A Randomized, Phase II, Open-Label Study Evaluating the Nu-V3 Cranial Nerve Stimulation Treatment Device in Patients With Chronic Pain, Anxiety, Depression, and/or Sleeplessness
Phase: NA
Conditions: Chronic Pain, Anxiety, Depression, Sleeplessness
Sponsor: Nu-Life Solutions

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A Randomized, Phase II, Open-Label Study Evaluating the Nu-V3 
Cranial Nerve Stimulation Treatment Device in Patients with Chronic 
Pain, Anxiety, Depression, and/or Sleeplessness 
 
PROTOCOL NUMBER:  Nu-V3P2RCT 
 
PROTOCOL NAME: Nu-V3 RCT Protocol 
 
INVESTIGATIONAL PHASE: Phase II 
 
VERSION: 1.6 
 
NCT NUMBER:  NCT05335980 
                              
INVESTIGATIONAL DEVICE:  Nu-V3 
 
ORIGINAL PROTOCOL ISSUE DATE: April 20, 2022 
 
VERSION DATE:  April 20, 2022 
        
STUDY SPONSOR:  Nu-Life Solutions 
5252 E 82nd St., Suite 200 
Indianapolis, IN  46250 
United States 
 
STUDY CONTACTS: 
 
Medical Monitor 
Clinical Trial Manager 
Biostatistician 
Vipul Kella, MD 
Eric T. Siebeneck 
Jason Sutherland 
vkella@nu-
lifesolutions.com 
(317)941-6709 
jsutherland@nu-
lifesolutions.com 
esiebeneck@nu-
lifesolutions.com 
 
CONFIDENTIALITY STATEMENT 
This document is the property of Nu-Life Solutions. It contains confidential and proprietary information belonging to 
Nu-Life Solutions; therefore, its use is intended solely for physicians, clinical research staff, and contract research 
organizations (“study personnel”) participating in clinical studies of Nu-V3. Reproduction is authorized for and strictly 
limited to study personnel for Nu-Life Solutions, reproduction for any other purpose is prohibited. 
 
Sponsor Protocol Signature: 
 
 

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Protocol Signature Page 
 
A Randomized, Phase II, Open-Label Study Evaluating Nu-V3 Cranial 
Nerve Stimulation Treatment Device in Patients with Chronic Pain, 
Anxiety, Depression, and/or Sleeplessness  
 
Protocol Amendment 1.6: April 20, 2022 
 
By signing below, the Investigator attests that they will adhere to the protocol and 
Informed Consent Form and report, to the Study Sponsor and the IRB, any adverse 
device or participant study event. 
 
 
 
Investigator Name:       __________________________________________________ 
 
Title:                             __________________________________________________ 
 
Address:                      __________________________________________________ 
 
Address:                      __________________________________________________ 
 
Address:                      __________________________________________________ 
 
Phone:                        __________________________________________________ 
 
Facsimile:                    __________________________________________________ 
 
Signature:                    __________________________________________________ 
 
Date:                            __________________________________________________ 
 
 
 

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1.0 Introduction 
1.1 Background 
Research evidence has shown that the symptoms of chronic pain, anxiety, depression, 
and sleeplessness, or any combination of these symptoms are prevalent among patient 
populations with chronic medical conditions, particularly inflammatory arthritis (Psoriatic 
Arthritis, Rheumatoid Arthritis), Fibromyalgia, anxiety disorders (PTSD, Generalized 
Anxiety Disorder), Depression, Chronic Pain conditions (neuropathy, chronic neck and 
back pain, Osteoarthritis, TMJ Syndrome), and sleep disorders.  Patients with one of 
these chronic conditions often have clusters of one or more of these four symptoms 
(pain, anxiety, depression, and/or sleeplessness).  
These patient populations have a need for an innovative treatment approach to 
address these symptoms, as they often occur simultaneously.  By addressing all 
possible combinations of these symptoms in an individual patient or population, 
significant improvements in patients’ health and health outcomes can be achieved.  
Globally, the lifetime prevalence of anxiety disorders from a 2013 meta-analysis was 
7.3% (4.8-10.9%) and ranged from 5.3% (3.5-8.1%) in African cultures to 10.4% (7.0-
15.5%) in Euro/Anglo cultures.1 These statistics translate into 1 out of 13, and 1 out of 
10 people affected globally and in North America, respectively. In the United States 
alone, anxiety affects about 18% of the population or 40 million adults aged 18 and 
older at cost of more than $42 billion a year in 1990.2,3 
 
