LUPUS Brain: Transcranial Alternating Current Stimulation (tACS) to Target the Neurophysiology of Depression, Cognitive Deficits, and Pain in Patients With Systemic Lupus Erythematosus (SLE)
Phase: NA
Conditions: Systemic Lupus Erythematosus, Depression
Sponsor: University of North Carolina, Chapel Hill

 
Lupus Brain: Transcranial Alternating Current Stimulation (tACS) to Target the 
Neurophysiology of Depression, Cognitive Deficits, and Pain in patients with 
Systemic Lupus Erythematosus (SLE) 
 
 
 
NCT number NCT04141046 
Document Date 03/04/2022 
 

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Lupus Brain: Transcranial Alternating Current 
Stimulation (tACS) to Target the Neurophysiology of 
Depression, Cognitive Deficits, and Pain in patients with 
Systemic Lupus Erythematosus (SLE) 
Principal Investigators: Saira Sheikh, MD; Flavio Frohlich, PhD 
Co-Investigators: Crystal Schiller, PhD; Yueh Lee, MD, PhD 
 
Version: 1.8  
4 March 2022 
 
 
Summary of Changes from Previous Version: 
Affected Section (s) Summary of Revisions Made 
Rationale 
1.2.2, 1.2, 1.3, 4.1, 
8.1.3, 10.3 
Replacement of SCID with MINI  
Shorter and more applicable in remote 
settings  
1.2, 1.2.2 1.3, 8.2.3, 
10.1.3 10.3 
Removal of BDNF saliva collection and 
mention of genetic testing  
This was built into the initial protocol as 
an exploratory hypothesis prior to the 
COVID 19 pandemic. Given the current 
climate of the pandemic, we have 
decided that this poses unnecessary 
risk and would therefore like to remove 
it from the protocol. This also 
eliminates the only potential genetic 
testing that was built into the protocol.  
 
8.1.5 
Removal of Bartonella questionnaire  
We have already removed the 
Bartonella blood draw but did not 
remove the related questionnaire until 
now 
5.1, 6.4 
Updating and clarifying inclusion criteria 
to state no changes to SLE or psychiatric 
Non-SLE related and non-psychiatric 
med changes should not confound 
analysis of study intervention  

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meds 4 weeks prior to screening instead 
of all meds 6 weeks prior 
8.3.2  
CTCAE Version 5.0 Published: November 
27th, 2017 
Updated to clarify version being used  
 
 
 

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Table of Contents 
Statement of Compliance .............................................................................................................................................. 6 
1 Protocol Summary ...................................................................................................................................................... 7 
1.1 Synopsis ............................................................................................................................................................... 7 
1.2 Schema ................................................................................................................................................................ 8 
1.2.1 Arm Allocation .............................................................................................................................................. 8 
1.2.2 Study Layout ................................................................................................................................................. 9 
1.3 Schedule of Activities (SoA) ............................................................................................................................... 11 
2 Introduction .............................................................................................................................................................. 13 
2.1 Study Rationale .................................................................................................................................................. 13 
2.2 Background ........................................................................................................................................................ 13 
2.3 Risk/Benefit Assessment.................................................................................................................................... 14 
2.3.1 Known Potential Risks ................................................................................................................................. 14 
2.3.2 Known Potential Benefits ........................................................................................................................... 16 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 16 
3 Objectives and Outcome Measures .......................................................................................................................... 17 
4 Study Design ............................................................................................................................................................. 19 
4.1 Overall Design .................................................................................................................................................... 19 
4.2 Scientific Rationale for Study Design ................................................................................................................. 20 
4.3 Justification for Dose ......................................................................................................................................... 21 
4.4 End of Study Definition ...................................................................................................................................... 21 
5 Study Population ...................................................................................................................................................... 22 
5.1 Inclusion Criteria ................................................................................................................................................ 22 
5.2 Exclusion Criteria ............................................................................................................................................... 22 
5.3 Lifestyle Considerations ..................................................................................................................................... 23 
5.4 Screen Failures ................................................................................................................................................... 24 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 24 
6 Study Intervention .................................................................................................................................................... 26 
6.1 Study Intervention(s) Administration ................................................................................................................ 26 
6.1.1 Study Intervention Description ................................................................................................................... 26 
6.1.2 Dosing and Administration ......................................................................................................................... 26 
6.2 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 28 
6.2.1 Randomization ............................................................................................................................................ 28 
6.2.2 Blinding ....................................................................................................................................................... 28 
6.3 Study Intervention Compliance ......................................................................................................................... 29 
6.4 Concomitant Therapy ........................................................................................................................................ 29 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................................. 30 
7.1 Discontinuation of Study Intervention .............................................................................................................. 30 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 30 
7.3 Lost to Follow-Up ............................................................................................................................................... 31 
7.4 Suspension or Termination of Study .................................................................................................................. 31 
7.4.1 Serious Adverse event (SAE) stopping rules ............................................................................................... 32 
7.4.2 treatment emergent Adverse event (TEAE) stopping rules ........................................................................ 32 
8 Study Assessments and Procedures ......................................................................................................................... 33 
8.1 Efficacy Assessments ......................................................................................................................................... 33 
8.1.1 physiological changes ................................................................................................................................. 33 

