Effect of Transcranial Alternating Current Stimulation in Chronic Low Back Pain: A Pilot Study
Phase: NA
Conditions: Chronic Low Back Pain
Sponsor: University of North Carolina, Chapel Hill

 
 
CONFIDENTIAL 
 
0 
 
 
 
 
EFFECT OF TRANSCRANIAL ALTERNATING CURRENT STIMULATION IN 
CHRONIC LOW BACK PAIN: A PILOT STUDY 
 
 
NCT03243084 
 
 
September 17, 2017 
 
 
 
 
 
 
 
 
 

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Effect of Transcranial Alternating 
Current Stimulation in Chronic Low 
Back Pain: A Pilot Study 
A PILOT, RANDOMIZED, CROSSOVER, DOUBLE-BLIND, SHAM-CONTROLLED, SINGLE-SITE STUDY OF THE 
EFFECT OF TRANSCRANIAL ALTERNATING CURRENT STIMULATION IN SUBJECTS WITH CHRONIC LOW 
BACK PAIN 
Funding Mechanism: 
National Institute of Mental Health (NIMH) 
Principal Investigator: 
Karen L McCulloch, PT, PhD, MS, NCS 
Co-Investigator: 
Flavio Frohlich, PhD 
Protocol Number: 
17-0870 
Version Number: 
1.0 
Date: 
March 29, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Initial version: 3/19/17 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ......................................................................................................................... 6 
STUDY SUMMARY ................................................................................................................................... 9 
1 KEY ROLES ....................................................................................................................................... 10 
1.1 INDIVIDUALS.................................................................................................................................... 10 
1.2 INSTITUTIONS .................................................................................................................................. 11 
1.3 OPTIONAL ....................................................................................................................................... 11 
1.4 FUNDING SOURCES ........................................................................................................................... 11 
2 INTRODUCTION ............................................................................................................................... 12 
2.1 BACKGROUND ................................................................................................................................. 12 
2.2 INVESTIGATIONAL AGENT ................................................................................................................... 13 
2.3 DOSE RATIONALE ............................................................................................................................. 13 
2.4 STUDY AIMS/HYPOTHESES ................................................................................................................. 13 
2.4.1 PRIMARY OBJECTIVE ....................................................................................................................... 14 
2.4.1 SECONDARY OBJECTIVE ................................................................................................................... 14 
3 SUBJECT SELECTION AND WITHDRAWAL ........................................................................................ 15 
3.1 INCLUSION CRITERIA ......................................................................................................................... 15 
3.2 EXCLUSION CRITERIA ......................................................................................................................... 15 
3.3 STRATEGIES FOR RECRUITMENT AND RETENTION .................................................................................... 16 
3.3.1 RECRUITMENT ............................................................................................................................... 16 
3.3.2 RETENTION ................................................................................................................................... 16 
4 BASIC STUDY DESIGN ...................................................................................................................... 18 
4.1 TREATMENT ASSIGNMENT PROCEDURES ............................................................................................... 18 
4.1.1 RANDOMIZATION PROCEDURES ......................................................................................................... 18 
5 STUDY SCHEDULE ............................................................................................................................ 20 
5.1 SCREENING...................................................................................................................................... 20 
5.1.1 SCREENING TELEPHONE CALL ............................................................................................................ 20 
5.1.2 INITIAL SCREENING SESSION (VISIT 1) ................................................................................................. 20 
5.2 STIMULATION SESSIONS..................................................................................................................... 21 
5.2.1 DAY 1 OF STIMULATION (VISIT 1 CONTINUED) ...................................................................................... 21 
5.2.2 DAYS 2 OF STIMULATION (VISIT 2) ..................................................................................................... 21 
5.3 FOLLOW-UP .................................................................................................................................... 21 

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5.3.1 FOLLOW-UP EMAIL ........................................................................................................................ 21 
5.3.2 UNBLINDING PROCEDURES ............................................................................................................... 21 
6 STUDY PROCEDURES/EVALUATIONS ............................................................................................... 22 
6.1 SELF-REPORT MEASURES .................................................................................................................... 22 
6.2 CLINICAL MEASURES ......................................................................................................................... 22 
6.3 SPECIAL ASSAYS OR PROCEDURES ......................................................................................................... 22 
6.3.1 SPECIAL PROCEDURES...................................................................................................................... 22 
6.3.2 EKG PROCEDURES ......................................................................................................................... 23 
6.3.3 PRESSURE PAIN THRESHOLD ................................................................................................................ 23 
EEG PROCEDURES ..................................................................................................................................... 23 
6.4 SAFETY MEASURES ............................................................................................................................ 23 
6.5 
LABORATORY EVALUATIONS ................................................................................................................ 23 
6.5.1 SCREENING LABORATORY EVALUATIONS .............................................................................................. 23 
6.5.2 SALIVA SAMPLE ............................................................................................................................. 24 
7 STUDY INVESTIGATIONAL PRODUCT ............................................................................................... 25 
7.1 SAFETY FEATURES ............................................................................................................................. 25 
7.2 PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT .............................................. 26 
7.3 ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT .................................. 27 
8 POTENTIAL RISKS AND BENEFITS..................................................................................................... 28 
8.1 BENEFITS TO SUBJECTS AND SOCIETY .................................................................................................... 28 
8.2 POTENTIAL RISKS.............................................................................................................................. 28 
8.2.1 PSYCHOLOGICAL ............................................................................................................................ 28 
8.2.2 PHYSICAL ..................................................................................................................................... 29 
8.3 REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING .................................................... 29 
8.3.1 PREGNANCY FOLLOW-UP................................................................................................................. 29 
9 DATA AND SAFETY MONITORING ................................................................................................... 31 
9.1 FROHLICH LAB MONITORING PLAN ...................................................................................................... 31 
9.3 EARLY WITHDRAWAL OF PARTICIPANTS ................................................................................................ 32 
9.3.1 REASONS FOR WITHDRAWAL ............................................................................................................ 32 
9.3.2 DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PARTICIPANTS ...................................................... 32 
9.4 TERMINATION OF STUDY .................................................................................................................... 32 
10 SAFETY & REPORTING ................................................................................................................... 33 
10.1 SAFETY PARAMETERS ...................................................................................................................... 33 
10.2 METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY PARAMETERS ....................... 33 
10.2.1 ADVERSE EVENTS ......................................................................................................................... 33 
10.2.1 SERIOUS ADVERSE EVENTS ............................................................................................................. 34 

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10.2.2 UNANTICIPATED PROBLEMS............................................................................................................ 35 
10.3 REPORTING PROCEDURES ................................................................................................................. 35 
10.3.1 REPORTING OF PREGNANCY ............................................................................................................ 36 
10.4 TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS ...................................... 36 
11 STATISTICAL PLAN ......................................................................................................................... 37 
11.1 STATISTICAL ANALYSIS STRATEGIES .................................................................................................... 37 
11.2 SAMPLE SIZE DETERMINATION ........................................................................................................... 37 
11.3 DATA MANAGEMENT ...................................................................................................................... 37 
12 DATA HANDLING AND RECORD KEEPING ...................................................................................... 38 
12.1 PHI AND HIPAA ............................................................................................................................ 38 
12.2 CONFIDENTIALITY ........................................................................................................................... 38 
12.2.1 ACCESS TO SOURCE DOCUMENTS .................................................................................................... 38 
12.2.2 SENSITIVE INFORMATION ............................................................................................................... 38 
12.2.3 OTHER ....................................................................................................................................... 39 
12.3 SOURCE DOCUMENTS ...................................................................................................................... 39 
12.4 DATA MANAGEMENT RESPONSIBILITIES .............................................................................................. 40 
12.5 DATA CAPTURE METHODS (REDCAP) ................................................................................................ 40 
12.6 PROTOCOL DEVIATIONS ................................................................................................................... 40 
12.7 RECORD RETENTION ........................................................................................................................ 40 
13 ETHICAL CONSIDERATIONS ........................................................................................................... 41 
13.1 ETHICAL STANDARD ........................................................................................................................ 41 
13.2 INSTITUTIONAL REVIEW BOARD (IRB) ................................................................................................ 41 
13.3 INFORMED CONSENT PROCESS .......................................................................................................... 41 
13.4 EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) .......................................... 42 
13.5 PARTICIPANT CONFIDENTIALITY ......................................................................................................... 42 
13.6 STUDY DISCONTINUATION ................................................................................................................ 42 
14 PUBLICATION POLICY .................................................................................................................... 43 
15 LITERATURE REFERENCES .............................................................................................................. 44 
ZAEHLE, T., RACH, S., & HERRMANN, C. S. (2010). TRANSCRANIAL ALTERNATING CURRENT 
STIMULATION ENHANCES INDIVIDUAL ALPHA ACTIVITY IN HUMAN EEG. PLOS ONE, 5(11), E13766.... 47 
APPENDIX A: SCHEDULE OF EVENTS ..................................................................................................... 48 
APPENDIX B: AE REPORT FORM ............................................................................................................ 49 
APPENDIX C: IRB AMENDMENT TRACKING LOG ................................................................................... 51 

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APPENDIX D: AE REPORT FORM ............................................................................................................ 52 
APPENDIX E: INFORMED CONSENT QUIZ .............................................................................................. 53 
APPENDIX F: NOTE TO FILE ................................................................................................................... 54 
APPENDIX G: TELEPHONE SCRIPT .......................................................................................................... 55 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
5x SST 
Five Times Sit-to-Stand Test  
AE 
Adverse Event/Adverse Experience 
ANOVA 
Analysis of Variance 
BIS/BAS 
Behavioral Inhibition System / Behavioral Approach System 
CFR 
Code of Federal Regulations 
cLBP 
Chronic low back pain  
CNS 
Central Nervous System 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
DASS-21 
Depression Anxiety Stress Scale  
DSMB 
Data and Safety Monitoring Board 
DVPRS 
Defense and Veterans Pain Rating Scale  
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram 
EKG 
electrocardiogram 
ERP 
Event Related Potential 
FDA 
Food and Drug Administration 
FTF 
Fingertip-to-Floor Test  
GCP 
Good Clinical Practice 
HAM-D 
Hamilton Psychiatric Rating Scale for Depression 
HIPAA 
Health Insurance Portability and Accountability Act 
HRV 
Heart Rate Variability 
Hz 
Hertz 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IRI 
Interpersonal Reactivity Index 
JAMA 
Journal of the American Medical Association 
LAR 
Legally Authorized Representative 
LBP 
Low back pain  
MCIS 
minimally clinical important difference  
NAMI 
National Alliance on Mental Illness 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NRB 
Neurosciences Research Building 
ODI 
Oswestry Disability Index  
OHRE 
Office of Human Research Ethics 
OHRP 
Office for Human Research Protections 
PCS 
Pain catastrophizing Scale  
PFC  
Pre-frontal cortex 