In a separate systematic review on depression, the global prevalence of major 
depressive disorder was 4.7% (4.4-5.0%).4  In 2015, over 16 million adults aged 18 or 
older have been estimated to have had at least one major depressive episode in the 
prior year, representing 6.7% of all U.S. adults.5 
 
Insomnia is a global public health issue and is believed to affect approximately 30-35% 
of the global population.6,7 Poor sleep has been associated with decreased immunity, 
depression, anxiety, poorer quality of life, obesity, increased pain, occupational errors, 
absenteeism from work, and motor vehicle crashes.7,8 
 
The prevalence of chronic pain, like all the previous conditions discussed, is highly 
variable among subgroups in population and by indication. It is estimated that 
approximately 20% of the adult European population suffers from chronic pain.9 
Similarly, approximately 17.6% (about 40 million) of US adults experience severe levels 
of pain along with over 11.2% (25.3 million) of adults suffering from daily pain for the 
prior 3 months at an annual estimated cost of approximately $560-$635 billion.10,11  
 
Given the high prevalence of conditions associated with chronic pain, anxiety, 
depression, and/or sleeplessness (CPADS), the associated economic burden, and lack 
of safe and cost-effective therapies, interest and research is expanding into the field of 
neuromodulation therapies, including TENS devices, to meet this need. 
 

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The Nu-V3 device is not considered to be a Transcutaneous Electrical Nerve 
Stimulation (TENS) device. TENS devices are applied only in the area of the body 
directly related to the pain. The Nu-V3 device is placed on the auricular (ear) area and 
utilizes a non-invasive electrical micro-signal to access the cranial nerves via three 
small electro-gel pads. There are no TENS devices currently approved or cleared by 
the FDA that qualify as being substantially equivalent.  
  
Under further research pertaining to accessing the cranial nerves, in particular the 
vagus nerve, we discovered that there are a variety of Vagal Nerve Stimulators 
available. However, none are non-invasive and small enough to be attached to the ear 
while stimulating multiple cranial nerves in the auricular area. 
 
In summary, while Nu-V3 is technically a transcutaneous device, the mechanism for 
mitigation of symptoms (chronic pain, anxiety, depression, and sleeplessness) is 
unique by TENS standards for the following reasons: 
 
A. TENS is typically placed in the general area where the pain exists.  Nu-V3 is 
placed only in the auricular area (on the ear) and accesses the cranial nerves as 
the mechanism for relief. 
B. TENS devices are known to stimulate muscular tissue and nerves in the area 
where pain exists, creating vasodilation (increased blood flow) and thereby the 
possibility of temporary relief. Nu-V3, by accessing the cranial nerves 
(specifically the vagus nerve) non-invasively, acts to stimulate the body’s natural 
enkephalins and elevate blood flow, and may result in the balancing or 
rebalancing of the Autonomic Nervous System (ANS).12-18   
C. By accessing the cranial nerves in the manner described above, the effect may 
be cumulative and residual and offer the patient immediate, intermediate, and 
longer lasting relief from their symptoms. 
 
In part, the purpose of this clinical study is to demonstrate the effect of the device upon 
the four specific symptoms of chronic pain, anxiety, depression, and sleeplessness. 
Any one or combination of these symptoms may result in Autonomic Nervous System 
dysfunction. 
 
1.2 Device Description 
 
The Nu-V3 device is a miniaturized, wearable, microchip-controlled, cranial nerve 
stimulation treatment device which delivers pulsed micro-signals over a period of 14 
days. The Nu-V3 device provides a continuous flow of intermittent, low frequency 
electrical pulses to the ear’s specific cranial nerve endings.  The Nu-V3 device is a 
patent pended, non-invasive transcutaneous stimulating device which offers useful 
features to the patient and clinical professional.  The Nu-V3 device control features are 
set by the manufacturer and prevent patient misuse of the device. 
 
