Beck Anxiety Inventory 
(BAI), Generalized Anxiety Disorder Questionnaire-IV (GAD-Q-IV), daily 
self-reports for anxiety severity (100-mm VAS), and pre- and post-treatment 
self-reports of anxiety severity (100-mm VAS)) 
o Reducing participant-reported anxiety interference with daily living (via 
daily self-reports for anxiety interference with daily living (via 100-mm 
VAS) 
o Reducing medication use (via self-reports) 
o Reducing clinician-assessed depression severity (via Hamilton Depression 
Rating Scale (HAM-D)) 
o Reducing participant-reported depression severity (via Patient Health 
Questionnaire-9 (PHQ-9)) 
o Reducing participant-reported post-traumatic stress disorder (PTSD) 
severity (via PTSD Checklist-5 (PCL-5)) 
o Improving sleep quality (via Pittsburg Sleep Quality Index (PSQI) survey) 
o Improving quality of life (via SF-12 survey) 
• Blinding:  Evaluate if the active and sham treatments are well-blinded per the 
blinding assessment 
 

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4 
STUDY DESIGN 
4.1 
Sponsor 
TheraNova, LLC 
101 Mississippi St. 
San Francisco, CA 94107 
Phone: 415-926-8616  
 
4.2 
Sponsor Contact 
Michael Jaasma 
Vice President of Research, Development, and Regulatory Affairs 
TheraNova, LLC 
101 Mississippi St. 
San Francisco, CA 94107 
Phone: 415-926-8616 
 
4.3 
Sites 
This is a single site study: 
University of Nebraska Medical Center and Nebraska Medicine 
985575 Nebraska Medical Center  
Omaha, NE 68198-5575 
 
4.4 
Study Overview 
This is a single site, sham-controlled, double-blinded trial. The overall study goal is to 
evaluate the feasibility and acceptability of the Empower Neuromodulation System as a 
daily therapy for GAD patients. The total duration of participant participation will be six 
weeks (Fig. 2), and the total duration of the study is expected to be 9 months. Screening 
data will be reviewed to determine participant eligibility. Participants who meet all of the 
inclusion criteria and none of the exclusion criteria will be eligible to be randomized.   
At enrollment, participants will be randomized (1:1) to either the active treatment arm 
(stimulation on the palm of the hand) or the sham treatment arm (stimulation on the skin 
superficial to the biceps muscle). Participants and clinician assessors will be blinded. For 
each enrollee’s 6-week participation in the study, the participant will be instructed to self-
administer twice daily 30-minute treatment sessions (each session includes 15 minutes of 
treatment per hand/arm) and complete daily surveys (self-reports on anxiety levels, 
medication use, and skin tingling felt during treatment) on the Empower app (on the 
provided smartphone). Weekly, the participant will be prompted to complete the BAI survey 

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on the Empower app. At the enrollment visit (Visit 1) and the final study visit (Visit 3), the 
participant will be assessed by one of the study clinicians for anxiety (HAM-A) and 
depression (HAM-D). At these study visits, the participant will also complete the following 
surveys on paper or electronically: PCL-5 GAD-Q-IV, PHQ-9, PSQI, and SF-12. At all 
clinic visits, the participant will be assessed for suicidality via the Columbia-Suicide 
Severity Rating Scale-Revised (C-SSRS-R). 
Once enrolled and trained on device and app use, the participant will be instructed to 
conduct treatment sessions and complete surveys as close as possible to 8:00 am and 8:00 
pm each day, or at least 6 hours apart during the day if his/her schedule does not allow 8am 
and 8pm sessions. The Empower device delivers stimulation at a user-adjusted intensity 
(maximum of 50 mA), and is designed to automatically shut off the stimulation at the end 
of each 15-minute treatment interval (reducing possibility of overstimulation or misuse of 
device). In addition, the participant can pause stimulation at any time (e.g. if the participant 
experiences discomfort) by pressing the pause button on the controller or removing the 
electrodes from the skin. The smartphone has a twice daily notification to remind the 
participant to complete treatment sessions. The participant will also receive text message 
reminders on his/her personal cell phone during participation in the study (daily text 
messages in the first week of the study and three times per week for the remainder of the 
study). The Empower Neuromodulation System (which includes a smartphone with 
Figure 2. Study outline. This 6-week study will include three study visits. For the duration of the study, 
participants will self-administer twice daily treatment sessions at home with the Empower Neuromodulation
System and complete daily and weekly surveys. At Visits 1 and 2, clinician assessments will be administered
and participants will complete surveys. The study completion visit will also include a usability survey and 
Study Completion Questionnaire. 

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Empower app) will be loaned to each participant for the duration of his/her participation in 
the study.  
 
The study will include three visits (all visits can be conducted by secure video call if the 
COVID-19 pandemic prevents in-person visits and Visit 2 can be conducted by phone):  
1) Enrollment clinic visit (Day 1),  
2) Mid-study clinic visit or phone/video call (Day 15 ± 7 days), and  
3) Study completion clinic visit (Day 43 ± 7 days).  
At Visit 1 (enrollment), the participant will first provide informed consent and be screened 
(screening includes clinician-administered M.I.N.I., C-SSRS-R, HAM-A, and HAM-D and 
participant-reported PCL-5). The warnings and contraindications as noted in the 
Instructions for Use (IFU) will also be discussed with the participant. If the participant 
meets all enrollment criteria, the participant will complete surveys (GAD-Q-IV, PHQ-9, 
PSQI, and SF-12). The participant will then be randomized to the active or sham treatment 
group (1:1, block size of 6) and trained on device and app use, which includes training on 
how to self-administer a treatment session with the Empower Neuromodulation System. If 
the subject is randomized to the active treatment group (stimulation on the palm of the 
hand), the participant’s hand will be measured to determine if the participant should receive 
the Small or Large size electrodes. The participant will then self-administer a treatment 
session and answer all pre- and post-treatment session survey questions on the Empower 
app. During this initial treatment session, the participant will, under investigator 
supervision, adjust the stimulation intensity to a perceptible, yet tolerable level. After the 
session is completed, the clinical research staff will ask the participant about potential 
adverse events (AEs) via open-ended questioning. The participant will then be given an 
Empower system, supplies (skin electrodes, batteries, chargers), and the IFU to take home 
with him/her for self-administering treatment sessions at home.  
At Visit 2 (mid-study visit), the participant will be asked about potential AEs via open-
ended questioning, and the participant will be assessed for suicidality via the C-SSRS-R. 
The participant will also complete the blinding assessment. This visit may be conducted by 
phone. 
At Visit 3 (study completion), the participant will undergo clinician-administered 
assessments (C-SSRS-R, HAM-A, and HAM-D) and complete surveys (PCL-5, GAD-Q-
IV, PHQ-9, PSQI, and SF-12). The clinical research staff will ask about potential AEs that 
may have occurred during the study. This will be done via open-ended questioning. The 
participant will also complete the blinding assessment, usability survey (system usability 
scale (SUS) questionnaire), and Study Completion Questionnaire, with surveys completed 
on paper or electronically. 
The Empower app automatically logs participant adherence to the treatment session 
regimen. For each treatment session, the app will record time/date of treatment and the 
duration of treatment. This data (de-identified, only includes the participant’s study ID 

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number and Empower controller MAC address) will be uploaded automatically to the 
sponsor’s password-protected cloud server for remote compliance monitoring. 
 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Endpoints 
The co-primary endpoints will be feasibility and acceptability of the Empower 
Neuromodulation System as a daily therapy for GAD. Feasibility will be evaluated via 
treatment adherence (% treatment sessions completed out of the total possible) and 
acceptability will be evaluated via usability as assessed by the System Usability Scale (SUS) 
questionnaire. As part of this study, it is critical to identify an appropriate sham treatment 
prior to initiating a follow-on pivotal study, so all feasibility and acceptability endpoints 
will be evaluated for the active (palm) and sham (biceps) treatments in this study. The effect 
of treatment group on these co-primary endpoints will also be evaluated. 
5.2 
Secondary Endpoints 
The following secondary endpoints will be evaluated: 
 