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PHI 
Protected Health Information 
PI 
Principal Investigator 
PSEQ 
Pain Self-Efficacy Questionnaire  
rTMS 
repetitive transcranial magnetic stimulation  
SAE 
Serious Adverse Event/Serious Adverse Experience 
SB 
Suicidal Behavior 
SI 
Suicidal Ideation 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SPI 
Serial Peripheral Interface 
tACS 
Transcranial Alternating Current Stimulation  
tACS 
Transcranial Alternating Current Stimulation 
tDCS 
transcranial direct current stimulation  
tDCS 
Transcranial Direct Current Stimulation 
TMS 
Transcranial Magnetic Stimulation 
UE 
Unexpected Event 
UNC 
University of North Carolina 
UNC-CH 
University of North Carolina at Chapel Hill 
US 
United States 
VAS 
Visual Analog Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY SUMMARY 
Title 
EFFECT OF TRANSCRANIAL ALTERNATING CURRENT STIMULATION IN 
CHRONIC LOW BACK PAIN: A PILOT STUDY 
Short Title 
CPS 
Protocol Number 
17-0870 
Phase 
Pilot 
Methodology 
Double-blind, randomized, active sham controlled, cross-over, single site 
Study Duration 
This study is expected to last 6 months 
Study Center(s) 
This is a single-site study performed at The University of North Carolina at 
Chapel Hill. 
Objectives (Purpose) 
To test the feasibility of using tACS to treat patients with chronic pain, and to 
collect pilot efficacy and EKG biomarker data for optimizing the design of 
subsequent large-scale studies. The treatment rationale is to renormalize the 
presumed pathological structure of alpha oscillations in the prefrontal cortex 
(PFC) of patients with chronic pain.  
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Eligible participants will be patients who have a diagnosis of chronic pain as 
defined by a clinician, a >4  on a VAS self-report pain rating, not taking 
opioids, and have low suicide risk. 
Description of 
Intervention 
(Procedures/methods) 
20 participants will be randomized into one of two arms: to receive either 40 
minutes of sham tACS or 40 minutes of 10 Hz tACS during their first 
stimulation visit (then crossover the next visit) while in a relaxed, yet 
experimentally controlled state, by watching a nature movie such as 
“Reefscape” during stimulation.  
Related IRB 
Applications 
n/a 
 
 
 

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1 
KEY ROLES 
1.1 
INDIVIDUALS 
Principal Investigator 
Karen L McCulloch, PT, PhD, MS, NCS 
Co-Investigator 
Flavio Frohlich, PhD 
Medical Monitor 
Karen L McCulloch, PT, PhD, MS, NCS 
Karen L McCulloch, PT, PhD, MS, NCS – Principal Investigator 
UNC – Division of Physical Therapy 
Email: kmac@med.unc.edu  
Office: 3024 Bondurant Hall 
Phone: (919)843-8783 
 
Flavio Frohlich, PhD – Co-Investigator 
UNC – Chapel Hill Department of Psychiatry 
Email: flavio_frohlich@med.unc.edu 
Office: 4109F Neuroscience Research Building 
Phone: (919) 966-4584 
 
Julianna Prim- Study Coordinator 
UNC- Department of Allied Health Science  
Email: jhprim@email.unc.edu 
Office: Medical School Wing C – Room 233 
Phone: (919) 962-5271 
 
Morgan Alexander, BS/BA – Research Assistant  
UNC – Chapel Hill Department of Psychiatry 
Email: morgan_alexander@med.unc.edu 
Office: Medical School Wing C – Room 233 
Phone: (919) 966-4755 
 
Charles Zhou, BS – Research Assistant 
Neuroscience Center 
Email: zhouz@email.unc.edu 
Office: Neuroscience Research Building 
Phone: (919) 966-2682 
 
Juliann Mellin, BA – Research Assistant  
UNC – Chapel Hill Department of Psychiatry 
Email: juliann_mellin@med.unc.edu 
Office: Medical School Wing C – Room 233 
Phone: (919) 966-9929 

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1.2 
INSTITUTIONS 
The University of North Carolina at Chapel Hill 
1.3 
OPTIONAL 
IRB 
The University of North Carolina – Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-3113 
 
1.4 
FUNDING SOURCES 
Please list below the funding sources for this project:  
Sponsor Name 
UNC Ramses 
Number 
Sponsor Type 
Prime Sponsor 
Name 
Prime Sponsor 
Type 
Sponsor/Grant 
Number 
National 
Institute of 
Mental Health 
(NIMH) 
R01MH101547 
Federal 
 
 
 
External Funding: This project is externally funded but UNC-CH is not the direct recipient of federal 
funds. 
UNC-CH Funding: This project is not funded through UNC-CH. 
Classified: This project is not classified. 
 
 

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2 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according to U.S. 
and international standards of Good Clinical Practice (FDA Title 21 Part 312 and International 
Conference on Harmonization guidelines), applicable government regulations and Institutional research 
policies and procedures. 
2.1 
BACKGROUND 
Chronic pain is a severe disabling problem within society, affecting 25-30% of the United States 
population (Baliki and Apkarian, 2015). The Institute of Medicine estimates that 116 million adults in the 
United States experience chronic pain, with direct and indirect annual costs totaling over half a trillion 
dollars (Institute of Medicine Committee on Advancing Pain Research, 2012).   Low back pain (LBP) is the 
second most prevalent  cause of disability in US adults and a common  reason for lost work days with an 
estimated 149 million lost days of work per year (Freburger et al., 2011).  The lifetime prevalence is as 
high as 79% in adults (Walker et al, 2004) and 84% in adolescents (Jeffries et al, 2007). The poor rates of 
recovery (58% at 1 month) and high rates of recurrence (73% in 12 months) contribute to high social and 
economic costs (Pengel et al., 2003). Chronic low back pain (cLBP) does not have a defined source, and 
the mechanism of development is not fully understood (Luedtke et al. 2015). In chronic pain the 
relationship between nociception and pain is often weak or lost indicating abnormal integration and 
recent neurobiological investigations corroborate the crucial role of the brain by showing substantial 
structural and metabolic changes (Pioner et al., 2016). It’s been hypothesized that in the absence of a 
peripheral pathology, central sensitization contributes to the development and maintenance of non-
specific chronic low back pain (Luedtke et al. 2015). The hypothesized mechanisms are an increased 
release of excitatory neurotransmitters at spinal level, influencing pain perception via the spinothalamic 
pathway and altered top down pain control from the brain (Luedtke et al. 2015). Chronic pain is 
currently extensively studied, but therapeutic options to date are limited, and duration of the symptoms 
tends to make pain increasingly resistant to treatment. Opioid therapy is helpful in the treatment of 
acute pain (Ferrari et al. 2015) limited evidence supporting its long-term effectiveness but a growing 
literature highlighting myriad risks of long-term use, including: misuse, abuse/dependence, overdose, 
and death (Chou et al., 2015 ). Deep brain stimulation has shown promising results, but less 
invasive forms of stimulation also might be effective (Antal et al., 2010). Some studies have shown 
that both a single session and repeated sessions of repetitive transcranial magnetic stimulation 
(rTMS) and transcranial direct current stimulation (tCDS) can relieve pain transiently in some patients 
with chronic pain (Naro et al,, 2016, Antal et al., 2010), but others have found the effect to be small and 
not significant (Jimenez-Torres et al, 2016; Luedtke et al. 2015). Heart rate variability (HRV) is commonly 
used to assess the autonomic nervous system function and has been shown to predict poor health 
outcomes (Gockel et al, 2008).  Initially developed to evaluate the prognosis of cardiac diseases 
(Balanescu et al., 2004), heart rate variability (HRV) analysis has been utilized to assess autonomic 
functions in chronic pain conditions (Staud et al., 2008, Kang et al., 2012).  When compared to healthy 
controls individuals with chronic pain had lower HF (high frequency band) powerin HRV representing 
less parasympathetic output in the altered cardiac autonomic regulation (Södervall et al., 2013). Gockel 
and colleagues (2008) found a significant association between heart rate variability and perceived 

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physical impairment in patients with chronic low back pain using Oswestry Disability Index scores. 
Patients with higher subjective disability had greater sympathetic dominance (lower high frequency 
band) than patients with minimal perceived disability. 
2.2 
INVESTIGATIONAL AGENT 
One alternative not yet explored is Transcranial Alternating Current Stimulation (tACS). tACS is a safe, 
non-invasive, easy-to-administer procedure that applies weak electrical currents to the scalp to 
modulate rhythmic brain activity patterns. In addition, the Frohlich Lab has used this technology in 
clinical trials to treat individuals with serious mental illness, such as depression and schizophrenia 
(Frohlich 2015, Frohlich et al., 2016). Previous research has demonstrated that tACS enhances alpha 
oscillations in healthy participants (Zaehle et al., 2010) and may thus help to renormalize the presumed 
pathological structure of alpha oscillations in the pre-frontal cortex (PFC) of patients with chronic pain 
(Lustenberger et al., 2015). 
Therefore, tACS may be an important next step in treating chronic pain. As stated above, some patients 
are resistant to other therapies including medications or in too much pain to do physical therapy. 
Treatment with tACS may provide an alternative for patients with disabling chronic pain who have few 
options. 
2.3 
DOSE RATIONALE 
Previous studies have shown a relationship between alpha oscillations (8-12 Hz) and attention (Cooper 
et al., 2003), arousal, and emotion (Weinreich, Stephani, & Schubert, 2016; Gaeta et al., 2015). The 
substantial comorbidity of chronic pain and mental disorders and the close relationship between chronic 
pain and psychological factors indicates that brain dysfunction plays a central role in the development 
and maintenance of chronic pain (Pioner et al., 2016).Pain stems from dynamic interactions between 
sensory and contextual (i.e., cognitive, emotional, and motivational) processes that are mediated by 
feed-forward and feedback processes in the human brain. Alpha/beta oscillations are linked to the 
feedback process and a suppression of oscillations at alpha frequencies is associated with tonic pain. 
Previous studies in chronic pain have found an increase of theta oscillations, slowing of the peak alpha 
frequency, and increase in beta oscillations in the frontal areas (Lim et al., 2016). These changes along 
with the alpha-gamma oscillation coupling having a strong pain predictive model (Pioner et al., 2016) 
provide evidence alpha oscillations play an important role in chronic pain. Our proposed intervention of 
transcranial alternating current stimulation (tACS) at the alpha frequency (~10 Hz) has been shown to 
alter alpha oscillations with sustained effects (Kasten, Dowsett, & Herrmann, 2016). These data suggest 
that α-tACS at 10 Hz applied to the prefrontal cortex could potentially alleviate many of the symptoms 
associated with chronic pain. While there is currently no literature in HRV response to tACS, a study in 
progress is investigating HRV during tACS in healthy individuals. Since tDCS has been shown to increase 
parasympathetic and decrease sympathetic activity (Montenegro et al., 2011) we hypothesize that tACS 
will also increase parasympathetic activation specifically the high frequency bands. 
2.4 
STUDY AIMS/HYPOTHESES 

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2.4.1 
PRIMARY OBJECTIVE 
NULL HYPOTHESIS. There is no difference in parasympathetic tone in Heart Rate Variability, shown 
by an increase in high frequency input via spectral analysis on EKG recordings between active 
and sham stimulation. 
ALTERNATIVE HYPOTHESIS. There is a difference in parasympathetic tone in Heart Rate Variability, 
shown by an increase in high frequency input via spectral analysis on EKG recordings between 
active and sham stimulation. 
2.4.1 
SECONDARY OBJECTIVE 
NULL HYPOTHESIS. There is no difference in self-reported perceived pain rating between baseline 
and the active stimulation. 
ALTERNATIVE HYPOTHESIS. There is a difference in self-reported perceived pain rating between 
baseline and active stimulation. 
 