Three miniature, non-invasive, electro-gel pads are utilized to deliver a micro signal at 1 

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Hz in a square plus minus waveform, which cycles on and off every three hours to 
provide a resting period and prevent adaption to the stimulation.  The device is 
powered by three (No.10) zinc air batteries at 1.4 volts each (4.2 volts in total), to 
provide the required stimulation for up to 14 days.  The low frequency, reliability of the 
zinc air batteries and consistency of the micro-signal through the eight-pin micro-chip 
technology, provides consistent and equivalent stimulation energy regardless of 
individual skin impedance.  
1.3 Non-significant Risk Medical Device Study 
 
The FDA considers other microcurrent transcutaneous devices (such as TENS 
devices) as nonsignificant risk devices for medical device studies.19  The Nu-V3 device 
used in this study reflects an investigational device that meets the definition of a 
nonsignificant risk device per review of the IRB.  
 
 
2.0 STUDY OBJECTIVE 
 
The objective of this research study is to collect data which demonstrates the ability of 
the Nu-V3 device to offer relief from one or more of the following symptoms: chronic 
pain, anxiety, depression, and/or sleeplessness.   
 
 
3.0 STUDY PARTICIPANT SELECTION CRITERIA 
3.1 Inclusion Criteria 
● Participant is at least 18 years of age 
● Participant presents with one or more of the following symptoms: chronic pain, 
anxiety, depression, and/or sleeplessness 
● Participants must score greater than or equal to a 5/10 for their primary 
symptom score on the Baseline Symptom Questionnaire 
● Patient’s chosen primary symptom must have an available accrual slot for the 
participant. If patient scores greater than or equal to a 5/10 for a second 
symptom, they can be selected to accrue to another symptom slot. 
● Participant has signed the Informed Consent Form 
3.2 Exclusion Criteria 
• Participants with a hearing aid 
• Participants with a pacemaker 
• Participants with irregular heart rate or a heart rate lower than 60 beats per 
minute (bradycardia) 
• Have had a transplant within the last 2 years 
• Have had a heart attack or cardiac bypass surgery within the last 12 months 
• Patients with complaints of dizziness or lightheadedness within the last 3 months 
• Women who are pregnant 

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• Participants with Diabetic Retinopathy 
• Current ear infection 
• SBP < 100 and/or DBP < 60 
• History of uncontrolled bipolar disorder within the last 12 months 
• History of uncontrolled seizures within the last 12 months 
• History of aneurysms 
• History of syncope within the last 12 months 
• Participants that have had a TIA or stroke within the last 12 months 
• Participants with health problems deemed at risk for the study by the Principal 
Investigator 
• Participants with any changes to Pain/Anxiety/Depression/Sleeplessness 
medications within last 60 days (participants that do not meet this medication- 
change washout period may be delayed until 60-day period is met) 
• Participants that are currently under adjudication process for disability support, 
VA or other 
4.0 STUDY PROTOCOL  
 
The Nu-V3 Clinical Study is a randomized, open-label study using the Nu-V3 cranial 
nerve stimulation treatment device in patients with chronic pain, anxiety, depression, 
and/or sleeplessness. Study participants are those who have signed the informed 
consent form, met the inclusion and exclusion criteria, and are enrolled in the study at 
one of multiple sites. 
 
Subjects randomized to receive the Nu-V3 treatment will undergo the following 
regimen: 
 
● At the baseline visit, patients will be asked to complete study questionnaires 
(Appendix 11) regarding all of the following symptoms: chronic pain, anxiety, 
depression, and/or sleeplessness, as well as their quality of life, active 
medications, medical history, and demographical information.  The subject’s 
primary symptom of concern will also be notated at baseline, for later 
assessment of continuation after week 12. 
● At each subsequent visit, patients will be asked to complete study 
questionnaires regarding all the following symptoms: chronic pain, anxiety, 
depression, and/or sleeplessness, as well as their activity level and quality of 
life. 
● The sessions will begin with the Nu-V3 device being clipped on the ear and 
three small pads (non-invasive) adhered to the surface of the ear.  Each Nu-V3 
device lasts for up to 28 days with a change in the pads approximately 7 days 
into the treatment. 
● Each session takes approximately 15-20 minutes. The placement of the device 
takes approximately 5 minutes, and the remaining time is spent verifying ePRO 
form completion, and evaluating the patient for all device effects. 
● The Nu-V3 device is mobile and is worn externally on the left ear 24 hours a day 
during treatment, fitting comfortably behind the ear. An electrical signal is sent to 