• Feasibility: For each treatment group, the percentage of treatment sessions that 
provide effective nerve stimulation as assessed via participant-reported 
confirmation of tingling sensation 
• Acceptability: For each treatment group, the overall satisfaction with treatment (via 
100-mm VAS) 
• Effectiveness: 
o Effect of treatment group on change in clinician-assessed anxiety severity 
(via HAM-A) 
o Effect of treatment group on change in weekly participant-reported anxiety 
severity (via BAI)  
o Effect of treatment group on change in participant-reported GAD symptoms 
(via GAD-Q-IV) 
o Effect of treatment group on change in daily self-reports for anxiety severity 
(via 100-mm VAS) 
o Effect of treatment group on change in self-reports of anxiety severity 
immediately after vs. before treatment (via 100-mm VAS) 
o Effect of treatment group on change in daily self-reports for anxiety 
interference with daily living (via (100-mm VAS) 
o Effect of treatment group on medication use (via self-reports) 
o Effect of treatment group on change in clinician-assessed depression severity 
(via HAM-D) 
o Effect of treatment group on change in participant-reported depression 
severity (via PHQ-9) 
o Effect of treatment group on change in participant-reported PTSD severity 
(via PCL-5) 
o Effect of treatment group on change in sleep quality (via PSQI survey) 

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o Effect of treatment group on change in quality of life (via SF-12 survey) 
• Blinding:  For each treatment group, the blinding index and 95% confidence interval 
(via Bang et al.26 blinding assessment method) 
 
All of these secondary endpoints provide valuable information on the effectiveness of the 
Empower Neuromodulation System for GAD treatment as well as the acceptability to the 
intended patient population. 
5.3 
Safety Evaluations 
Safety evaluations will include the incidence and severity of device-related AEs and the 
incidence and severity of SAEs (regardless of relationship to the device). 
6 
PARTICIPANT SELECTION 
6.1 
Study Population 
The study population is adults with generalized anxiety disorder (GAD). Participants who 
meet all of the inclusion and none of the exclusion criteria will be eligible to be randomized 
for full participation in the study.   
6.2 
Inclusion Criteria 
1. 
≥19 years old 
2. 
Current diagnosis of GAD per DSM-5 via M.I.N.I. assessment by clinician 
3. 
HAM-A ≥18 
4. 
Negative urine pregnancy test at screening (females only) 
5. 
Able to provide informed consent 
6. 
Capable and willing to follow all study-related procedures 
 
6.3 
Exclusion Criteria 
1. Has current (past 30 days) psychotic or bipolar disorder, homicidal ideation, psychiatric 
hospitalization, or moderate/severe SUDs per clinician assessment via M.I.N.I. 
2. HAM-D ≥18 
3. PCL-5 ≥34 
4. Exhibits suicidal intent as confirmed on the Columbia-Suicide Severity Rating Scale-
Revised (C-SSRS-R) with a “Yes” response to question 4 or question 5, or to question 
6 in the past 3 months. 
5. Changes in psychoactive medications in the past 30 days (including but not limited to 
psychotropic medications, thyroid hormone medication, steroids), with the exception 
of benzodiazepines 
6. If regularly taking benzodiazepines, has had changes in benzodiazepine dosing in the 
past 30 days or average use >2 days per week 
7. Psychotherapy was initiated or discontinued in the past 30 days or psychotherapy 
modality was changes in the past 30 days 
8. Has a history of epilepsy or a seizure disorder  

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9. Has been diagnosed with peripheral nerve damage of the arm or hand or has numbness 
or tingling in the arm or hand at least weekly 
10. Is currently pregnant or breastfeeding, has been pregnant within the past 6 months or 
intends to become pregnant during the study period 
11. Currently has an active implant and/or an electrical or neurostimulator device, 
including but not limited to cardiac pacemaker or defibrillator, vagal neurostimulator, 
deep brain stimulator, spinal stimulator, sacral stimulator, bone growth stimulator, or 
cochlear implant 
12. Has an electrically conductive metal object (e.g. jewelry) that cannot be removed from 
the palm or biceps and will directly contact the gel electrodes of the Empower 
Neuromodulation System at either anatomic location 
13. Has an open incision, wound, scar, active infection or otherwise compromised skin at 
the palm or biceps and will directly contact the gel electrodes of the Empower 
Neuromodulation System at either anatomic location 
14. Does not have daily access to an electrical outlet for charging the investigational device 
and associated smartphone 
15. Has used of an investigational drug/device therapy within the past four weeks 
16. Unable to provide informed written consent 
17. Has any medical condition that would, in the opinion of the investigator, make the 
participant ineligible 
 
7 
CONCURRENT MEDICATIONS 
Each participant should be maintained on the same psychotropic/psychoactive medications 
throughout the entire study period, as medically feasible, with no introduction of new 
chronic therapies.  
7.1 
Allowed Medications and Treatments 
As outlined in the inclusion criteria, at the time of enrollment, participants may be taking 
scheduled antianxiety, psychotropic, or psychoactive medications (>30 days on a stable 
dose preceding enrollment) or benzodiazepines (≤2 days per week). Participants may also 
be in psychotherapy as long as no changes have been made in psychotherapy in the 30 days 
preceding study enrollment. Only treatments and medications noted in the exclusion criteria 
described above will be considered a protocol violation. All other medications are allowed.  
8 
STUDY PROCEDURES 
8.1 
Method of Assigning Participants to Treatment Groups 
This is a randomized, controlled study. At enrollment participants will be randomized (1:1, 
block size of four) to the active or sham treatment group. Men and women will be 
randomized separately to ensure that the distribution of men and women in the active and 
sham arms are consistent. Women account for approximately 64% of American adults with 
GAD.46 Thus, to ensure that we enroll a study cohort that is both representative of the 
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exploratorily evaluate sex as a biological variable, we will enroll a maximum of 21 women 
and a maximum of 12 men. 
 
Participants will also be randomized for the body side that they should apply stimulation to 
first (right vs. left, 1:1 simple randomization). Participants will be instructed to begin 
treatment with this hand/arm for every treatment session in the study. 
8.2 
Investigational Device 
8.2.1 
Device Description 
The investigational device is called the Empower Neuromodulation System (Fig. 3). 
8.2.2 
Device Description 
The Empower Neuromodulation System is a transcutaneous electrical nerve stimulation 
(TENS) device. The Empower Neuromodulation System consists of a controller (i.e. 
electrical signal generator), electrodes, extension cable, and smartphone with the Empower 
app. The electrodes set consists of two off-the-shelf gel electrodes (TENS Unit Electrodes 
Pads, Syrtenty) that are trimmed to the correct size for use. There are two sizes of electrodes: 
Small (2.25 x 0.75 inches) and Large (2.75 x 0.75 inches). All participants in the sham group 
(stimulation on the biceps) will receive the Small electrodes. For participants in the active 
treatment group, the hand will be measured and participants who have a palm width of ≤2.25 
inches will be given Small size electrodes while participants who have a palm width of 
>2.25 inches will be given Large size electrodes. The two electrodes (called the stimulation 
and return electrodes) are connected by the extension cable to the 9-volt battery‐powered 
controller. The controller housing is a molded plastic enclosure with an incorporated 
overlay that has the on/off switch, adjustable current control, mode switch button, and liquid 
crystal display (LCD) screen facing the operator. The controller housing contains a 9-volt 
battery and printed circuit board assembly with microprocessor and embedded software that 
delivers pulses of direct current (DC) energy to the participant via the two electrodes. The 
controller housing has a removable door for replacement of the 9-volt battery. The housing 
encloses the internal electronics and prevents user contact with them. The controller 
produces an adjustable electrical pulse that stimulates the nerves beneath where the 
electrodes are attached to the skin. For the active stimulation, which stimulates the ulnar 
and median nerves, the electrodes are placed on the palmar surface of the hand over the 
ulnar and median nerves (Fig. 3B). For the sham stimulation, which does not appreciably 
stimulate the ulnar or median nerves, the electrodes are placed on the crown of the biceps 
muscle on the upper arm (Fig. 3B). The current delivered by the electrodes is controlled by 
the operator. At start-up the current is set at 0 mA. The current is then increased to a 
comfortable level, to a maximum of 50 mA. The user can increase/decrease the current 
setting level or pause stimulation at any time during a treatment session. The controller 
display continuously shows the current level during stimulation. 
 