 

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3 
SUBJECT SELECTION AND WITHDRAWAL 
A total of 20 participants will be recruited for this study and all data will be collected at UNC-CH. No 
specific plans have been made to enroll participants from vulnerable populations.  
3.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, a participant must meet all of the following criteria: 
 
Provide signed and dated informed consent 
 
Male or female, aged 18-65 
 
Diagnosed with nonspecific chronic low back pain  by clinician, normal MRi if  they had imaging done 
 
BMI is less than 30 
 
Suffered from chronic pain for > 6 months 
 
Self-report pain measures (VAS) >4 
 
Meets criteria for low depression and suicide risk as defined by the HAM-D 
 
1 month free anticonvulsant medications, 48 hours of opioids and benzodiazepines (can take over the 
counter pain killers) 
 
Can be taking over the counter pain killers not day of session (Refrain from taking over the counter 
medications such as antihistamines, albuterol, nasal decongestants for one week prior to stimulation 
sessions ) 
 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
 
Willing to comply with all study procedures and be available for the duration of the study 
 
Women of reproductive potential must test negative on a pregnancy test prior to start of treatment 
 
Speak and understand English 
3.2 
EXCLUSION CRITERIA 
A potential participant who meets any of the following criteria will be excluded from participation in the 
study: 
 
Radicular Pain 
 
Diagnosis of eating disorder (current or within the past 6 months) 
 
Diagnosis of OCD (lifetime) 
 
ADHD (currently under treatment) 
 
Neurological disorders and conditions, including, but not limited to: 
o 
History of epilepsy 
o 
Seizures (except childhood febrile seizures and ECT-induced seizures) 
o 
Dementia 
o 
History of stroke 
o 
Parkinson’s disease 
o 
Multiple sclerosis 
o 
Cerebral aneurysm 
o 
Brain tumors 
 
Medical or neurological illness or treatment for a medical disorder that could interfere with study 
participation (e.g., unstable cardiac disease, HIV/AIDS, malignancy, liver or renal impairment) 
 
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 
Any brain devices/implants, including cochlear implants and aneurysm clips 
 
Traumatic brain injury 
 
(For females) Pregnancy or breast feeding 
 
Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude 
the participant’s full compliance with or completion of the study 
Justifications for any exclusions based on race, gender, or ethnicity: Non-English speaking individuals 
are excluded because the ability to accurately and completely communicate study information, answer 
questions about the study, and obtain consent are necessary. 
Justification for excluding women or women who become pregnant: Pregnant participants will be 
excluded despite the fact that theoretical risk to mother or fetus is exceedingly small, since no safety 
data for pregnancy is known to exist for tDCS/tACS studies. We will verify pregnancy status via a urine 
pregnancy test for all female participants prior to receiving treatment on Day 1 of Stimulation. 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
3.3.1 
RECRUITMENT 
This clinical trial will utilize multiple recruitment strategies in order to communicate this 
opportunity to as many potential participants as possible. Participants will be recruited from the 
following sources using IRB approved flyers and email scripts: 
 
UNC University Physical Therapy clinic  locations 
 
UNC Hospital and Carolina Data Warehouse 
 
North Carolina Institutions of Higher Learning 
The UNC community will also be notified of the study through the informational notify.unc.edu system and a 
research listing will be created on http://allyresearch.org/ as well as on http://jointheconquest.org. A short 
description of the study will also be included on the Frohlich lab website .We will also have a posting on the 
Frohlich lab website. 
 
The prevalence of chronic LBP in North Carolina has increased from 1992 to 2006 as it more 
than doubled in the 14 year interval from 3.9 to 10.2 percent (Freburger et al., 2009). Studies 
have also documented increases in visits to physicians, physical therapists, and chiropractors 
(Martin et al., 2008). UNC Healthcare has a chronic pain clinic as well multiple physical therapy 
locations allowing local access to a large chronic pain population.  
3.3.2 
RETENTION 
Our retention strategy includes a payment schedule of two times per participant. The 
participant will receive payment on both days of stimulation. The research staff will also give 
each participant a reminder call or email for the day 1 of stimulation and day 2 of stimulation. 
Each research staff member will be easily available for the participants to contact via email or 
phone. 

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The inclusion criteria state that each participant must be able to understand all risks and 
benefits associated with this study. We will be asking each participant to answer questions 
about the consent form to determine that the study process and the duration of participation 
are completely understood by all participants. We will aim to have a specific research team 
member assigned to complete all sessions with the same participant to establish rapport and 
encourage the participant to continue attending sessions. The study team will work hard at 
forming a professional relationship with each participant so that they feel comfortable and 
willing to discuss what may be sensitive information. Retention will be quantified by the fraction 
of participants coming to each scheduled session (the data from each session will be scored and 
documented the day of the session).  
 
 

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4 
BASIC STUDY DESIGN 
This study is a pilot clinical trial with a randomized, double-blind, crossover design. This is a single site 
study with 2 arms. We estimate six months to complete study enrollment. 
Figure 1. 
 
 
 
Active sham treatment will include 10 seconds of ramp-in to 1 minute of 10 Hz tACS with a ramp-out of 
10 seconds for a total of 80 seconds of stimulation. The choice of an active sham is motivated to 
enhance success of patient blinding by mimicking skin sensations associated with tACS. 10 Hz tACS will 
have a 10 second ramp-in and ramp-out with 40 minutes of stimulation for a total of 2420 seconds of 
stimulation. Stimulation waveform is a sine-wave with peak-to-peak amplitude of 2 mA. In both arms, 
participants will stay in a relaxed yet controlled state by watching a nature movie (“Reefscape”) during 
stimulation. 
Eligible participants who complete this clinical trial will have a total of 2 visits; 2 days of stimulation (with 
1-3 weeks in between). Day one of stimulation will take approximately 2.5 hours as eligibility will be 
confirmed at the beginning. Day 2 of stimulation will take approximately 2 hours. Two days after each 
stimulation day, participants will receive via email a follow-up survey to complete that will take 
approximately 15 minutes. We estimate that total participation will be approximately 6 hours over the 
course of 6 weeks. All time estimates take into consideration breaks and time variance in administration. 
4.1 
TREATMENT ASSIGNMENT PROCEDURES 
Participants will be randomized into one of 2 arms (see Figure 1 above). This is a double-blind study, so 
neither the participant nor the research will know which treatment the participant is receiving, if any. 
4.1.1 
RANDOMIZATION PROCEDURES 
Charles Zhou will randomize 6-digit stimulation codes which will be used by the study 
coordinator and research assistants and will be linked to the participant numbers of enrolled 
participants. These stimulation codes are directly linked to which treatment participants receive 
(sham or 10 Hz tACS) and will be used with the XCSITE100 stimulator. An unblinded code sheet 
that matches these stimulation codes to treatment arm will be kept by Charles Zhou and will not 
be available to the study coordinator or research assistants.  
The unblinded code sheet will have the following information: 
1. The initial identifier codes for all potential participants 
2. Stimulation code: 6-digit numerical code for the stimulation session 
3. Condition number: Numerical code for the condition 
4. Condition name: Name of the condition 
Phone Screening
Phone Screening
Randomization
Randomization
Sham tACS
Sham tACS
10 Hz tACS
10 Hz tACS
10 Hz tACS
10 Hz tACS
Sham tACS
Sham tACS

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A copy of this code sheet with condition number and condition name REMOVED is provided to 
the study coordinator and research assistants. This blinded code sheet will be used to ensure 
the correct stimulation code is provided for each session. 
These linked codes ensure that the study coordinator and research assistants are kept blinded 
to which treatment each participant receives. Please see Data and Safety Monitoring for more 
information on unblinding this information. 
 