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the external ear through coated wire leads attached to the device and adhesive 
pads which attach to three sites on the ear. 
● Participants should be able to perform their typical day-to-day activities while 
wearing the device. They may shower while wearing the Nu-V3 device, if they 
do not get the device wet and use the small disposable ear covers that are 
provided for them. 
● In the event the Nu-V3 gel pads are inadvertently removed or the device comes 
off, the participant will contact the site coordinator.  The participant is 
encouraged to adjust the device placement as needed for comfort. 
● Patients should not change their existing forms of treatment or medications 
without discussion with the study investigator. 
 
Subjects randomized to the observation control arm of the study will undergo the 
following regimen: 
 
● At the baseline visit, patients will be asked to complete study questionnaires 
(Appendix 11) regarding all the following symptoms: chronic pain, anxiety, 
depression, and/or sleeplessness, as well as their quality of life, active 
medications, medical history, and demographical information.  The subject’s 
primary symptom of concern will also be notated at baseline. 
● At each subsequent visit, patients will be asked to complete study 
questionnaires regarding all the following symptoms: chronic pain, anxiety, 
depression, and/or sleeplessness, as well as their activity level and quality of 
life. 
● Patients should not change their existing forms of treatment or medications 
without discussion with the study investigator. 
● At completion of 12 weeks of standard of care treatment post study enrollment, 
observation (control arm) subjects will be offered a crossover into the treatment 
arm of the study for an additional 24 weeks. 
Sample size 
For this Phase II study, a total of 100-200 subjects will be randomized 1:1 to either the 
Nu-V3 treatment arm or to the observation treatment arm (SOC, control).  
 
Recruitment 
Participants are enrolled into relevant symptom cohorts based on their chronic pain, 
anxiety, depression, and/or sleeplessness symptom presentation at baseline and 
treated with the Nu-V3 device for 24 weeks.  
 
Analyses 
Interim analysis of reported data will be based on baseline symptom cohort and 
conducted at 6, 12, 18, and 24 weeks during this time.  The participant will be 
evaluated after the initial 12-week treatment period to assess for further therapeutic 
need.  Upon having three consecutive weeks of mean symptom reduction of ≥70% via 
patient reported numerical scales, the participant will continue as described in the study 
assessments table, but without device therapy.  Then if the participant’s primary 

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symptom score increases at any time by ≥20%, they may again continue device 
therapy until week 24, as depicted in section 4.1.   
 
Study subjects randomized to the observation arm will be offered the opportunity to 
cross-over to the Nu-V3 study treatment arm upon completion of the initial 12-week 
observation study period. 
 
4.1 Phase II Study Assessment Tables 
  
 
 
  

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5.0 DATA COLLECTION AND RETENTION 
 
The study endpoints data will be collected from each participant’s study questionnaires. 
The data will be collected electronically via the patient’s own device and uploaded to an 
electronic data capture system. The data will be used to measure whether the Nu-V3 
device provides participants with a reduction in participants’ chronic pain, anxiety, 
depression, and/or sleeplessness.  
The data analysis will include baseline data for each participant’s questionnaire prior to 
beginning treatment with the Nu-V3 device. Longitudinal data will consist of 
participant’s weekly questionnaires measuring chronic pain, anxiety, depression, and 
sleeplessness during the treatment phase. The final data collection will be completed 
by participants at the end of the treatment with the Nu-V3 device and will measure 
chronic pain, anxiety, depression, and sleeplessness. 
The Principal Investigator at each site will be responsible for recording, collecting, and 
storing the research participant’s study data.  The written records will be stored in a 
secure location.  Only the Principal Investigator or designated study staff will have 
access to the study records and all electronic files will be password protected. The 
Principal Investigator will also maintain adequate records for the study including:   
● all correspondence with the IRB and Sponsor 
● other pertinent data related to the study 
All records are to be retained by the Principal Investigator for a period of three (3) 
years following the closure of the study. Following study closure, the Principal 
Investigator shall inform Nu-Life of the location of study records and storage changes 
(i.e., the Principal Investigator leaves the institution where the study was conducted). In 
such cases, the study records may be transferred to another institution, investigator, or 
to Nu-Life upon written agreement between the Principal Investigator and Nu-Life. 
 