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8.2.3 
Intended Use 
The Empower Neuromodulation System is intended to provide transcutaneous electrical 
nerve stimulation to reduce anxiety. 
 
8.2.4 
Technical Specifications 
The controller output an electrical pulse with the following characteristics: 
 
 
8.2.5 
User Interface 
The Empower Neuromodulation System has a simple user interface. The two components 
of the user interface are the controller (Fig. 5A) and the smartphone-based Empower app 
(Fig. 5B). The controller has the following user interface components: on/off button, mode 
button, up/down buttons, and a display. The Empower app has several screens that facilitate 
device use and recording of responses to surveys.  
To self-administer a treatment session, the participant first opens the Empower app and 
presses the “Begin Session” button on the Home screen. After completing the survey, if 
applicable, the participant connects the two electrodes to the controller at their appropriate 
locations. The participant then connects the electrodes on the skin surface per the 
Instructions for Use. The Empower app will then guide the participant through treatment 
administration with the controller. Briefly, the participant will press the “Start” button on 
the controller and increase the stimulation intensity (i.e. output current) until the maximum 
tolerable level is reached. After the 15-minute treatment is completed, the controller will 
stop the stimulation (i.e. output current will be set back to 0 mA). The participant will then 
transfer the skin electrodes to the opposite hand/arm to administer the second 15-minute 
treatment session. The participant will press the “Start” button on the controller and increase 
the stimulation intensity until the maximum tolerable level is reached. After the second 15-
minute stimulation session is completed, the controller will stop the stimulation (i.e. output 
current will be set back to 0 mA). After the two 15-minute sessions are completed, the 
controller will turn off and the app will return to the Home screen. 
 
8.2.6 
Participant-Contacting Materials 
8.2.6.1 
Gel Electrodes 
For the Empower Neuromodulation System, standard TENS skin gel electrodes are used 
to apply the stimulation. The electrodes are FDA-cleared, purchased off-the-shelf (TENS 
Unit Electrodes Pads, Syrtenty) that are trimmed to the correct size for use with the 
Empower Neuromodulation System. There are two sizes of electrodes: Small (2.25 x 0.75 
inches) and Large (2.75 x 0.75 inches). All participants in the sham group (stimulation on 

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the biceps) will receive the Small electrodes. For participants in the active treatment group, 
the hand will be measured and participants who have a palm width of ≤2.25 inches will be 
given Small size electrodes while participants who have a palm width of >2.25 inches will 
be given Large size electrodes. The gel electrodes consist of biocompatible conductive 
hydrogel adhesives on the participant contact surfaces connected to conductive backings 
with various top layers. Only the conductive hydrogel adhesive and the top surface are 
participant-contacting.  
8.2.6.2 
Controller 
The patient-contacting components of the controller are the plastic housing and the overlay, 
which includes the buttons for controlling the stimulation (i.e. power, mode, and up/down 
buttons). The plastic housing is made of injection molded acrylonitrile butadiene styrene 
(Lustran 348 (white), Ineos, Addyston, OH), which has an established history of safe use in 
skin-contacting applications. No mold release is used in making this part. The overlay has 
a top layer of polyethylene terephthalate (Autoflex EBG77, MacDermid Autotype, 
Waterbury, CT), a material that is standard for overlays and has a long history of safe use 
in skin-contacting displays/controls.  
8.3 
Measures of Compliance 
The device keeps a log of when the participant administers a treatment session and the 
duration of each session. This data is transmitted to the smartphone via Bluetooth at the end 
of each treatment session. The smartphone then transmits the data to the Sponsor’s 
password-protected cloud server (Amazon Web Services) via cellular connection. All 
compliance data will be analyzed by the Sponsor and stored on the Sponsor’s password-
protected server. Data files transmitted to and saved on the password-protected cloud server 
and the Sponsor’s server will be de-identified. These files will only include the participant’s 
study ID number and smartphone MAC address.  
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the participant. Assent must also be obtained prior to conducting any study-related 
activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Screening.  
Dose, route, unit frequency of administration, and indication for administration and dates 
of medication will be captured. 

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9.1.2 
Demographics  
Demographic information (date of birth, gender, race, ethnicity) will be recorded at 
Screening. 
9.1.3 
Medical History  
Relevant medical history, including history of current disease, other pertinent psychological 
history (e.g. depression, PTSD, etc.), and information regarding underlying diseases will be 
recorded at Screening. 
9.1.4 
Physical Examination 
An abbreviated physical examination as needed to determine eligibility (specifically for 
evaluating the exclusion criteria for jewelry that cannot be removed and open wounds at the 
hands and upper arms) will be performed by a study clinician at Screening. Site staff will 
also measure the palm width on participants randomized to the active treatment group. 
9.1.5 
Psychiatric Examination 
An abbreviated psychiatric examination as needed to determine eligibility will be performed 
by either the investigator or qualified staff (MD, NP, or PhD) at screening. The Mini-
International Neuropsychiatric Interview (M.I.N.I.) will be used to evaluate the DSM-5 
criteria for GAD and other psychiatric disorders that are in the inclusion and exclusion 
criteria. The Columbia-Suicide Severity Rating Scale-Revised (C-SSRS-R) will be used to 
evaluate suicidality risk at each clinical visit. 
9.1.6 
Medical chart review 
The participant will be asked about the following, and if available, the participant’s medical 
chart will also be reviewed to determine if the participant has been diagnosed with any of 
the following: 
• Epilepsy or seizure disorder 
• Peripheral neuropathy or nerve damage of the upper extremities 
 
The participant will be asked about the following, and if available, the participant’s medical 
chart will be reviewed to determine if the participant has any of the following: 
• Has used an investigational drug or device within the past four weeks 
• Has implanted electrical and/or neurostimulator device (e.g. pacemaker, defibrillator, 
vagal neurostimulator, deep brain stimulator, spinal stimulator, sacral stimulator, bone 
growth stimulator, or cochlear implant) 
9.1.7 
Surveys 
Throughout the study, the participant will provide responses and complete surveys that 
cover medication use, skin tingling during treatment, anxiety, depression, sleep quality, and 
quality of life. Daily surveys (medication use, skin tingling during treatment, anxiety 

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severity and interference with daily living) and weekly surveys (BAI) will be completed on 
the Empower app. Surveys will be completed at the same time as Empower treatment (the 
participant will be guided by the app as to when each survey is to be completed). Surveys 
conducted at Visits 1 and 3 (GAD-Q-IV, PHQ-9, PSQI, and SF-12) will be completed 
electronically or on paper. At each clinic visit, the participant will complete the daily and 
weekly surveys if they have not been completed for that day/week. At the final clinic visit, 
the participant will also complete the following electronic or paper-based surveys: usability 
survey (SUS), rating of overall satisfaction with treatment (100-mm VAS), blinding 
assessment, and a Final Study Questionnaire that includes questions regarding feedback on 
device features, device comfort and tolerability, and marketing questions. 
9.1.7.1 
Daily Surveys 
The daily survey questions will be completed on the Empower app and include questions 
about non-scheduled anxiety medication use (e.g. benzodiazepine dose taken over the past 
24 hours and day/time of last dose), anxiety severity over the past 24 hours, anxiety 
interference with daily life over the past 24 hours, and anxiety severity at the present time. 
For anxiety severity, the participant will be asked to rate it on a 100-point visual analog 
scale (VAS) [0=”No anxiety at all” through 100=”Severe Anxiety”]. For anxiety 
interference with daily life, the participant will be asked to rate it on a 100-point visual 
analog scale (VAS) [0=”Not at all” through 100=”Extreme”]. 
The app will guide the participant to complete the daily survey prior to self-administering 
the first treatment session of each calendar day. Immediately after the session, the 
participant will also be asked about anxiety severity at the present time and if a tingling 
sensation was felt on the skin at the site of stimulation application to confirm effective nerve 
stimulation. 
9.1.7.2 
Weekly Surveys 
The weekly surveys (BAI) will be completed on the Empower app. The app will guide the 
participant to complete the weekly survey prior to self-administering the first treatment 
session of each calendar week. 
9.1.7.3 
Surveys only at Visits 1 and 3 
Surveys conducted at Visits 1 and 3 (GAD-Q-IV, PHQ-9, PSQI, and SF-12) will be 
completed electronically or on paper. At Visit 3, the participant will also complete the 
following electronic or paper-based surveys: usability survey (SUS), rating of overall 
satisfaction with treatment (100-mm VAS), blinding assessment, and a Final Study 
Questionnaire that includes questions regarding feedback on device features, device 
comfort and tolerability, and marketing questions. 
9.1.8 
Treatment Session 
The participant will be instructed to self-administer two 30-minute treatment sessions per 
day. The participant will be asked to administer treatment sessions as close as possible to 