 

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5 
STUDY SCHEDULE 
In order to increase data quality, the assessments for an individual participant will be administered by 
the same researcher.  
It is important to note that consent, scales, and experiments will all take place in a private room. Any 
phone calls will take place in a private lab environment as well.  
5.1 
SCREENING 
The screening process has been divided into two steps: phone screening and an initial session. The 
phone screening allows researchers to screen out participants based on self-report responses and for 
potential participants to become familiar with the study schedule, including procedures. The initial 
session allows researchers to confirm any preliminary diagnoses and assess for exclusion criteria that 
cannot be confirmed via phone. 
5.1.1 
SCREENING TELEPHONE CALL 
During the telephone screening, researchers will provide a brief background about chronic pain 
and tACS. The timeline of visits will be explained, including the number of visits and the time 
commitment required. The participant will be informed of compensation, both amount and 
payment schedule. The participant will be asked if they have any questions. Once all questions 
have been answered, the participant will be asked if he/she is still interested in participating in 
the study. If yes, the researcher will ask if the participant will provide verbal consent to begin 
the initial phone screening which will determine eligibility for the initial session. A telephone 
script, which includes the screening questions, is provided in Appendix G. If the participant meets 
initial criteria with these two assessments, the initial session will be scheduled and a reminder 
call or email will be given at least 24 hours before the initial session. 
5.1.2 
INITIAL SCREENING SESSION (VISIT 1) 
At day 1 of stimulation, participants will be guided through the consent form and the HIPAA 
authorization form and be given the time to ask any questions about the information discussed. 
To ensure that all aspects of the research are understood, participants may be asked a series of 
questions about the research they are about to take part in (Appendix E). Once it is clear that 
the participant understands the consent form and HIPAA authorization, they may sign the 
forms.  
Following the consent process, the participant completes the ODI and DVPRS to measure 
disability and pain intensity on 0-11 scale. The HAM-D and DASS-21 will access low suicide risk 
and depression level. The self-report measures: UCLA Activity Score, PCS, and PSEQ will access 
physical activity limitations, pain experience, and confidence in daily activities. Data on 
demographics, handedness, stai, bis-bas, and opinion pre-treatment will also be collected.  
Once eligibility has been confirmed and all relevant data collected, Day 1 of stimulation will 
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5.2 
STIMULATION SESSIONS 
5.2.1 
DAY 1 OF STIMULATION (VISIT 1 CONTINUED) 
Prior to starting any study procedures, female participants will be asked to take a urine 
pregnancy test to ensure continued eligibility. The 5xSST, FTF, and pressure pain threshold test 
will be administered before stimulation. A resting state EEG will be recorded for 5 min before 
and after stimulation.  The participant will receive 40 minutes of sham or 10 Hz tACS stimulation 
(as per the initial randomization) while watching “Reefscape”. The stimulation will be followed 
by the pressure pain threshold, 5xSST, FTF, stimulation adverse effects questionnaire and 
perceived improvement ending the session. 
5.2.2 
DAYS 2 OF STIMULATION (VISIT 2) 
Prior to starting any study procedures, female participants will be asked to take a urine 
pregnancy test to ensure continued eligibility. The ODI, DVPRS, 5xSST, FTF, and pressure pain 
threshold test will be administered before stimulation. A resting state EEG will be recorded for 5 
min before and after stimulation.  The participant will receive 40 minutes of sham or 10 Hz tACS 
stimulation (as per the initial randomization) while watching “Reefscape”. The stimulation will 
be followed by the pressure pain threshold, 5xSST, FTF, stimulation adverse effects 
questionnaire and perceived improvement ending the session. 
5.3 
FOLLOW-UP 
5.3.1 
FOLLOW-UP EMAIL 
Two days after both sessions of stimulation, participants will receive an email with a follow up 
survey to access any change in pain perception. The ODI and DVPRS will take approximately 15 
minutes to complete.  
5.3.2 
UNBLINDING PROCEDURES 
There are no current plans to systematically unblind participants to the treatment they may or 
may not have received during the clinical trial. However, following the completion of data 
collection, participants may contact the Frohlich Lab for unblinding information.  
 
 
 

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6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
SELF-REPORT MEASURES 
During the initial session, researchers will collect demographics, which include medical history and 
medication history. In addition, several other self-report measures will be used throughout this study. 
These measures are listed below and can be found in the attached documents. 
A. OSWESTRY DISABILITY INDEX (ODI) is a 10 item self-report assessment to measure level of disability and 
monitor change over time. It takes only 5 minutes to complete with a MCID of 10 pts. (Fritz et al., 2001) 
B. DEFENSE AND VETERANS PAIN RATING SCALE (DVPRS) is a modified numeric rating scale with faces and word 
descriptors. The MCID is 2 pts. It also includes supplementary questions on the impact of chronic pain on 
other aspects of daily living (Buckenmaier et al., 2013). 
C. UCLA ACTIVITY SCORE is a self-report measure of 1 question to measure activity level and change.  
D. PAIN CATASTROPHIZING SCALE (PCS)  is a 13 item self-report measure designed to quantify an individual's pain 
experience.(Sullivan et al., 1995) 
E. PAIN SELF-EFFICACY QUESTIONNAIRE (PSEQ) is a 10-item questionnaire measuring confidence in ability to 
perform specific tasks or coping with pain (Nicholas, 2007) 
F. DEPRESSION ANXIETY STRESS SCALE (DASS-21) is a 21 item short form self-report questionnaire (Original DASS is 
42 items) that provides a quantitative measure of depression, anxiety, and stress experienced in the past 
week. It is important to note that the DASS-21 is not a diagnostic tool (Lovibond & Lovibond, 1995). 
6.2 
CLINICAL MEASURES 
In addition to self-report measures, several clinical measures will be used throughout this study, both 
for measuring change over time and for diagnostic use. These measures are listed below and can be 
found in the attached documents. 
A. HAMILTON PSYCHIATRIC RATING SCALE FOR DEPRESSION (HAM-D) is a 21-item assessment to rate the severity of 
depression in patients (Hamilton, 1960). This measure is being used to assess levels of depressive 
symptoms and to determine suicide risk. Low suicide risk for this study is defined as scoring 2 or less on 
the Suicide question on this assessment. 
B. FIVE TIMES SIT-TO-STAND TEST (5XSST) is a quick and easy to administer test of an individual’s ability to 
transition between sitting and standing five times in a row and has been previously tested in chronic LBP 
populations. We will use as a measure of functional lower limb muscle strength and in quantifying 
functional change of transitional movements with MCIS between 4-9 seconds (Simmonds et al., 1998, 
Andersson et al., 2010) . 
C. FINGERTIP-TO-FLOOR TEST (FTF) is a valid, reliable, and responsive test in individuals with chronic low back 
pain. It measures trunk flexion and the MCIC varies (approx. 10 cm) (Perret et al., 2001) 
6.3 
SPECIAL ASSAYS OR PROCEDURES 
6.3.1 
SPECIAL PROCEDURES 
Each participant will attend two days of stimulation for this study. Each participant will be 
randomly assigned to one of two treatment arms (sham or 10 Hz tACS) then the opposite on the 
second visit. For more information on the stimulation procedures, see section 7.2 Preparation 
and Administration of Study Investigational Product.  

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6.3.2 
EKG PROCEDURES  
To obtain a measure of the heart rate during both stimulation conditions, ECG electrodes as part 
of the EEG acquisition system are placed on the participant's body. Ideally one electrode will be 
placed below the left collarbone and a second below the right chest. The EKG will be recorded 
for the full 40 minutes stimulation session during spontaneous breathing and will be divided into 
10 minute intervals for analysis. A standard spectral analysis will be applied to a 10-minute 
interval, including total power, HF, LF, and VLF. The HF component reflects the parasympathetic 
modulation of the heart rate. 
6.3.3 PRESSURE PAIN THRESHOLD 
The Wagner FDX Algometer will be used for the pressure pain threshold test. Algometers are 
designed to quantify and document levels of pain sensitivity via pain tolerance measurement. 
Pressure algometry is a reliable measure of pain in muscle, joints, tendons, and ligaments 
Pressure will be applied on both forearms and on the place of most pain on the lower back. The 
assessment will be done three times in a row at each location and the average of the trials will 
be used. 
EEG PROCEDURES 
 
In addition, in order to detect any change(s) at the neurophysiological level, a resting state EEG 
will be recorded before and after stimulation during both sessions. This measurement will 
contribute to the design of novel network-level biomarkers of chronic pain and of response to 
pain. 
 
6.4 
SAFETY MEASURES 
We will be monitoring the safety of our participants throughout the study with the following measures. 
These measures are listed below and can be found in the attached documents. 
A. A stimulation adverse effects questionnaire used in previous studies (IRB #14-1622, #14-3285, and #14-
0600) will be administered at the end of each stimulation session. This questionnaire will be used as a 
safety measure and to collect data on participant experience. Please see 10.1 Safety Parameters for more 
information.  
B. More as needed. Refer to previous IRB applications as needed. 
6.5 
LABORATORY EVALUATIONS 
6.5.1 
SCREENING LABORATORY EVALUATIONS 
A urine pregnancy test will be performed for any female participant who is unable to confirm 
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INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE. For this laboratory evaluation, 
results are available after only a few minutes. Once the results are clear, the researcher will 
make a note and the sample will be disposed. All samples will be handled using single-use 
disposable medical gloves. 
6.5.2 
SALIVA SAMPLE 
We will be collecting a saliva sample during the first visit. This sample will be used to test for a 
single nucleotide polymorphism in the BDNF gene whose presence may have an influence on 
effectiveness of brain stimulation. Within the central nervous system, BDNF regulates survival, 
proliferation, and synaptic growth as well as directly influences synaptic plasticity in the adult 
human brain (Antal et al., 2010a). Egan et al. (2003) demonstrated that Val66Met, a single 
nucleotide in the BDNF gene, has function consequences in healthy humans, including 
decreased episodic memory and hippocampal inducing a reduction in recall capacity. This 
polymorphism is common in over one third of the Caucasian population (65% Val66Val to 35% 
Val66MET) (Pezawas et al, 2004; Hariri and Weinberger, 2003). Kleim et al. (2006) found that 
individuals with the Val/Val polymorphism respond to tDCS and transcranial magnetic 
stimulation (TMS) treatments with expected change, whereas, individuals expressing Val/MET 
allele do not. These authors indicate the difference to be caused by the impairment in synaptic 
plasticity caused by the Val/MET allele. These findings suggest that individual efficacy of 
treatments using brain stimulation may be partially genetically predetermined and should be 
taken into account when preforming such procedures. Accordingly, we will conduct genotyping 
of all participants in this study in order to assess BDNF status.  We will perform exploratory 
analyses in which we group participants by BDNF status. A saliva sample will also test for levels 
of progesterone, estradiol, 
INSTRUCTIONS FOR SPECIMEN PREPARATION, HANDLING, AND STORAGE. The saliva sample will be collected 
using 2mL DNA collection kit from DNA Genotek. Before sample collection, it is imperative that 
the participant does not eat, drink, smoke or chew gum for at least 30 minutes before providing 
a sample.  Once the participant provides the 2mL sample, the collection tube is closed and a 
liquid from the lid will be released into the tube. The original lid will be removed and replaced 
with a small cap and the tube will be agitated for 5 seconds.  The sample is then returned to the 
plastic packaging and labeled with the date of collection, the study name, and the participant ID.  
These samples are kept in a secure location until the completion of data collection. 
 