 
6.0 DATA DISCLOSURE AND SUBJECT CONFIDENTIALITY 
Medical record confidentiality and data protection will be maintained at every visit. 
Subject medical information obtained because of this study is considered confidential 
and disclosure to third parties, other than those noted below, is prohibited. Data 
generated during this study is to be available for inspection on request by the FDA or 
other government regulatory agency auditors, the Sponsor's authorized 
representatives, and the IRB. 
 
 
7.0 ADVERSE EVENT(S) 
 
Subjects will be evaluated for safety if they have received any study treatment. Adverse 
event assessments will be continuous during the 24-week trial (see section 4.1). During 

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treatment visits, toxicity assessments should be done in person. Once subjects reach 
symptom stabilization and are not actively receiving device therapy, follow-up either in 
person or documented via telephone call, is acceptable. Adverse events and will be 
graded according to the NIH-CTCAE version 5.0.  
 
Potential unanticipated problems require prompt reporting to the central IRB and study 
sponsor. These problems potentially place subjects or others at greater risk of physical 
or psychological harm than was previously recognized, and warrant consideration of 
substantive changes in the protocol or informed consent process or other action to 
protect the safety, welfare, or rights of participants.  The central IRB must be notified 
within 5 calendar days of the event and the study sponsor within 24 hours.  The 
completed IRB Unanticipated Problem Form (Appendix 7) must be received by the 
central IRB within 10 calendar days of the event to avoid a major deviation. 
 
Unanticipated problems are defined as those problems which alter the risks to subjects 
or others.  This includes any study suspensions or holds.  This form will be used to 
report any problem that is unforeseen or involves risk.  One form will be used per event 
or problem. 
 
8.0 STUDY ENDPOINT and DATA ANALYSIS 
 
8.1 Primary Endpoints: Primary endpoints consisted of the following: 
 
Safety:  At screening/baseline, a medical history will be obtained to capture 
relevant underlying conditions. The screening/baseline examinations will include 
BP, and HR. Baseline signs and symptoms are those that are assessed within 
14 days prior to week 1 treatment.  
Concomitant medications will be collected from within 14 days prior to 
enrollment through the study treatment period and maintenance period (see 
Study Assessments Table section 4.1).  
The primary safety endpoint is the occurrence of reported unanticipated 
problems involving risk to subjects or others (“UPIRTSOs”). These UPIRTSOs 
are defined as those problems which alter the risks to subjects or others.  This 
includes any study suspensions or holds. The primary safety endpoint analyses 
will be based on a risk-benefit conclusion. 
Effectiveness: There are four instruments measuring participant’s symptoms of 
chronic pain, anxiety, depression, and sleeplessness. The primary effectiveness 
endpoint is a statistically significant reduction in one or more of measures of: 
chronic pain, anxiety, depression, or sleeplessness between baseline and 12 or 
24 weeks after initiating treatment.  
The null hypothesis to disprove is that there is no statistically significant 
reduction from baseline to 12 or 24 weeks in mean chronic pain, anxiety, 

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depression, or sleeplessness symptom severity scores using the Nu-V3 device 
compared with the usual care cohort. 
The instruments used in this study are: 
Chronic Pain – Pain intensity (P), interference with enjoyment of life (E), and 
interference with general activity (G) (PEG Scale),  
The PEG is a three-item instrument that measures pain intensity (one item) and 
pain interference (two items). Each item is valued from 0 (no pain/interference) 
to 10 (as bad as you can imagine). The instrument score is calculated as the 
average of the three item values. 
 