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8:00 am and 8:00 pm each day. The smartphone will have two daily notifications to remind 
the participant to complete sessions and surveys. 
To self-administer a treatment, the participant will open the Empower app, complete any 
surveys as prompted, place the gel electrodes at the instructed location (first treatment side 
(left vs. right; 1:1 randomization) will be assigned to each participant during training), and 
turn on the Empower controller. The Empower app will guide the participant through 
treatment administration with the controller. Briefly, the participant will press the “Start” 
button on the controller and increase the stimulation intensity (i.e. output current) until the 
maximum tolerable level is reached. After the 15-minute treatment is completed, the 
controller will stop the stimulation (i.e. output current will be set back to 0 mA), and the 
app will ask a question about skin tingling sensation. The participant will then transfer the 
gel electrodes to the opposite hand/arm to administer the second 15-minute treatment. The 
participant will press the “Start” button on the controller and increase the stimulation 
intensity until the maximum tolerable level is reached. After the second 15-minute treatment 
is completed, the controller will stop the stimulation (i.e. output current will be set back to 
0 mA), and the app will ask a question about tingling sensation and a question about current 
anxiety severity. The controller will automatically transmit use data to the smartphone and 
then automatically turn off. Then, the app will upload data files to the sponsor’s secure 
cloud server and return to the home screen. 
9.1.9 
Treatment regimen reminders sent to participants via text message 
To remind participants of the treatment regimen, participants will receive text message 
notifications periodically through the study. These messages will be sent to his/her personal 
phone number at the following frequency: 
• Once per day for the first week in the study 
• Three times per week for the remainder of the study. 
 
The following text messages will be sent to participants (study days sent in brackets): 
 
[Day 1] “(Empower Study) Thank you for taking part in the Empower Study. You will 
receive text message reminders during your participation in the study. Please remember to 
administer Empower treatments twice per day: once in the morning and once in the evening, 
if possible. If you have any questions or device issues, please email bvaughan@unmc.edu. 
Thanks!” 
 
[Day 2, 5, 8, 15, 22, 29, 36] “(Empower Study) Hello, please remember to use the Empower 
device twice per day. If you have any questions or device issues, please email 
bvaughan@unmc.edu.” 
 
[Day 3, 6, 10, 17, 24, 31, 38] “(Empower Study) Hi, thanks for your participation in the 
Empower Study. Please remember to administer Empower treatments twice per day. 
Thanks!” 
 
[Day 4, 7, 12, 19, 26, 34, 40] “(Empower Study) Hi, just another friendly reminder to use 
the Empower device twice per day. If you have any questions, please email 
bvaughan@unmc.edu.” 
 

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For text messaging, the participant’s personal phone number will be stored with the 
participant ID number, which will be stored within a password-protected server that can be 
accessed by the clinical site research staff and sponsor clinical research staff during that 
participant’s participation in the study. Once a participant completes the study or is 
withdrawn, his/her personal cell phone number will be deleted from the server. 
9.1.10 
Contact with participants who are not adhering to the treatment regimen 
The study smartphone transmits treatment adherence data to the Sponsor’s password-
protected cloud server (Amazon Web Services) via cellular connection. All compliance data 
will be analyzed by the Sponsor and stored on the Sponsor’s password-protected server. If 
a participant has not administered a treatment session for over 48 hr or if a participant has 
not administered at least five treatment sessions in a calendar week (Monday to Sunday), 
the clinical site research staff will contact the participant and request that they comply with 
the study procedures. 
9.1.11 
Adverse Events 
Information regarding occurrence of AEs and serious AEs (SAEs) will be captured 
throughout the study. Duration (start and stop dates), severity/grade, outcome, treatment 
and relation to study device and procedures will be recorded on the case report form (CRF).  
If the participant’s skin becomes too irritated to comfortably carry out the treatment 
sessions, the participant will be instructed to refrain from administering a treatment session 
until the skin is no longer irritated. 
9.1.12 
Suicidality Evaluation 
The C-SSRS-R will be used to evaluate suicidality risk at each clinic visit. If a participant 
exhibits suicidality or is determined to be at risk for harm to self/others by the clinician, the 
participant will be referred to his/her current mental health provider or primary care 
provider and will be provided information on community resources. In the event of acute 
suicidality, as confirmed on the C-SSRS-R with a “Yes” response to question 4 or question 
5, or to question 6 in the past 3 months, the participant will be referred to the emergency 
department or psychiatric emergency services and withdrawn from the study. 
9.1.13 
Participant Compensation 
Participants will be compensated a nominal amount for their time and expenses associated 
with the study. Each participant will be compensated $100 for the screening/enrollment visit 
(Visit 1), $100 each for the remaining two visits (Visits 2 and 3), and a bonus of $25 for 
returning the study equipment (Empower controller and smartphone), for a total 
compensation of up to $325 per participant. Compensation at Visits 2 and 3 includes 
compensation for the time and effort of conducting twice daily treatment sessions at home 
during the study. 

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9.2 
Clinical Laboratory Measurements 
9.2.1 
Pregnancy Test 
A urine pregnancy test will be obtained from female participants at the screening visit. 
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Day 1) 
1. 
Review the study with the participant and obtain written informed consent and 
HIPAA authorization and assent 
2. 
Assign the participant a unique screening number 
3. 
Record demographics data 
4. 
Record medical history 
5. 
Record concomitant medications 
6. 
Perform an abbreviated physical examination 
7. 
Perform an abbreviated psychiatric examination, including M.I.N.I. and C-SSRS-R 
8. 
Collect urine sample and perform a urine pregnancy test, if applicable 
9. 
Perform clinician-administered assessments (HAM-A and HAM-D) and participant-
reported survey (PCL-5) 
10. 
Final review of eligibility 
11. 
Complete self-report surveys (GAD-Q-IV, PHQ-9, PSQI, SF-12) 
12. 
Randomize participant 
13. 
Train participant on Empower device, smartphone, and app. 
14. 
Self-administer a treatment session and complete app-based surveys (BAI, 
medication use, anxiety severity and interference, skin tingling) 
15. 
Record adverse events, if applicable 
16. 
Schedule participant for Visit 2 in 14 days 
10.2 Visit 2 (Day 15 ± 7) 
1. 
Complete blinding assessment 
2. 
Record adverse events, if applicable 
3. 
Perform assessment of suicidality (C-SSRS-R) 
4. 
Schedule participant for Visit 3 in 28 days 
10.3 Visit 3 (Day 43 ± 7) 
1. 
Perform clinician-administered assessments (C-SSRS-R, HAM-A, HAM-D) 
2. 
Complete self-report surveys (PCL-5, GAD-Q-IV, PHQ-9, PSQI, SF-12) 
3. 
Record adverse events, if applicable 
4. 
Complete blinding assessment, usability survey, and Study Completion Questionnaire 
5. 
Return of all device and study materials 
6. 
Participant reimbursement 