 

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7 
STUDY INVESTIGATIONAL PRODUCT 
We will be using the XCSITE100 stimulator designed in the Frohlich Lab for investigational purposes. The 
device is not implanted and has not been designed for or being used to support or sustain human life. 
This device does not have a potential for serious risk to the health, safety, or welfare of the participant. 
There has never been an instance of serious side-effect reported due to the use of transcranial brain 
stimulation. Previous studies in the Frohlich lab that used comparable devices (i.e., the commercial, CE-
certified Neuroconn Plus stimulator) have always been classified as “non-significant risk” by the full UNC 
IRB. The Neuroconn Plus stimulator and the XCSITE100 stimulator are electrically equivalent and provide 
the same stimulation.  
The XSCITE100 is the first non-invasive brain stimulator designed for research purposes to provide an 
active sham for tACS and record the stimulation output for later validation. This stimulator may apply 
either tDCS or tACS for up to 40 minutes (2400 seconds) with appropriate current ramp-up at the 
beginning of stimulation and ramp-down at the end of stimulation. Both tDCS and tACS may be applied 
for currents between 100 μA and 2 mA (peak-to-peak for tACS). 
The stimulator has two main components: 
1. Android tablet with user interface application (i.e., App) 
2. Stimulator with: 
a. Microprocessor 
b. Function generator chip 
c. 
Voltage controlled current source 
d. Safety circuitry 
To ensure appropriate blinding for each stimulation session, there are designated unblinded individuals 
to ensure the appropriate stimulation parameters are applied to each participant. These individuals will 
not interact with participants and will only be involved with the creation of a study file and validation of 
stimulation waveform. 
7.1 
SAFETY FEATURES 
Current Sensor Circuit. A 33.2 Ω sense resistor is placed in series with the stimulation electrodes on the 
high side. Since high-side current sensing is used, any short circuit of the electrode terminals to ground 
will be detected. The stimulation current flows through this resistor and creates a voltage. The voltage 
across this resistor is sensed and amplified by the AD628 difference amplifier. The gain of the difference 
amplifier is set to 9.9039. The current sensor voltage is then shifted before it is read by the 
microprocessor and the hardware current safety feature. 
Voltage Sensor Circuit. The differential voltage across the electrodes is measured so that the impedance 
can be calculated. The voltage is measured by buffering the positive electrode and negative electrode 
each with a unity gain op-amp circuit. The voltage output is then shifted before it is read by the 
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The device is equipped with 4 different stages of safety precautions, all of which protect the participant 
from high currents. The stages are as follows: 
1. AUTOMATIC SOFTWARE CURRENT CUTOFF. The output of the current sensor described above is read by a 
microprocessor, which compares the reading to a value of ±3 mA peak. If the current exceeds these limits, 
stimulation is stopped, a relay in series with the electrode is opened, and the power supply used for 
stimulation is turned off. The user is then given the option to investigate the issue , and cancel or resume 
the test. Since high-side current sensing is used (described above), any short circuit of the electrode 
terminals to ground will be detected. 
2. AUTOMATIC HARDWARE CURRENT CUTOFF. The output of the current sensor is fed into a pair of comparators 
which detect if the current exceeds ±4.5 mA. If so, the fault is latched such that the relay in series with the 
electrodes is opened. Additionally, the microprocessor is notified of this instance through an interrupt. 
Upon this interrupt, the microprocessor immediately stops stimulation and the power supply used for 
stimulation is turned off. 
Figure 1. Example of a successful hardware cutoff function 
 
3. PERMANENT HARDWARE CURRENT CUTOFF. A 5 mA fast-acting fuse is in series with the electrode connector. If 
the above two over-current detection methods fail, the fuse will below, and the stimulator will no longer 
be electronically connected to the device. 
4. POWER SUPPLY FUSE. Finally, if for no other reason the entire device draws too much current, the main 
power supply fuse is blown. This fuse is sized with a cutoff of 200% of steady-state operating current.  
7.2 
PREPARATION AND ADMINISTRATION OF STUDY INVESTIGATIONAL PRODUCT 
Yellow: Relay control line 
Green: Current through 
electrode (goes from 
negative current to zero) 
Blue: Current sensor 
output (has lowpass

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After participants have completed the daily questionnaire, they will be comfortably seated. The researcher(s) will 
first measure their head using the 10-20 system for accurate electrode placement. Participants will then be fitted 
with the 3 electrodes for stimulation. Electrodes will be applied using Ten20 conductive paste, 5x5cm electrodes 
placed over F3 and F4 with a 5x7cm placed over CZ as a return electrode. The participant will be in a relaxed yet 
experimentally controlled state by watching “Reefscape”. One session of stimulation will be performed per day for 
40 minutes. For the 10 Hz tACS stimulation, there will be a 10 second ramp-in and ramp-out with 40 minutes of 
stimulation for a total of 2420 seconds. Stimulation waveforms are sine-waves with a peak-to-peak amplitude of 2 
mA. The sham stimulation will include 10 seconds of ramp-in to 1 minute of 10 Hz tACS with a ramp-out of 10 
seconds for a total of 80 seconds of stimulation. As a covariate, heart rate will be recorded throughout stimulation.  
Stimulation devices will be programmed and codes will be randomized to one of the two experimental arms. 
Researchers will enter the participant-specific code into the App that controls the stimulation and monitor 
participants during the 40 minutes of stimulation. 
The study coordinator and/or the research assistant will be thoroughly trained and have trainings documented on 
the transcranial stimulation device and will be present during all stimulation sessions. To monitor side effects of 
stimulation, a daily questionnaire will be administered after each stimulation session.  
7.3 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT 
Compliance for this study includes making both stimulation sessions. Participants have the ability to 
schedule their second stimulation 1-3 weeks after the first. Follow-up emails will be sent out 2 days after 
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8 
POTENTIAL RISKS AND BENEFITS 
8.1 
BENEFITS TO SUBJECTS AND SOCIETY 
Chronic pain is a debilitating disorder that involves problem in the feedback (top-down) mechanism in 
pain processing. Our novel approach introduces non-invasive brain stimulation for brain dysfunction and 
has the potential to treat symptoms not only in chronic pain, but also in depression and schizophrenia 
(Frohlich, 2015; Frohlich et al., 2016). Additionally, tACS has the potential to provide a treatment option 
that is safe, scientifically-supported, low-cost, easy-to-administer method to effectively reduce 
symptoms in patients suffering from chronic pain. The chance to understand and develop a new 
treatment for chronic pain is an important step in helping the millions of people in the world who suffer 
from its effects, from physical handicaps to common psychiatric comorbidities including opioid 
addictions and depression. If tACS is feasible and effective for patients with chronic pain, findings will 
provide persuasive preliminary results for the National Institutes of Health (NIH) and National Institute 
of Mental Health (NIMH) proposals to fund a large-scale clinical trial for patients with this serious 
disorder.  
This study has not been designed to benefit the individual participants. However, participants in this 
study may experience some degree of relief from chronic pain symptoms as a result of tACS treatment. 
There are no serious risks to the participant from the treatment used in this study.  
8.2 
POTENTIAL RISKS 
8.2.1 
PSYCHOLOGICAL 
Risk of Embarrassment: Self-report and clinical assessments contain questions regarding 
sensitive personal information. This risk is necessary in order to assess symptomology. 
Participants will be assured upon intake that only study personnel will see any clinical ratings. 
Risk of Confidentiality. All subjects will be informed during the consent process that if they 
report violent or suicidal ideation/behavior, this information will be kept confidential unless the 
subject reports a plan to hurt themselves or an identified victim. In this case, appropriate 
referrals will be made and the subject will be advised to end their participation in the study. 
In the unlikely event of a breach of confidentiality, people might discover that an individual was 
involved in this research study. Some people might not agree with the principle of participating 
in research or of changing natural brain activity. To avoid breaches in confidentiality, study 
documents that contain personal information, including the informed consent, and the 
document that links study ID numbers to personal identifying information are kept in locked 
filing cabinets in locked rooms, separate from any source documents containing participating 
dummy identifiers. All data is stored in locked cabinets inside locked offices; electronic data will 
be stored only on password-protected computers, and data encryption methods will be used 
during communication between investigators. Only study personnel will have access to these 
data. All study staff participate in annual human participating training that includes education 
about responsibilities to minimize the risk of confidentiality breach. 

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8.2.2 
PHYSICAL 
Risk of Injury and Discomfort: Transcranial current stimulation has been used without any 
reports of serious side-effects for more than a decade. This stimulation made has NOTHING to 
do with electroconvulsive therapy that applies many orders of magnitude higher stimulation 
current. Rather, transcranial current stimulation is so weak that it does not cause super-
threshold activation of neurons (Frohlich and McCormick, 2010). In particular, tACS has been 
used without reports of any serious side-effects. Some participants report a transient mild 
tingling, burning, or itching underneath the electrodes and headache, but no other side effects 
have been noted. Importantly, it remains unclear if these mild side-effects were caused by the 
transcranial brain stimulation. In order to monitor these side-effects, we will be administering 
an adverse effects stimulation questionnaire after each stimulation session to determine 
whether these effects were experienced. Research personnel present during these sessions will 
also check in with the participant periodically during the stimulation to see whether they are 
comfortable. If any side-effect occurs (rated by the participant as stronger than “moderate”) or 
the participant is experiencing severe discomfort, the stimulation will be immediately stopped. 
8.3 
REFERRALS FOR MEDICAL FOLLOW-UP OR PSYCHOLOGICAL COUNSELING 
There is a purely theoretical likelihood that stimulation of neuronal circuits can lead to epileptic 
discharge. To minimize this occurrence, we screen and exclude patients with personal and family history 
of neurological conditions from the study. If abnormalities or a seizure is witnessed during the course of 
the study, a referral will be made to the UNC Department of Neurology for follow-up. In the theoretical 
event that a seizure is witnessed that involves the loss of consciousness, the patient will be told not to 
operate a motor vehicle until cleared by the DMV. 
We will be using the Hamilton Psychiatric Rating Scale for Depression (HAM-D) to assess depression and 
suicide risk at the initial session. Inclusion criteria states that the patient must be low suicide risk, 
potential participants that have an above “low risk” designation that is currently clinically relevant will 
not be eligible for the study. 
To ensure participant comfort, a study coordinator or research assistant will periodically check in with 
the participant about any side-effects he/she may be experiencing during each stimulation session. 
Following the conclusion of the stimulation session, the participant will receive an Adverse Effects 
Questionnaire to report on any of the side-effects he/she may have experienced. This questionnaire 
reports side-effects on a likert scale (1=Absent, 2=Mild, 3=Moderate, 4=Severe). If the participant 
reports side-effects of Moderate to Severe intensity, a study coordinator or research assistant will 
discuss the side-effects experienced and note this response. The medical monitor will be contacted 
based on the reported intensity on the Adverse Events Questionnaire and the participant’s verbal 
confirmation of intensity.  
8.3.1 
PREGNANCY FOLLOW-UP 
Every female participant will take a pregnancy test on Day 1 of Stimulation. If, after testing 
negative at Day 1 of Stimulation (meeting inclusion criteria), a participant reports becoming 

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pregnant during the course of the study, she will be withdrawn from further participation. There 
are no plans to follow participants who become pregnant while enrolled in the study. 
 