Anxiety - Generalized Anxiety Disorder 7-item (GAD-7) 
The GAD-7 is a seven-item instrument that measures respondents’ symptoms of 
anxiety. Each item is scored on a four-point Likert scale, and values range from 
0 (“Not at all”) to 3 (“Nearly every day”.) Items are summed to determine the 
instrument’s score. Values of 10 or higher have been associated with moderate 
anxiety, while values of 15 or higher have been associated with severe anxiety. 
 
Depression - Patient Health Questionnaire (PHQ-9) 
The PHQ-9 is a nine-item instrument that measures depression-related 
symptoms and functional impairment. Each item is scored on a four-point Likert 
scale and values range from 0 (“Not bothered at all”) to 3 (“Bothered nearly 
every day.”) The items’ values are summed to determine the instrument’s score. 
PHQ-9 values of 10 and 15 represent moderate and moderately severe 
depression respectively. 
 
Sleeplessness - PROMIS short form 4a 
This eight item instrument measures sleep disturbance and sleep-related 
impairment.  
 
   
8.2 Secondary Endpoints: Secondary endpoints consisted of the following:  
Effectiveness: There are two secondary effectiveness endpoints: 
1. In the Nu-V3 device treatment arm, the study will report the mean time 
from treatment initiation to reduction of symptoms of at least 30% in any 
of the four domains of symptom measurement.  
2. In both the Nu-V3 device treatment arm and the observation arm, the 
study will report the mean percentage change in symptoms severity from 
initiation to 12 and 24 weeks for each instrument. 
 
Additional secondary endpoints of this study are: 
• Mean improvement in quality of life measured with Patient’s Global 
Impression of Change (PGIC) between the treatment and usual care arm, 
and  

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• Mean improvement in activities of daily living via Perceived Treatment 
Benefit Form (PTB-6) between the treatment and usual care arm. 
 
8.3 Sub-Analyses: Sub-Analyses consist of the following: 
 
The study has several sub-analyses. They include: 
 
• The mean number of weeks that chronic pain, anxiety, depression, and 
sleeplessness response are achieved and sustained, without utilization of 
another device or change in other treatments, during the full 24-week 
intervention in the Nu-V3 device treatment arm.  
  
• The mean number of weeks to initial benefit from Nu-V3 device use in the 
Nu-V3 device treatment arm. Benefit is defined as a reduction of at least 
30% of symptoms in at least one of chronic pain, anxiety, depression, or 
sleeplessness. 
 
• The device’s comfort-of-use, and patient’s perceived treatment 
benefit in the Nu-V3 device treatment arm. 
 
9.0 STUDY MONITORING 
 
Nu-Life will monitor the study according to good clinical practice. Monitoring will begin 
upon enrollment of the first 5 patients at the site and will continue every 8 weeks until 
completion of the study. The Principal Investigator will work with a representative from 
Nu-Life to ensure the study is conducted according to this protocol and that all study 
matters are properly communicated. 
 
 
 