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10.4 Early Withdrawal Visit 
1. 
Perform clinician-administered assessments (C-SSRS-R, HAM-A, HAM-D) 
2. 
Complete self-report surveys (PCL-5, GAD-Q-IV, PHQ-9, PSQI, SF-12) 
3. 
Record adverse events, if applicable 
4. 
Complete blinding assessment, usability survey, and Study Completion Questionnaire 
5. 
Return of all device and study materials 
6. 
Participant reimbursement 
11 ADVERSE 
EXPERIENCE 
REPORTING, 
DOCUMENTATION, 
AND 
MONITORING 
11.1 Definitions 
11.1.1 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject during participation 
in the clinical study or with use of the experimental agent being studied. An adverse finding 
can include a sign, symptom, abnormal assessment (laboratory test value, vital signs, 
electrocardiogram finding, etc.), or any combination of these regardless of relationship to 
participation in the study. 
11.1.2 
Unanticipated Problem (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
(UPs) involving risks to subjects or others to include, in general, any incident, experience, 
or outcome that meets all of the following criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
11.1.3 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any AE that meets one or more of the following 
criteria: 
• 
Results in death 
• 
Is life-threatening (places the study participant at immediate risk of death from the 
event as it occurred) 

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• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in a persistent or significant disability or incapacity 
• 
Results in a congenital anomaly or birth defect. 
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  
11.2 Time Period and Frequency for Event Assessment and Follow-Up 
Unanticipated problems will be recorded in the data collection system throughout the study.  
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of 
study participation. At each study visit, the investigator or clinical research coordinator will 
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until resolution or stabilization. 
11.3 Characteristics of an Adverse Event 
11.3.1 
Relationship to Study Intervention 
To assess relationship of an event to study intervention, the following guidelines are used: 
1. Related (Possible, Probable, Definite) 
a. The event is known to occur with the study intervention. 
b. There is a temporal relationship between the intervention and event onset. 
c. The event abates when the intervention is discontinued. 
d. The event reappears upon a re-challenge with the intervention. 
2. Not Related (Unlikely, Not Related) 
a. There is no temporal relationship between the intervention and event onset. 
b. An alternate etiology has been established. 
11.3.2 
Expectedness of SAEs 
The Study PI and Independent Safety Monitors will be responsible for determining whether 
an SAE is expected or unexpected. An AE will be considered unexpected if the nature, 
severity, or frequency of the event is not consistent with the risk information previously 
described for the intervention.   
11.3.3 
Severity of Event 
The following scale will be used to grade adverse events: 

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1. Mild: no intervention required; no impact on activities of daily living (ADL) 
2. Moderate: minimal, local, or non-invasive intervention indicated; moderate impact 
on ADL 
3. Severe: significant symptoms requiring invasive intervention; subject seeks medical 
attention, needs major assistance with ADL. 
11.4 Reporting Procedures 
AEs will be monitored at frequent intervals during the study. Study participants will be 
monitored during the study at each clinic visit for expected and unexpected AEs related to 
the Empower Neuromodulation System. The Site PI or research coordinator will probe, via 
discussion with the participant, for the occurrence of AEs during each participant visit and 
record the information in the AE case report form (CRF). AEs will be described by duration 
(start and stop dates), severity, outcome, treatment and relation to study device, or if 
unrelated, the cause.  
During the study, site clinical research personnel will note any change in the participant’s 
symptoms (anxiety, depression, etc.) and the occurrence and nature of any AEs. Important 
clinical information that comes to light during study participation will be communicated by 
research coordinators to the study PI in real time. 
The study investigator (either the Site PI, Dr. Lauren Edwards, or, in her absence, the Site 
co-investigator, Dr. Justin Weeks) will review each participant’s safety at each study visit. 
• Moderate and severe AEs reported by participants will be reviewed on the same day 
as they are reported by the study participant. Mild AEs reported by participants will 
be reviewed within 72 hours of being reported by the study participant. 
• Adverse effect assessment will be done by the research coordinators and discussed 
with the Site PI on a daily basis, immediately after these AEs are reported by the 
participant to the study coordinator. 
The Site PI, if not immediately present at the time of adverse effect data collection, will be 
contacted in real time by the study coordinator by phone, pager, or text message, so that 
AEs can be discussed with the Site PI. 
At least every 6 months, the Site PI will report to the independent monitoring committee 
and study sponsor the assessment of the potential relatedness of each AE to protocol 
procedure, studied disease state, and study device via the CRF. For each AE recorded on 
the AE CRF, the PI will make an assessment of seriousness, severity, and causality. 
The PI will follow all unresolved AEs until the event has resolved to baseline grade or 
better, the event is assessed as stable by the PI, new therapy is initiated, the participant is 
lost to follow-up, the participant withdraws consent, or until 7 (for non-serious AEs) or 30 
days (for SAEs) after the last day of study participation. 

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Every effort will be made to follow all SAEs considered to be related to study procedures 
until a final outcome can be reported. During the study period, resolution of AEs (with 
dates) will be documented on the AE CRF and in the participant’s medical record to 
facilitate source data verification. If, after follow-up, return to baseline status or stabilization 
cannot be established, an explanation should be recorded on the AE CRF. 
In the event that an SAE or death occurs, the event will be reported by the Site PI within 48 
hours after she first learns of the event to the sponsor and the reviewing IRB per the UNMC 
IRB reporting requirements. The initial report of an SAE must be made by phone as well as 
by email. The sponsor will immediately conduct an evaluation of the SAE(s) and report the 
results of the evaluation to FDA and NCCIH within 5 working days after first receives 
notice of the SAE(s). 
The Site PI must report any UPs within the same timeframe. The Site PI must report any 
protocol deviations or violations to the sponsor within 7 days of PI awareness. The Site PI 
must also submit all reports to the UNMC IRB in accordance with the institutional policies. 
11.4.1 
Unanticipated Problem Reporting 
Incidents or events that meet the OHRP criteria for unanticipated problems require the 
creation and completion of the UP report form. To satisfy the requirement for prompt 
reporting, UPs will be reported using the following timeline:   
• Unanticipated problems that are serious adverse events will be reported to the IRB, 
Independent Safety Monitors, and sponsor (who will then report to the funding 
agency, NCCIH) within 7 days of the investigator becoming aware of the event.  
• Any other unanticipated problem will be reported to the IRB, Independent Safety 
Monitors, and sponsor (who will then report to the funding agency, NCCIH) within 
14 days of the investigator becoming aware of the problem.  
11.4.2 
AE Reporting 
SAEs that are unanticipated, serious, and possibly related to the study intervention will be 
reported to the Independent Safety Monitors, IRB, and sponsor (who will then report to the 
funding agency, NCCIH).   
• Unexpected fatal or life-threatening AEs related to the intervention will be reported 
to the Independent Safety Monitors, IRB, and sponsor (who will then report to the 
funding agency, NCCIH) within 48 hours of the investigator becoming aware of the 
event. Other serious and unexpected AEs related to the intervention will be reported 
within 7 days. 
• Anticipated or unrelated SAEs will be handled in a less urgent manner but will be 
reported to the Independent Safety Monitor, IRB, and sponsor (who will then report 
to the funding agency, NCCIH) within 7 days.   
• All other AEs documented during the course of the trial will be reported to NCCIH 
on an annual basis by way of inclusion in the annual report and in the annual AE 

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summary which will be provided to NCCIH and to the Independent Monitors. The 
Independent Safety Monitors Report will state that all AEs have been reviewed. 
11.4.3 
Reporting of Pregnancy 
Due to the unknown effects of transcutaneous electrical nerve stimulation (TENS) on a fetus 
or breastfeeding infant whose mother is receiving TENS treatment, an exclusion criterion 
for this study is: “Currently pregnant or breastfeeding, has been pregnant within the past 6 
months or intends to become pregnant during the study period.” If a study participant 
becomes pregnant during study participation, she will be instructed to discontinue 
treatment, return the study materials, and will continue to be followed up for safety 
monitoring. This will be reported by the Site PI to the IRB, and sponsor (who will then 
report to the funding agency, NCCIH) within 5 days. 
11.5 Halting Rules 
The study will be stopped if, in the judgment of the Site PI, there are sufficient safety 
concerns that arise during the conduct of the study that would indicate that participants are 
being harmed by the study interventions, e.g., multiple SAEs that are judged to be related 
to study interventions. Subsequent review of serious, unexpected, and related AEs by the 
Independent Safety Monitors, IRB, sponsor, or FDA or relevant local regulatory authorities 
may also result in suspension of further study interventions/administration of study product. 
The FDA and study sponsor retain the authority to suspend additional enrollment and study 
interventions/administration of study product for the entire study, as applicable. 
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
12.1 Early Discontinuation of Study 
A participant may be discontinued from study at any time if the participant, the investigator, 
or the Sponsor feels that it is not in the participant’s best interest to continue.  The following 
is a list of possible reasons for study discontinuation:  
• Participant withdrawal of consent (or assent) 
• The PI believes it is in the best interest of the participant to withdraw from the study. 
This could be due to worsening anxiety or depression symptoms, suicidal or 
homicidal ideation, or for other reasons that the PI determines warrant it being in 
the participant’s best interest to discontinue study participation 
• Participant is not compliant with study procedures, including not administering at 
least one treatment session per two week period 
• AE that in the opinion of the investigator would be in the best interest of the 
participant to discontinue study participation 
• Protocol violation requiring discontinuation of study participation 
• Lost to follow-up 
• Sponsor request for early termination of study 
• Positive pregnancy test (females) 