 

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9 
DATA AND SAFETY MONITORING 
9.1 
FROHLICH LAB MONITORING PLAN 
The purpose of this monitoring plan is to present the Frohlich Lab’s approach to monitoring clinical 
trials. The plan facilitates compliance with good clinical practice (GCP): 
a. The rights and well-being of human subjects are protected. 
b. The reported trial data are accurate, complete, and verifiable from source documents 
c. 
The conduct of the trial is in compliance with the currently approved protocol/amendment(s) with GCP, 
and with applicable regulatory requirement(s) 
This section identifies key monitoring activities and specifies the data to be reviewed over the course of 
a clinical trial. This is a single site, investigator-initiated, clinical trial, so there will be no site monitoring 
plan in place. 
The latest version of the approved IRB application for this clinical trial will be followed at all times. This 
responsibility falls into the hands of the study coordinator and research assistants. If at any time there is 
a deviation from protocol, the deviation from protocol log will be filled out. All team members will be 
trained on how and when to use this log. The most up-to-date IRB application will be on file in the 
Clinical Trials office in Room 233 of the Medical School Wing C. Deviations will be sent to the IRB every 
4-6 weeks (if necessary). 
Periodically, study staff should review 3 randomly selected inform consent forms to ensure that (1) 
these forms have been filled out appropriately, and (2) the consent form process was followed and 
properly documented. Should any consent form be in violation, the research team will perform and 
document a complete review of all consent forms.  
AE and SAE are clearly defined in this document. Documents of AE and SAE can be found in the study 
binder on file in the Clinical Trials office in Room 233 of the Medical School Wing C. It is the 
responsibility of the study coordinator to report all events to the PI in a timely manner (see 9.3 
Reporting Procedures). All AEs and SAEs will be discussed with the PI. For our practices, we have adapted 
the decision tree provided by the UNC-CH IRB to assist with reporting of such events. 
Periodically, the study coordinator should also choose one CRF/eCRF and Source Document to assess for 
completion and maintenance. In addition, the PI will assess completeness of data on REDCap. The PI has 
read-only access. This allows the PI to view reports that provide information on any missing data on an 
individual participant basis, but does not allow the PI to add, change, or input any data. 
A data safety monitor will review blinded AEs every month. The DSMB will assess recruitment and will 
only evaluate safety if an unanticipated concern arises. 
 
 

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9.3 
EARLY WITHDRAWAL OF PARTICIPANTS 
9.3.1 
REASONS FOR WITHDRAWAL 
A study participant will be discontinued from further participation if: 
 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
 
Anything that, in the opinion of the investigator, would place the participant at increased risk or 
preclude the participant’s full compliance with or completion of the study. 
Participants are free to withdraw from participation in the study at any time upon request. 
9.3.2 
DATA COLLECTION AND FOLLOW-UP FOR WITHDRAWN PARTICIPANTS 
We will collect safety data on any participant discontinued because of an AE or SAE. In any case, 
every effort will be made to undertake protocol-specific follow-up procedures. If voluntary 
withdrawal occurs, the participant will be asked to continue scheduled evaluations and 
complete an end-of-study evaluation. If an AE has been reported, researchers will help the 
participant seek the medical care they need and a follow-up will be performed by the PI and Co-
I. In the case of an early withdrawal, the researcher will make a note to file indicating this. 
9.4 
TERMINATION OF STUDY 
If a seizure occurs at the time of a study visit, a temporary hold will be placed over the study and further 
investigation will ensue. This could lead to stopping the study prematurely or continuing on with further 
safety measures in place. If two seizures are witnessed during the study visits, the entire study will be 
stopped prematurely. These individuals would be referred for further medical attention. It is very 
unlikely that a seizure will occur, given that previous studies using tDCS in patients with depression and 
schizophrenia have had no seizures occur (Berlim et al., 2013). 
The study will also be stopped (at least temporarily) if studies provide evidence that transcranial current 
stimulation caused brain damage or other harmful effects on subjects, either short-term or long-term. 
Examples of findings that might trigger a safety review are the number of SAEs overall, the number of 
occurrences of a particular type of SAE, severe AEs/reactions, or increased frequency of events. 
The reasons for stopping the study and asking for further investigation include: 
 
Increased pain due to treatment (>25% of participants asked to seek additional health care) 
 
If a seizure occurs during a study visit, a temporary hold will be placed on the clinical trial 
The IRB will also be informed promptly and provided the reason(s) for the termination of suspension 
of by the investigator, as specified by the applicable regulatory requirement(s). 
 

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10 
SAFETY & REPORTING 
It is important to assess safety over the course of this study. This section describes in detail how safety is 
assessed, reporting of Adverse Events, Serious Adverse Events, and Unanticipated Problems. This section 
is a reference for internal use. 
10.1 
SAFETY PARAMETERS 
SUICIDE RISK. Participants with high suicide risk (SI or SB) will be excluded from our study.  
STIMULATION SIDE EFFECTS. A stimulation adverse effects questionnaire used in previous studies will be 
administered at the end of each stimulation session and at the 4 week follow-up visit. This questionnaire 
will be used as a safety measure and to collect data on participant experience. The adverse effects 
questionnaire asks participants to respond on a 4 point likert scale on the severity of symptoms 
experienced during the stimulation session (1 = abstent, 2 = mild, 3 = moderate, 4 = severe). The side 
effects listed are headache, neck pain, scalp pain, tingling, itching, ringing/buzzing noise, burning 
sensation, local redness, sleepiness, trouble concentrating, improved mood, worsening of mood, 
dizziness, flickering lights, and other (specify). Participants are also asked to rate on a 5 point likert scale 
how related they believe the side effects to be to stimulation (1 = no relation, 2 = remote, 3 = possible, 4 
= probable, 5 = definite). 
In addition to this survey, the study coordinator or research assistant will periodically check in with the 
participant during the stimulation session to assess side effects.  
10.2 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY 
PARAMETERS 
10.2.1 ADVERSE EVENTS 
All AEs, including local and systemic reactions not meeting the criteria for “serious adverse 
events”, will be captured on the appropriate CRF. In addition, the AE Report Form will be 
completed by the study coordinator (Appendix B). The AE Report Form includes the following: 
 
What is known about the therapy 
 
What is known about previous reported side effects 
 
If the AE occurred in temporal relation to the therapy 
 
Whether or not the AE improves or disappears when treatment is stopped 
 
Whether the AE is worsening of baseline symptoms 
 
Whether the AE is related to concurrent medical condition or medication use 
Once complete, this form will be given to the PI and Co-I, who will review, comment, and sign 
this form. Completed forms will be placed in the participant’s folder. 
In addition, the study coordinator will document any AE occurrence on the AE log (Appendix D), 
which includes information such as the date of the AE, severity, relationship to the treatment 
(assessed by the PI and Co-I*), actions taken, and outcome(s). The log will be reviewed and 

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initialed by the PI 72 hours after being completed. All AEs occurring during the clinical trial will 
be documented appropriately regardless of relationship to tACS. All AEs will be followed to 
adequate resolution and will be graded for severity and relationship to study treatment. Any 
medical condition noted at the initial session will be considered at baseline and not reported as 
an AE. 
All AEs will be graded for severity using the following guidelines: 
 
ASYMPTOMATIC. The participant is exhibiting no symptoms due to this event; no treatment 
needed. 
 
MILD. Event results in mild or transient discomfort, not requiring intervention or treatment; does 
not limit or interfere with daily activities (e.g., insomnia, mild headache) 
 
MODERATE. Event is sufficiently discomforting so as to limit or interfere with daily activities; may 
require interventional treatment (e.g., fever requiring antipyretic medication). In the case of a 
moderate AE, the medical advisor may recommend an over the counter medication. 
 
SEVERE AND UNDESIRABLE. Event results in significant symptoms that prevent normal daily activities; 
may require hospitalization or invasive intervention (e.g., anemia resulting in blood transfusion). 
Changes in the severity of an AE will be documented with the Note to File document (Appendix 
E) and will be filed in the participant’s folder. 
*Relationship to Study Products: The PI and Co-I will together determine whether an AE is 
associated with the study treatment. The event will be labeled associated if the event is 
temporally related to the administration of a therapy and no other factors can explain the event. 
The event will be labeled as not associated if the event is temporally independent of the study 
treatment and can be explained by external factors, such as major life events. 
10.2.1 SERIOUS ADVERSE EVENTS 
Serious Adverse Event (SAE): An SAE, as defined by the NIH, consists of adverse events that 
result in death, require either inpatient hospitalization or the prolongation of hospitalization, 
are life-threatening, result in a persistent or significant disability/incapacity or result in 
congenital anomaly/birth defect.  Other important medical events, based upon appropriate 
medical judgment, may also be considered Serious Adverse Events if a trial participant’s health is 
at risk and intervention is required to prevent an outcome mentioned. 
All SAEs will be recorded on the Serious Adverse Events Form (Appendix B), documented in the 
UE/SAE log and reported to the IRB.  The SAE Form will be completed by the study coordinator, 
and includes information relating to the onset and nature of the SAE, relationship to the study 
treatment, seriousness of the SAE, treatment required as a response to the SAE, and outcome.  
This form will be filed in the participant’s folder at the resolution of the event.  The study 
coordinator will complete the UE/SAE log (Appendix D) which includes information such as the 
date of the event, time at which the study team was informed of the event, details, when the 
IRB was notified, and the date that the SAE form was completed. 

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10.2.2 UNANTICIPATED PROBLEMS 
Unexpected Events (UE) will be recorded on the UE/SAE log (Appendix D) and will include 
information such as the date of the event, when the study team was informed of this event, 
details of the event, when the IRB was notified, and whether the SAE form was completed.  The 
IRB will be notified of each UE that may occur during the study. 
The Office for Human Research Protections (OHRP) considers unanticipated problems 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 (in the guidance document, 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. 
If an UE occurs the IRB will be notified and the study will be adjusted as needed to protect the 
health and safety of the participants.  Depending on the nature of the UE, the research protocol, 
inclusion/exclusion criteria, and informed consent will be changed to reflect the possibility of 
this event reoccurring. During this time, no new participants will be recruited and the research 
procedures for currently enrolled participants will be stopped.  Each UE will be recorded and 
reported throughout the study.      
10.3 
REPORTING PROCEDURES 
We will be adopting the following table for reporting procedures: 
What Event is Reported 
When is Event Reported 
By Whom the Event is 
Reported 
To Whom the Event is 
Reported 
Fatal or life-threatening 
unexpected, suspected 
serious adverse reactions 
Within 24 hours of initial 
receipt of information 
Investigator 
Local/internal IRBs 
Non-fatal, non-life 
threatening unexpected, 
suspected serious 
adverse reactions 
Within 48 hours of initial 
receipt of information 
Study Coordinator 
Local/internal 
IRBs/Institutional 
Officials, DSMB 
Unanticipated adverse 
device effects 
Within 10 working days 
of investigator first 
learning of effect 
Investigator 
Local/internal IRBs 
Unanticipated problem 
that is not an SAE 
Within 7 days of the 
investigator becoming 
aware of the problem 
Investigator 
Local/internal 
IRBs/Institutional officials 
All Unanticipated 
Within 30 days of the 
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Problems 
IRB’s receipt of the report 
of the UP from the 
investigator 
Investigator 
External IRBs 
10.3.1 REPORTING OF PREGNANCY 
Pregnancy tests will be administered on Day 1 of Stimulation to all women of child-bearing 
potential. There are no studies that suggest tACS would interfere with pregnancy. However, 
should a participant become pregnant during the study, their participation will be immediately 
terminated and will be sent to consult with the Co-I and medical monitor. 
10.4 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS 
Medical monitors and Co-I will follow up with participants within one week of an AE. 
 