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10.0 REFERENCES CITED 
 
1. 
Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence of anxiety disorders: a 
systematic review and meta-regression. Psychol Med. 2013 May;43(5):897-910. 
2. 
National Institutes of Health. U.S. Department of Health and Human Services, n.d. Web. 
25 Jan. 2017. 
3. 
Greenberg PE, Sisitsky T, Kessler RC, et al. The economic burden of anxiety disorders in 
the 1990s. J Clin Psychiatry. 1999 Jul;60(7):427-35. 
4. 
Ferrari, A.J., Somerville, A.J., Baxter, A.J., Norman, R., Patten, S.B., Vos, T. and 
Whiteford, H.A. (2013) ‘Global variation in the prevalence and incidence of major 
depressive disorder: a systematic review of the epidemiological literature’, Psychological 
Medicine, 43(3), pp. 471–481. 
5. 
Center for Behavioral Health Statistics and Quality. (2016). Key substance use and 
mental health indicators in the United States: Results from the 2015 National Survey on 
Drug Use and Health (HHS Publication No. SMA 16-4984, NSDUH Series H-51). 
Retrieved from http://www.samhsa.gov/data/  
6. 
PharmaPoint: Insomnia - Global Drug Forecast and Market Analysis to 2023. Feb-2015 
7. 
Roth T. Insomnia: Definition, Prevalence, Etiology, and Consequences. Journal of Clinical 
Sleep Medicine : JCSM : official publication of the American Academy of Sleep Medicine. 
2007;3(5 Suppl):S7-S10. 
8. 
Mai E, Buysse DJ. Insomnia: Prevalence, Impact, Pathogenesis, Differential Diagnosis, 
and Evaluation. Sleep medicine clinics. 2008;3(2):167-174. 
9. 
Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in 
Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006 May;10(4):287-
333. 
10. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 
2012. Journal of Pain. 2015;16(8):769-780. 
11. "2 Pain as a Public Health Challenge." Institute of Medicine. 2011. Relieving Pain in 
America: A Blueprint for Transforming Prevention, Care, Education, and Research. 
Washington, DC: The National Academies Press 
12. Ueno N et al. Innervation of the external ear in humans and musk shrew. Nihon Jibiinkoka 
Gakkao Kaiho. 1993 Feb;92(2):212-8. Japanese 
13. He W, Wang X, Shi H, et al. Auricular Acupuncture and Vagal Regulation. Evidence-
based Complementary and Alternative Medicine : eCAM. 2012;2012:786839. 
doi:10.1155/2012/786839 
14. Jean-Pierre Barral and Alain Croibier, Chapter 25 - Ear, In Manual Therapy for the Cranial 
Nerves, Churchill Livingstone, Edinburgh, 2009, Pages 227-238, ISBN 9780702031007, 
https://doi.org/10.1016/B978-0-7020-3100-7.50028-8. 
15. Torsten Liem, Chapter 17 - The organ of hearing and balance, In Cranial Osteopathy 
(Second Edition), Churchill Livingstone, Edinburgh, 2004, Pages 605-633, ISBN 
9780443074998, https://doi.org/10.1016/B978-044307499-8.50024-7. 
16. Terry Oleson, 2 - Theoretical Perspectives of Auriculotherapy, In Auriculotherapy Manual 
(Fourth Edition), Churchill Livingstone, Saint Louis, 2014, Pages 25-86, ISBN 
9780702035722, https://doi.org/10.1016/B978-0-7020-3572-2.00002-1. 

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17. Review of the Uses of Vagal Nerve Stimulation in Chronic Pain Management. 
Chakravarthy K, Chaudhry H, Williams K, Christo PJ. Curr Pain Headache Rep. 2015 
Dec;19(12):54. doi: 10.1007/s11916-015-0528-6. Review. 
18. Pavlov VA, Tracey KJ. The vagus nerve and the inflammatory reflex—linking immunity 
and metabolism. Nature reviews Endocrinology. 2012;8(12):743-754. 
doi:10.1038/nrendo.2012.189. 
19. Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors,: U.S. 
Department of Health and Human Services, Food and Drug Administration, Center for 
Devices and Radiological Health (CDRH), January 2006, 
http://www.fda.gov/downloads/Regulatory Information/Guidances/UCM126418.pdf 

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Appendix 1: Study Process Maps 
Figure 1- Baseline Visit
 
Figure 2- Weekly Visits 
 

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Appendix 2: Eligibility Checklist 
 
 

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Appendix 3: IRB Unanticipated Problem Form 
 
 

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Appendix 4:  Adverse Event Form 
 
 
 

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Appendix 5:  Medical History Form 
 

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Date: 20-APR-2022                                                                                                       Page 26 of 38 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 27 of 38 
 
Appendix 6:  Treatment Form 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 28 of 38 
 
Appendix 7:  Medications and Standard of Care Treatment Form 

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Date: 20-APR-2022                                                                                                       Page 29 of 38 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 30 of 38 
 
Appendix 8:  ePRO Questionnaires 
 
 

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Date: 20-APR-2022                                                                                                       Page 31 of 38 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 32 of 38 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 33 of 38 
 
 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 34 of 38 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 35 of 38 
 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 36 of 38 
 
 
 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 37 of 38 
 
 
 
 

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Date: 20-APR-2022                                                                                                       Page 38 of 38 
 
Appendix 9:  Baseline Symptom Questionnaire