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If a participant is withdrawn from the study due to an AE, the participant will be followed 
and treated by the PI until the abnormal parameter or symptom has resolved or stabilized. 
All participants who discontinue study participation should come in for an early 
discontinuation visit as soon as possible and then should be encouraged to complete all 
remaining scheduled visits and procedures. All participants are free to withdraw from 
participation at any time, for any reason, specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for participant 
withdrawals. The reason for the participant’s withdrawal from the study will be specified in 
the participant’s source documents. Refer to Section 10 for early withdrawal procedures. 
12.3 
Withdrawal of Participants from the Study 
If a participant who does not meet enrollment criteria is enrolled, the study sponsor will be 
contacted. In such cases, the PI will provide information on the participant´s anticipated 
benefit or current benefit from being enrolled in the study or continuing to receive study 
interventions. In addition, the PI will discontinue participants from the study in the 
following circumstances: 
• The PI decides that the participant should be withdrawn from the study due to an 
SAE judged to be due to study interventions. 
• The participant or his or her medical provider requests withdrawal of the participant 
from the study. 
• The PI stops the participant’s participation in the study for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and good 
clinical practice (GCP). 
• Per C-SSRS-R assessment at a clinic visit, the participant exhibits acute suicidality, 
as confirmed on the C-SSRS-R with a “Yes” response to question 4 or question 5, 
or to question 6 in the past 3 months 
• The participant is not compliant with study procedures, including not administering 
at least one treatment session per two week period. Exceptions may be made after 
discussions with the PI, with sponsor’s approval. 
• The participant has not been in contact with the research staff for at least two weeks 
after at least three research staff attempts for contact. Exceptions may be made after 
discussions with the PI, with sponsor’s approval. 
• In the clinical judgment of the investigator, the participant's clinical condition 
worsens substantially and it is felt to be in the participant's best interest to obtain 
alternative treatment including, but not limited to, additionally psychotherapy, 
pharmacotherapy, hospitalization, etc. 
• The participant’s skin becomes too irritated to comfortably carry out the treatment 
sessions, and after refraining from administering a treatment session until the skin 
is no longer irritated, the irritation returns upon administering another treatment 
session. 
 
When a participant withdraws before completing the study, the reason for withdrawal will 
be documented in the CRF and in the source document.  
 

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Participants who discontinue study participation early (i.e., they withdraw prior to Visit 3) 
should have an early discontinuation visit. Refer to Section 10 for early withdrawal 
procedures.  Participants who withdraw after Visit 1 but prior to Visit 3 should be 
encouraged to come in for a final visit (and the procedures to be followed would include 
those listed in Section 10).   
12.4 
Replacement of Participants 
Participants who withdraw from the study will not be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the participant, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, participant safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
• Failure to meet inclusion/exclusion criteria 
• Use of a prohibited concomitant medication 
• Failure to comply with Good Clinical Practice (GCP) guidelines will also result in 
a protocol violation. The Sponsor will determine if a protocol violation will result 
in withdrawal of a participant. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
14 DATA SAFETY MONITORING  
14.1 Independent Monitoring Committee  
The Independent Monitoring Committee (IMC) for this study will be comprised of up to 
three Independent Safety Monitors. The monitors will not be associated with this research 
project and will be required to work independently of the Site PI Lauren Edwards, MD, or 
sponsor representative (and NCCIH grant PI), Michael Jaasma, PhD. No member of the 
Committee will be allowed to have collaborated or co-published with the grant PI or Site PI 
within the past three years. They will be qualified to review the patient safety data generated 
by this study because of their unique expertise. 
14.2 Safety Review Plan 
Study progress and safety will be reviewed monthly (and more frequently if needed) by the 
PO.  Progress reports, including patient recruitment, retention/attrition, and AEs will be 
provided to the Independent Safety Monitors semi-annually. An Annual Report will be 
compiled and will include a list and summary of AEs. In addition, the Annual Report will 
address (1) whether AE rates are consistent with pre-study assumptions; (2) reason for 

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dropouts from the study; (3) whether all participants met entry criteria; (4) whether 
continuation of the study is justified on the basis that additional data are needed to 
accomplish the stated aims of the study; and (5) conditions whereby the study might be 
terminated prematurely. The Annual Report will be sent to the Independent Safety Monitors 
and will be forwarded to the sponsor (who will submit to the funding agency, NCCIH). 
14.3 Study Report Outline for the Independent Safety Monitors (Interim or Annual 
Reports) 
The study team will generate Study Reports for the Independent Safety Monitors and will 
provide information on the following study parameters:  enrollment status, subject status, 
demographics, adverse events, serious adverse events, deaths, unanticipated problems, any 
laboratory findings for tests conducted based on adverse events. Study Report tables will 
be generated only from aggregate (not by group assignment) baseline and aggregate safety 
data for the study population. 
14.4 Submission of On-Site Monitoring/Audit and Inspection Reports 
The IMC and sponsor (who will then submit to the funding agency, NCCIH) will receive 
copies of all study monitoring/audit or inspection reports within 14 day of PI receipt. Any 
FDA inspection report will be submitted to the IRB, IMC, and the sponsor (who will then 
submit to the funding agency, NCCIH). 
14.5 Stopping Rules 
This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse effects that call into question the safety of the intervention; (2) difficulty in study 
recruitment or retention will significantly impact the ability to evaluate the study endpoints; 
(3) any new information becomes available during the trial that necessitates stopping the 
trial; or (4) other situations occur that might warrant stopping the trial.   
15 STATISTICAL METHODS AND CONSIDERATIONS  
15.1 Data Sets Analyzed 
All eligible patients who receive at least one stimulation session with the study device (the 
Safety Population) will be included in the safety analysis. 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, gender, age, 
primary antianxiety medication currently taking, and primary psychotherapy treatment 
currently participating in. 
15.3 Analysis of Primary Endpoint 
The primary endpoints will be feasibility and acceptability of the Empower 
Neuromodulation System as a daily therapy for GAD. Feasibility will be evaluated via 

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treatment adherence, and acceptability will be evaluated via usability as assessed by the 
SUS questionnaire.  
Feasibility: We will calculate adherence (treatment sessions administered as a percentage 
of total possible) for each participant. We will consider a treatment session to be completed 
if at least 20 minutes of the session was administered. We will also compare adherence 
between the active and sham treatment groups (t-test). 
 
Acceptability: We will compare SUS scores for the active and sham treatment groups (t-
test), and compare each against the average (SUS≥68) and excellent (SUS≥80) 
benchmarks.27 
15.4 Analysis of Secondary Endpoints 
Secondary endpoints will be analyzed via the methods described below. Unless otherwise 
noted, for daily and weekly metrics, we will use a random-intercept linear mixed model 
with restricted maximum likelihood to compare results between the active and sham 
treatment groups. As a secondary analysis for each of these endpoints, we will evaluate the 
correlations for duration since last benzodiazepine dose and dose amount vs. the endpoint. 
If this relationship is significant for an endpoint, we will include time since last dose in our 
statistical analysis.  
 
Feasibility: Effective nerve stimulation: We will calculate effective nerve stimulation 
(treatment sessions that elicit skin tingling as a percentage of total treatment sessions) for 
each participant. We will also compare effective nerve stimulation between the active and 
sham treatment groups (t-test). 
 
Acceptability: Overall satisfaction with treatment: We will compare overall satisfaction 
with treatment scores between the active and sham treatment groups (t-test). 
 