 
 
 

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11 
STATISTICAL PLAN 
11.1 
STATISTICAL ANALYSIS STRATEGIES 
Our study design is a AB/BA crossover and we will ensure a washout effect by scheduling 1-3 weeks 
between stimulation sessions. A continuous outcome approach will be used to analyze the crossover 
trial data where carryover effects will be assumed to be equal.  
Primary outcome: Use kubios software to analyze HRV over before and after stimulation. A standard 
spectral analysis will be applied to the pre and post intervals, including total power, HF, LF, and HP. 
Specifically looking at the HF component since it reflects the parasympathetic modulation of the heart 
rate. Use a repeated measure ANOVA with factor session (1 vs 2) and factor treatment (active vs sham) 
(R software). We hypothesize a treatment main effect and with no session effect and no interaction. 
Secondary outcome: A Mann-Whitney-Wilcoxon rank-sum testMann Whitney U test (R software) will be 
performed on the self-report VAS pain scale (nonparametric scale) (from DVPRS) before and after 
stimulation as well as between sessions to analyze any differences in self-report perceived pain. 
Grouped ANOVAs and unpaired t-tests may also be used to analyze correlations within other self-report 
measures 
11.2 
SAMPLE SIZE DETERMINATION 
This clinical trial represents a pilot study. A pilot study is a clinical trial that is conducted to decide 
whether a new treatment should be tested in a large controlled trial; therefore, we do not calculate 
sample size. This study can be considered a pilot study, as it is the first time this specific treatment will 
be performed on this clinical population. The results from this study will be used to determine sample 
sizes for future, large-scale clinical trials. In addition, we have to restrict the number of included 
participants to a small sample size due to limited funding resources.  
11.3 
DATA MANAGEMENT 
Data will be stored in a password-protected cloud-based data system that does not contain any patient 
information. Individual records are referred to by dummy identifiers that cannot be traced back to the 
study participants except with the master code list that is stored separately in a secured location. 
 
 

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12 
DATA HANDLING AND RECORD KEEPING 
The study coordinator and research assistants are responsible for the accuracy, completeness, legibility, 
and timeliness of the data reported. 
12.1 
PHI AND HIPAA 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 
What protected health information (PHI) will be collected from the participants in this study 
 
Who will have access to that information and why 
 
Who will use or disclose that information 
 
The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization. For participants that have revoked authorization to collect or use PHI, attempts should be 
made to obtain permission to collect at least vital status (i.e., that the subject is alive) at the end of their 
scheduled study period. 
12.2 
CONFIDENTIALITY 
To ensure confidentiality, all data will only be referenced by a dummy identifier. Source documents (i.e. 
paper forms) will be kept in a locked file cabinet in a locked office. In addition, all data will be stored on 
a password-protected computer using a password-protected data collection tool (REDCap). The key 
linking dummy identifiers with participant information will be securely located separate from all other 
data collected. 
12.2.1 ACCESS TO SOURCE DOCUMENTS 
The research coordinator, research assistants, and PI will have access to all of the source 
documents collected over the course of the study. The Co-I and medical monitor will have 
access to files upon request, as they will need access to the locked rooms and filing cabinets in 
which these documents are located.  
Data will stay on a password-protected computer. Subsequently, a copy will be processed on a 
separate, password-protected desktop computer in the Frohlich Lab (Neuroscience Research 
Building 4129). 
12.2.2 SENSITIVE INFORMATION 
Sensitive information will be collected in this study, including information about medical 
conditions and drug use. We are using the DASS-21and HAM-D to assess comorbid depression 
and ensure that the participant meets eligibility criteria (low suicide risk).  

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12.2.3 OTHER 
Please note that there is no significant risk of deductive disclosure in this study. In addition, 
none of the groupings or subgroupings used in analysis will be small enough to allow individuals 
to be identified. 
12.3 
SOURCE DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents. Source data include: 
PARTNERS HUMAN RESEARCH COMMITTEE (IRB). 
 
All IRB correspondences are documented 
 
The study staff is IRB approved prior to performing any study procedures 
 
Adverse events and deviations are reported to the IRB per current guidelines and stored appropriately 
 
All versions of the IRB protocols and informed consent forms are on file 
INFORMED CONSENT. 
 
Ensure that participant identification is not recorded on the ICF (i.e., no participant ID) 
 
There is documentation that the participant is given a copy of the consent form 
 
The participant and study representative signed and dated the consent form for him/herself 
 
The participant initialed and dated all appropriate pages on the informed consent form 
 
Note to file (Appendix F) made for any informed consent deviations 
 
Ensure a valid (current version date) copy of the consent form was used 
PROTOCOL DEVIATIONS. 
 
Any and all protocol deviations (exceptions and violations) are documented in the participant folder and 
reported to the IRB as required 
OTHER SOURCE DOCUMENTS. 
 
Each participant folder will contain a checklist to ensure that all source documents are administered and 
collected properly. The checklist will be dated by the researcher for each time an assessment is 
administered 
 
Review participant folders to ensure the accuracy, completeness, and legibility of the data. 
 
Any correction made to the source documents is dated, initialed, and explained. The original entry should 
not be obscured. 
 
The protocol-specific source documents are on file. 
 
Source documents are completed in ink. 
 
Note to files (Appendix F) are made for missing or incomplete data and to explain any discrepancies or 
additional comments. 
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 
Participant names will not be on any of the samples collected. DNA is sequenced to check for one 
nucleotide. When testing is performed, only de-identified information is shared with an outside party. 
This information will not be shared with anyone outside of the study personnel, including the participant.  
12.4 
DATA MANAGEMENT RESPONSIBILITIES 
The responsibilities designated to each member of the research team are documented on the 
Delegation of Authority Form. The study coordinator and research assistants will be responsible for the 
informed consent process, review for eligibility, questionnaire administration, data entry, device 
administration, and EKG administration. The study coordinator will be responsible for AE/SAE 
documentation and reporting, while the PI will be responsible for the AE assessment, review of the AE 
documentation forms, and overview of the research staff. Karen McCulloch will be the medical monitor 
for the study.  
REDCap will serve as a secure data management tool for this study. The study coordinator and research 
assistants will have complete access to the REDCap system, while the PI and Co-I will have read-only 
ability. This will enable to researchers to enter the data and the PI and Co-I to review. 
12.5 
DATA CAPTURE METHODS (REDCAP) 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into a data capture system provided by REDCap. The data system 
includes password protection and internal quality checks, such as automatic range checks, to identify 
data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
All assessments completed by the participant at home will be completed via REDCap as well, ensuring 
participant security and confidentiality.  
12.6 
PROTOCOL DEVIATIONS 
All deviations from the protocol will be addressed in study participant source documents. The 
researcher will complete a Protocol Deviation Log using the participant code as the identifier. This form 
will collect information such as the date the deviation occurred, details of what the deviation consisted 
of, any corrective and preventative actions that were taken as a result of the deviation, and the date 
that the PI and IRB were notified. The PI will review the information and initial once approved. A 
completed copy of the Protocol Deviation Form will be maintained in the regulatory file, as well as in the 
participant’s source document. Protocol deviations will be sent to the IRB per their guidelines. The site 
PI/study staff will be responsible for knowing and adhering to their IRB requirements. 
12.7 
RECORD RETENTION 
According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services 
schedule for General Records Retention and Disposition Schedule 6.10, records will be kept for 5 years 
after the completion of the study or grant end date, whichever is later. 
 
 

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13 
ETHICAL CONSIDERATIONS 
13.1 
ETHICAL STANDARD 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in 
the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, 
as drafted by the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal 
Regulations 25691 (1997). 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) 
The Office of Human Research Ethics is responsible for ethical and regulatory oversight of research at 
UNC-Chapel Hill that involves human participants. The OHRE administers, supports, and guides the work 
of the Institutional Review Boards and all related activities. Any research involving human participants 
proposed by faculty, staff, or students must be reviewed and approved by an IRB before research may 
begin, and before related grants may be funded. OHRE and the IRBs are critical components of the 
coordinated Human Research Protection Program, which serves to protect the rights and welfare of 
human participants. All components of this program must work together to ensure institutional 
compliance with ethical principles and regulatory requirements. The following is a mission statement for 
the coordinated Human Research Protection Program: 
The University of North Carolina at Chapel Hill is committed to expanding and disseminating knowledge 
for the benefit of the people of North Carolina and the world. An important part of that commitment to 
knowledge is research of the highest quality on all aspects of the health and behavior of people, and 
such research is only possible through the participation of humans as research participants. Human 
participants are partners in research and a precious resource to the university. At UNC-Chapel Hill, 
human participant research is a privilege, but not a right. Consistent with that philosophy, it is the 
mission of the UNC-Chapel Hill Human Research Protection Program to ensure that: 
a. The rights and welfare of human participants are paramount in the research process; 
b. The highest standards of ethical conduct are employed in all research involving human participants; 
c. 
Research investigators are properly trained in the ethical and regulatory aspects of research with human 
participants; 
d. Research investigators deal honestly and fairly with human participants, informing them fully of 
procedures to be followed, and the risks and benefits of participating in research; and 
e. Research using human participants at UNC-CH conforms to applicable local, state, and federal laws and 
regulations and the policies of the university. 
13.3 
INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Extensive discussion of risks and 
possible benefits of tACS will be provided to the participants and their families. Consent forms 
describing, in detail, the study intervention, device, procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to the administration of any treatment 