Safety: We will tabulate AEs across all participants. This will include tabulating the number 
of participants for whom the event occurred, the rate of occurrence, and the severity and 
relationship to the study device.   
Effectiveness: Change in HAM-A score: We will compare the change in HAM-A score 
between the active and sham treatment groups (t-test).  
 
Effectiveness: Change in GAD-Q-IV score: We will compare the change in GAD-Q-IV 
score between the active and sham treatment groups (t-test). 
 
Effectiveness: Change in BAI score: We will compare the change in BAI score between the 
active and sham treatment groups (mixed models).  
 
Effectiveness: Change in daily anxiety severity self-report: We will compare the change in 
daily anxiety severity scores between the active and sham treatment groups (mixed models).  
 

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Effectiveness: Change in daily anxiety interference self-report: We will compare the change 
in daily anxiety interference scores between the active and sham treatment groups (mixed 
models).  
 
Effectiveness: Change in anxiety severity self-report as an immediate result of treatment: 
We will compare the short-term effect of Empower treatment on anxiety severity score (% 
change for post-treatment score vs. pre-treatment score) (repeated measures ANOVA with 
Tukey correction, active vs. sham treatment group).  
 
Effectiveness: Medication use: We will calculate average benzodiazepine use per week. We 
will compare medication use between the active and sham treatment groups (mixed 
models).  
 
Effectiveness: Change in HAM-D score: We will compare the change in HAM-D score 
between the active and sham treatment groups (t-test).  
 
Effectiveness: Change in PHQ-9 score: We will compare the change in PHQ-9 score 
between the active and sham treatment groups (t-test).  
 
Effectiveness: Change in PCL-5 score: We will compare the change in PCL-5 score 
between the active and sham treatment groups (t-test).  
 
Effectiveness: Change in PSQI score: We will compare the change in PSQI score between 
the active and sham treatment groups (t-test). 
 
Effectiveness: Change in SF-12 score: We will compare the change in SF-12 score between 
the active and sham treatment groups (t-test). 
 
Blinding: We will statistically assess blinding for the active and sham treatment groups 
using the blinding index from Bang et al.26 
 
15.5 Randomization and Sample Size 
At enrollment, participants will be randomized (1:1, block size of four, stratified by sex) to 
the active or sham stimulation. Participants will also be randomized for the body side that 
they should apply stimulation to first (right vs. left, 1:1 simple randomization). Men and 
women will be randomized separately. 
 
As a pilot study, our primary goal is to demonstrate feasibility for GAD treatment. 
Accordingly, the study sample size is based on similar pilot GAD studies in the literature. 
For two rTMS studies, each treatment arm had 12-25 participants, with an average of 15 
participants.28, 29 To be consistent with these studies, we will enroll 15 participants per 
treatment arm, for a total of 30 participants.  

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16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
Study personnel will enter data from source documents corresponding to a participant’s visit 
into the protocol-specific electronic Case Report Form (eCRF) OR paper CRF when the 
information corresponding to that visit is available. Participants will not be identified by 
name in the study database or on any study documents to be collected by the Sponsor (or 
designee), but will be identified by a participant study ID number. 
For eCRFs: If a correction is required for an eCRF, the time and date stamps track the 
person entering or updating eCRF data and creates an electronic audit trail. For paper 
CRFs: If a correction is made on a CRF, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change. 
16.2 Data Management Responsibilities 
The study staff are responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The investigators will maintain adequate 
case histories of study subjects, including accurate case report forms (CRFs), and source 
documentation. 
The PI is responsible for all information collected on participants enrolled in this study. All 
data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the PI, Co-I, or CRC. A copy of the CRF will remain at the 
PI’s site at the completion of the study. 
16.3 Database Protection 
This study will use an electronic database and on-paper surveys and CRFs. The electronic 
database will be secured with password protection. The informatics manager will receive 
only coded information that is entered into the database under those identification numbers. 
Electronic communication with outside collaborators will involve only unidentifiable 
information. The database incorporates an electronic audit trail to show change(s) to data 
after original entry including the date/time and user making the change. For all paper-based 
study records will be kept in a locked filing cabinet. Code sheets linking a participant’s 
name to the participant’s study identification number will be stored separately in another 
locked filing cabinet or on a password-protected computer. 
16.4 Source Document Protection 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of 
Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only. All study records will be kept 

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in a locked filing cabinet or on a password-protected computer or server. Code sheets 
linking a participant’s name to a participant study identification number will be stored 
separately in another locked filing cabinet or on a password-protected computer.  
All study data collected on an electronic CRF will be entered into a validated database. The 
database is safeguarded against unauthorized access by established security procedures. 
Throughout the study, device use data (i.e. frequency and duration of use, stimulation 
intensity used in a treatment session) and daily survey data will be upload by the 
smartphone’s cellular data plan to a cloud-based, password-protected, secure server 
(Amazon Web Services). This data will also be stored securely on a password-protected 
server maintained by the sponsor at the sponsor’s facility. Note that data files transmitted 
to and saved on the password-protected cloud server and the sponsor’s server will be de-
identified. These files will only include the participant’s study ID number and Empower 
controller MAC address.  
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. 
16.5 Archival of Data 
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.   
16.6 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request. A file for each participant must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that participant. The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the study 
has been discontinued. There may be other circumstances for which the Sponsor is required 
to maintain study records and, therefore, the Sponsor should be contacted prior to removing 
study records for any reason. 
16.7 Schedule and Content of Reports 
The study team will generate Study Reports for the Independent Monitors and will provide 
information on the following study parameters:  enrollment status, subject status, 
demographics, adverse events, serious adverse events, deaths, unanticipated problems, any 
laboratory findings for tests conducted based on adverse events. A Final Study Report will 

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also be generated after study completion. The Final Study Report will include analysis of 
adverse events, primary and secondary endpoints, blinding to treatment group, and 
participant qualitative feedback on the Empower Neuromodulation System that is collected 
via a questionnaire. 
16.8 Monitoring 
The sponsor’s QA Reviewer will review de-identified source documents and data collected 
at least quarterly. This includes review of subject screening and enrollment logs, informed 
consent forms of enrolled subjects, critical data used to evaluate eligibility criteria of 
enrolled subjects, CRFs used to log study visits and treatments, documented AEs and SAEs, 
and protocol deviations. If any errors are identified, the QA Reviewer will notify site study 
personnel to resolve the error or errors. Corrective action will also be taken to prevent a 
similar error from occurring again. This could include such steps as re-training of site staff 
or double-data entry. The frequency of all quality assurance/quality control checks is 
incorporated into Table below.   
 
16.9 Participant Confidentiality 
In order to maintain participant confidentiality, only a participant study ID number will 
identify all study participants on CRFs and other documentation submitted to the study 
monitor or Sponsor. For text messaging of study notifications to participants, the participant 
 
Data type 
Frequency of review 
Reviewer 
Subject accrual (including 
compliance with protocol 
enrollment criteria) 
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
Independent Monitors 
Status of all enrolled subjects, as 
of date of reporting  
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
Independent Monitors 
Data entry quality control checks 
on 50% of charts 
Quarterly 
Internal QA Reviewer 
Adherence data regarding study 
visits and intervention 
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
Independent Monitors 
AEs and rates (including out-of-
range lab values) 
Monthly 
PI, Internal QA Reviewer 
Semi-annually 
 
Independent Monitors 
Annually 
NCCIH, FDA (If Applicable) 
SAEs (unexpected and related) 
Per occurrence 
PI, Independent  Monitors 
NIH/NCCIH, FDA (if applicable) 
SAEs (expected or unrelated) 
Per Occurrence 
PI, Internal QA Reviewer 
Annually 
Independent Monitors, 
NIH/NCCIH 
Unanticipated Problems 
Monthly 
PI, Internal QA Reviewer 
Per Policy 
IRB, FDA (if applicable) 

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phone number will be stored with the participant ID number, which will be stored within a 
password-protected server.  
Subject confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to any study information relating to subjects. 
The study monitor or other authorized representatives of the sponsor may inspect all study 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) for the study subjects. The clinical 
study site will permit access to such records. 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only. All study records will be kept 
in a locked filing cabinet or on a password-protected computer. Code sheets linking a 
patient’s name to a patient identification number will be stored separately in another locked 
filing cabinet or on a password-protected computer. Clinical information will not be 
released without written permission of the participant, except as necessary for monitoring 
by the FDA. The Investigator must also comply with all applicable privacy regulations (e.g., 
Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of 
Clinical Investigators (21 CFR 312). 
17.1 Non-Significant Risk Determination for the Study 
Given the well-established safety profile of TENS devices and the fact that the Empower 
Neuromodulation System controller, which provides the electrical stimulation, is powered 
by a single 9-volt battery, we believe that this study qualifies as a non-significant risk (NSR) 
study. In further support of a NSR determination, the Empower Neuromodulation System 
has been used in four prior or ongoing investigations that were all determined to be NSR or 
minimal risk studies (see Section 1.3). These studies are pilot investigations in similar 
patient populations (alcohol use disorder, opioid use disorder, and chronic pain). In addition, 
in these four studies, no device-related AEs has occurred. Given the similarities of the 
current study with that of past studies with this device, we believe the current study should 
also be granted an NSR determination.  
Furthermore, this study with the Empower Neuromodulation System can be designated a 
NSR study per FDA guidance provided in “Information Sheet Guidance for IRBs, Clinical 
Investigators, and Sponsors - Significant Risk and Non-significant Risk Medical Device 
Studies”. The NSR determination can be made from answering “no” to the following four 
questions from the FDA guidance document for determining Significant Risk: 

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• Is intended as an implant and presents a potential for serious risk to the health, 
safety, or welfare of a participant; → No, this device is not an implant. 
• Is purported or represented to be for use supporting or sustaining human life and 
presents a potential for serious risk to the health, safety, or welfare of a participant; 
→No, this device is not intended for supporting or sustaining human life. 
• Is for a use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and presents a 
potential for serious risk to the health, safety, or welfare of a participant; → No, this 
is a feasibility study, so in this study this device is not used in the diagnosis, curing, 
mitigating or treating of disease. 
• Otherwise presents a potential for serious risk to the health, safety, or welfare of a 
participant; → No, this device does not present a potential for serious risk to the 
health, safety, or welfare of participants.  
17.2 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor and approved by the PI prior 
to submission. Protocol amendments cannot be implemented without prior written IRB 
approval except as necessary to eliminate immediate safety hazards to patients. A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRB is notified within five working days. 
17.3 Institutional Review Board (IRB) 
The protocol and consent form will be reviewed and approved by the UNMC IRB prior to 
study initiation. Serious adverse experiences regardless of causality will be reported to the 
IRB in accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study. The Investigator 
will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB. The IRB’s written unconditional approval of the study 
protocol and the informed consent form will be in the possession of the Investigator before 
the study is initiated. The IRB’s unconditional approval statement will be transmitted by 
the Investigator to the Sponsor or designee prior to the shipment of study supplies to the 
site. This approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.   

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The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance 
with the standard operating procedures and policies of the IRB; new information that may 
affect adversely the safety of the patients of the conduct of the study; an annual update 
and/or request for re-approval; and when the study has been completed. 
17.4 Informed Consent   
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Participants (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB.  The consent form generated by the Investigator must be acceptable to the Sponsor 
and be approved by the IRB.  The written consent document will embody the elements of 
informed consent as described in the International Conference on Harmonisation and will 
also comply with local regulations. The Investigator will send an IRB-approved copy of the 
Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each participant prior 
to entering the participant into the trial.  Information should be given in both oral and written 
form and participants must be given ample opportunity to inquire about details of the study.  
Because it is unknown if transcutaneous electrical nerve stimulation can affect a fetus, 
women of child-bearing age will be advised about the importance of using at least one form 
of contraception during study participation. The subject will sign the informed consent 
document prior to any study-related assessments or procedures. Subjects will be given the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate. They may withdraw consent at any time throughout the course of the study. A 
copy of the signed informed consent document will be given to subjects for their records. 
The rights and welfare of the subjects will be protected by emphasizing to them that the 
quality of their clinical care will not be adversely affected if they decline to participate in 
this study. To complete the informed consent process at the end of study participation, study 
staff will inform the subject when his/her participation has come to an end and will 
document this in the study record. 
17.5 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions. The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
17.6 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 

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1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or welfare 
of participants. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to participants or others. 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/participants. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 

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APPENDIX 1.  STUDY VISITS 
 
VISIT 1 
(Day 1) 
VISIT 2 
(Day 15 ± 7) 
VISIT 3 
(Day 43 ± 7) 
Informed consent 
X 
 
 
Assign unique screening number 
X 
 
 
Demographic information 
X 
 
 
Medical history 
X 
 
 
Record concomitant medications 
X 
 
 
Abbreviated physical exam 
X 
 
 
Psychiatric exam, including M.I.N.I  
X 
 
 
C-SSRS-R 
X 
X 
X 
Perform clinician-administered assessments 
(HAM-A, HAM-D) 
X 
 
X 
Pregnancy test (if applicable) 
X 
 
 
Eligibility review 
X 
 
 
Randomization 
X 
 
 
Complete self-report surveys (PCL-5, GAD-Q-
IV, PHQ-9, PSQI, SF-12) 
X 
 
X 
Device and App Training 
X 
 
 
Treatment Administration 
X 
 
 
Complete app-based surveys (BAI, medication 
use, anxiety severity and interference, skin 
tingling) 
X 
 
 
Adverse event reporting 
X 
X 
X 
Blinding assessment 
 
X 
X 
Complete 
usability 
survey 
and 
Study 
Completion Questionnaire 
 
 
X 
Participant compensation 
 
 
X 
 
 
 

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APPENDIX 2.  REFERENCES CITED 
1. 
Revicki DA, Travers K, Wyrwich KW, Svedsater H, Locklear J, et al. (2012). 
Humanistic and economic burden of generalized anxiety disorder in north america 
and europe. J Affect Disord 140(2):103-112. 
2. 
Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU (2012). 
Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and 
mood disorders in the united states. Int J Methods Psychiatr Res 21(3):169-184. 
3. 
Wittchen HU (2002). Generalized anxiety disorder: Prevalence, burden, and cost to 
society. Depress Anxiety 16(4):162-171. 
4. 
Kelly KM, Mezuk B (2017). Predictors of remission from generalized anxiety 
disorder and major depressive disorder. J Affect Disord 208:467-474. 
5. 
Reinhold JA, Rickels K (2015). Pharmacological treatment for generalized anxiety 
disorder in adults: An update. Expert Opin Pharmacother 16(11):1669-1681. 
6. 
Hoffman DL, Dukes EM, Wittchen HU (2008). Human and economic burden of 
generalized anxiety disorder. Depress Anxiety 25(1):72-90. 
7. 
Health NIoM. Generalized anxiety disorder: When worry gets out of control. 
(2016); Available from: https://www.nimh.nih.gov/health/publications/generalized-
anxiety-disorder-gad/index.shtml. 
8. 
Bandelow B, Michaelis S, Wedekind D (2017). Treatment of anxiety disorders. 
Dialogues Clin Neurosci 19(2):93-107. 
9. 
Gomez AF, Barthel AL, Hofmann SG (2018). Comparing the efficacy of 
benzodiazepines and serotonergic anti-depressants for adults with generalized 
anxiety disorder: A meta-analytic review. Expert Opin Pharmacother 19(8):883-
894. 
10. 
Strawn JR, Geracioti L, Rajdev N, Clemenza K, Levine A (2018). Pharmacotherapy 
for generalized anxiety disorder in adult and pediatric patients: An evidence-based 
treatment review. Expert Opin Pharmacother 19(10):1057-1070. 
11. 
Babaev O, Piletti Chatain C, Krueger-Burg D (2018). Inhibition in the amygdala 
anxiety circuitry. Exp Mol Med 50(4):18. 
12. 
Hall J, Kellett S, Berrios R, Bains MK, Scott S (2016). Efficacy of cognitive 
behavioral therapy for generalized anxiety disorder in older adults: Systematic 
review, meta-analysis, and meta-regression. Am J Geriatr Psychiatry 24(11):1063-
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