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or assessments used in this study. All consent forms will be IRB-approved and updated with any new 
information as modifications are made throughout the study. 
Together, the researcher and potential participants will review the clinical trial in its entirety by 
reviewing the consent form together in a private location. At several intervals during the consent 
review, the researcher will ask the participant questions that will assess the comprehension of the 
information in the consent. If the participant is unsure or does not know, the researcher will return to 
that section and more carefully explain the information. Participants must sign the informed consent 
document prior to any procedures taking place.  If needed, the participants will have the opportunity to 
discuss the study with their surrogates or think about it prior to agreeing to participate.  Participants 
may withdraw consent at any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the participants for their records.  The rights and welfare of the participants 
will be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) 
Non-English speaking individuals are excluded because the ability to accurately and complete 
communicate study information, answer questions about the study, and obtain consent is necessary. 
Female participants will be asked if there is any reason to believe they might be pregnant. Pregnant 
participants will be excluded despite the fact that theoretical risk to mother or fetus is exceedingly 
small, since no safety data for pregnancy is known to exist for transcranial current stimulation studies. 
All women of child-bearing potential will be asked to take a pregnancy test during the initial session in 
order to determine eligibility for the study. 
13.5 
PARTICIPANT CONFIDENTIALITY 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
research team.  This confidentiality is extended to cover testing of biological samples and genetic tests 
in addition to the clinical information relating to participants. 
All data will only be referenced by dummy identifier code. Data will be stored on a password protected 
computer. A key connecting names and code numbers will be kept in a locked cabinet, accessible only by 
research personnel. All data will be stored and analyzed on password protected computers, also only 
accessible by research personnel. Participants will not be identified in any report or publication about 
this study. See 10 Data Handling and Record Keeping for more information on source documentation 
storage and security. 
13.6 
STUDY DISCONTINUATION 
In the event that the study is discontinued, participants who have completed or who are still enrolled in 
the study will be notified.  Any new information gained during the course of the study that might affect 
participant’s willingness to continue will be communicated within 2 days of the PI learning this 
information. 
 
 

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14 
PUBLICATION POLICY 
This study will be registered on clinicaltrials.gov once IRB approved. There are no restrictions on 
publications since this is an investigator-initiated study funded by a grant agency that has no influence 
on the publications resulting from this study. The aim is to publish the results of this study in a peer-
reviewed, psychiatry or physical therapy journal. 
 
 

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15 
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APPENDIX A: SCHEDULE OF EVENTS 
A detailed schematic describing all visits and assessments.  
Procedures 
Phone Screening 
First Stimulation 
(Sham or 10 Hz) 
2 Days Later 
Second 
Stimulation 
(Sham or 10 Hz) 
2 Days Later 
Provide Verbal Consent 
x 
 
 
 
 
Signed Consent Form 
 
x 
 
 
 
Signed HIPAA Authorization 
 
x 
 
 
 
Assessment of Eligibility Criteria 
x 
x 
 
 
 
Review of Medical History 
x 
x 
 
 
 
Review of Concomitant Medications 
x 
x 
 
 
 
Baseline Assessments (list 
assessments) 
 
x 
 
 
 
Clinical Assessments 
 
x 
 
x 
 
Pressure Pain Threshold Test 
 
x 
 
x 
 
Urine Pregnancy Test 
 
x 
 
 
 
Randomization 
 
x 
 
 
 
Stimulation 
 
x 
 
x 
 
Stimulation Questionnaire, Perceived 
Improvement Questionnaire, HAM-D  
 
x 
 
x 
 
Email Questionnaires (Follow-up) 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B: AE REPORT FORM 
 
Adverse Effects Report:  
Reasons for Report (adverse event, time, date and place of occurrence if available):  
1. What do we already know about the therapy? 
a.  
2. What is the temporal relationship of the AE to the study therapy? 
a.  
3. Does the AE improve or disappear when the therapy is stopped? 
a.  
4. Is the AE a worsening of baseline symptom(s)? 
a.  
5. Is the AE a result of an underlying concurrent medical condition(s) or concurrent 
medication(s)? 
a.   
6. Additional Information provided by research team  
a.  
Research team member signature ______________________________________ 
Date____________ 
Co-Investigator:  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________ 
Co-I signature 
_______________________________________________________Date___________ 
 
PI Comments:  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________

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______________________________________________________________________________
______________________________________________________________________________
______________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________ 
 
PI signature 
_______________________________________________________Date___________ 
 
 

 
 
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APPENDIX C: IRB AMENDMENT TRACKING LOG 
 
Change Initiated By: 
Description of IRB: Type and Brief Summary 
Date 
Submitted 
to IRB 
Date of 
IRB 
Response 
Requires 
Stipulations? 
(Y/N) 
Requires 
Updated 
Consent 
Form? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date 
Initials 
Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX D: AE REPORT FORM 
 
Participant 
ID 
 if AE meets 
definition of 
serious* 
Grade/Intensity 
1. Asymptomatic 
2. Mild 
3. Moderate 
4. Severe 
 
Date of 
Incident 
Relationship to 
study device 
1. Related 
2. Possibly 
3. Not Likely 
4. Not Related 
Was Action 
Taken? 
 
 
 
 
Action(s) Taken: 
Outcome: 
1. Recovered 
2. Not Recovered 
3. Recovered 
w/Sequel 
4. Fatal 
5. Unknown 
PI Initials / Date 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 

 
 
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53 
 
APPENDIX E: INFORMED CONSENT QUIZ 
Name of Research Study:  
You have been asked to be in a research study. This sheet will help you think of questions to ask 
but you may have other questions.  This is not a test.  We want to be sure you understand what 
it means to be in this research study.  You should understand the research before you decide 
whether or not to participate. 
1. What is the purpose of the research? 
2. What are the possible benefits of the research? 
3. What are the possible risks of the research? 
4. Will everyone receive the same treatment? 
5. How is this research different than the care or treatment I would get if I wasn’t in the 
research study?  
6. Does the research cost me anything extra? 
7. Can you stop being in the research once you’ve started? 
8. Who will view your medical records? 
9. Who do you call if I have questions about being a research subject? 
10. Any questions?   

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APPENDIX F: NOTE TO FILE 
 
IRB#: 15-2125  
 
 
 
 
 
 
      
       PI: Karen McCulloch 
Study Title: [Insert Short Name] 
Researcher: ________________ 
 
 
 
       Date of Occurrence: ____________ 
Participant ID: _________________ 
 
Reason for Note: 
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
Note: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
Corrective action (if applicable): 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
 
 
Signature: ______________________________      Date: _______________ 
 

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APPENDIX G: TELEPHONE SCRIPT 
Hello, my name is __________ and I am a study coordinator from the University of North Carolina at 
Chapel Hill conducting a research study about individuals with chronic low back pain. Based on your 
medical history, you may be eligible to participate in our study. 
 
 
If participant asks “How did you get my name and contact information?”   
o 
Answer:  We received IRB approval to access medical records of patients in the UNC Health Care 
System who meet our research study criteria.  Based on your medical history, you appear eligible 
to participate in this study.  If you are not interested in participating in this study, we will destroy 
all information that we have already collected about you. 
 
If participate states, “but I am not a UNC Health Care patient, I go to Rex Hospital.”  
o 
Answer: UNC Health Care System now includes several affiliate hospitals and clinics, include Rex. 
 
Do you have time now to hear about the study, answer a few screening questions, and schedule your 
first visit?  
(If ‘No’, ask for a good time to call back)  
(If ‘Yes’, proceed) 
 
Great!  This study is looking at abnormal rhythms of brain activity in patients with chronic low back pain 
and how they respond to very weak applied electric currents.  Findings from this study will help the 
development of treatments for the symptoms of chronic pain.  In this study, a very weak electric current 
will be applied to your scalp.  Some people report a mild tingling because of this stimulation, but no 
other side effects have been found.  It is not a shock and should cause no pain. 
 
Participation in this study includes two sessions, consisting 2 stimulation sessions, separated by 1-3 
weeks. You will be compensated for your time spent participating in the study. The maximum 
compensation for this study is $55 for completing all of the sessions. Are you still interested in 
participating? 
 
(If ‘No’, thank them for their time; if ‘Yes’, proceed) 
 
Great! In order to make sure you’re eligible for the study, I need to ask you a few questions. Please 
answer yes or no. You do not need to provide any further details.  
(If the answer given is not the same as the answer shown, thank the individual for his or her interest and 
say, unfortunately, they do not qualify for the current study) 
 
 
Are you 18 years old or older?  (Yes) 
 
Have you ever, or are you currently being treated for a neurological condition (e.g., epilepsy, migraines)? (No) 
 
Are you currently taking medication for the treatment of chronic pain or any other psychiatric illness? 
o 
Have you ever taken medication for chronic pain? 
o 
Have you taken ever taken opioids, benzodiazepines or anticonvulsant medications? 
 
If yes, has it been at least 6 months since then? 
 
Have you ever had brain surgery? (No) 
 
Do you have any brain devices or implants, including a cochlear implant or aneurysm clip? (No) 
 
Have you ever been diagnosed with a traumatic brain injury? 
o 
If yes, how severe? 
 
(For females only) Is there a chance you may be pregnant? (No) 
 
Diagnostic 

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 
Have you been diagnosed with chronic lower back pain by a professional (i.e., a physical therapist or other 
license clinician)? 
 
Have you been diagnosed with any other co-morbid pain conditions such as fibromyalgia, nerve damage, or 
multiple sclerosis? 
 
Do you have chronic pain anywhere besides your back)?  
 
Does your pain radiate to other parts of your body (i.e. down your leg)? (radicular pain) 
Follow-up Questions 
 
Have you ever been hospitalized? 
o 
If yes, was it in anyway related to your chronic pain or another psychiatric condition?  
o 
If yes, when did this occur? 
 
Phone Screening: 
 Pass 
 Fail 
Reason for failing: ________________________________________________________ 
 
 
 _______________________________________________________________________ 
 
 
 _______________________________________________________________________ 
Initials _______ 
 
You are eligible for participation in the first session of the study. At the first session we will determine 
your eligibility for the remainder of the sessions and complete some baseline assessments.  I’d like to 
schedule your first session now. It will last approximately 2-4 hours. All testing will be conducted UNC 
Hospital. 
 
Scheduled Initial Session (Enter into Clinical Trials Calendar) 
 
 
Date: _______________ 
 
 
Time: _______________ 
 
I will send you an email confirming this time, and providing directions on how to find the specific 
location of your session. We will also send you an email to confirm your appointment 24 hours 
beforehand. Please respond to this email so we know you are still coming. If you have any questions 
before then, please don’t hesitate to contact us at this phone number or at jhprim@email.unc.edu.  
Thank you for your time.