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8.1.2 Pain Evaluations .......................................................................................................................................... 33 
8.1.3 Clinical evaluations ..................................................................................................................................... 34 
8.1.4 Physician Assessments of SLE Disease Activity ........................................................................................... 34 
8.1.5 Self-report Assessments ............................................................................................................................. 35 
8.2 Safety and Other Assessments .......................................................................................................................... 36 
8.2.1 Safety .......................................................................................................................................................... 36 
8.2.2 Cognition ..................................................................................................................................................... 37 
8.2.3 Laboratory Assessments ............................................................................................................................. 37 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 37 
8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 37 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................................ 37 
8.3.3 Classification of an Adverse Event .............................................................................................................. 38 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................................ 39 
8.3.5 Adverse Event Reporting ............................................................................................................................ 40 
8.3.6 Reporting of pregnancy .............................................................................................................................. 40 
8.4 Unanticipated Problems .................................................................................................................................... 41 
8.4.1 Definition of Unanticipated Problems (UP) ................................................................................................ 41 
8.4.2 Unanticipated Problem Reporting .............................................................................................................. 41 
8.4.3 Reporting Unanticipated Problems to Participants .................................................................................... 41 
9 Statistical Considerations ......................................................................................................................................... 42 
9.1 Statistical Hypotheses ........................................................................................................................................ 42 
9.1.1 Primary Efficacy Hypothesis ....................................................................................................................... 42 
9.1.2 Secondary Efficacy Hypothesis ................................................................................................................... 42 
9.2 Sample Size Rationale ........................................................................................................................................ 42 
9.3 Populations for Analyses ................................................................................................................................... 43 
9.4 Statistical Analyses............................................................................................................................................. 43 
9.4.1 General Approach ....................................................................................................................................... 43 
9.4.2 Analysis of the Primary Efficacy Outcome Measure(s) ............................................................................... 44 
9.4.3 Analysis of the Secondary Outcome Measure(s) ........................................................................................ 44 
9.4.4 Safety Analyses ........................................................................................................................................... 44 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 45 
9.4.6 Planned Interim Analyses ........................................................................................................................... 45 
9.4.7 Sub-Group Analyses .................................................................................................................................... 45 
9.4.8 Exploratory Analyses .................................................................................................................................. 45 
10 Supporting Documentation and Operational Considerations ................................................................................ 47 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 47 
10.1.1 Informed Consent Process ........................................................................................................................ 47 
10.1.2 Study Discontinuation and Closure ........................................................................................................... 47 
10.1.3 Confidentiality and Privacy ....................................................................................................................... 48 
10.1.4 Future Use of Stored Specimens and Data ............................................................................................... 48 
10.1.5 Key Roles and Study Governance ............................................................................................................. 48 
10.1.6 Safety Oversight ........................................................................................................................................ 49 
10.1.7 Clinical Monitoring .................................................................................................................................... 49 
10.1.8 Quality Assurance and Quality Control ..................................................................................................... 50 
10.1.9 Data Handling and Record Keeping .......................................................................................................... 50 
10.1.10 Protocol Deviations................................................................................................................................. 51 

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10.1.11 Publication and Data Sharing Policy ....................................................................................................... 51 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 51 
10.2 Additional Considerations ............................................................................................................................... 51 
10.3 Abbreviations ................................................................................................................................................... 51 
10.4 Protocol Amendment History .......................................................................................................................... 54 
11 References .............................................................................................................................................................. 56 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following: 
  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 

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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
Lupus Brain: Transcranial Alternating Current Stimulation (tACS) to Target 
the Neurophysiology of Depression, Cognitive Deficits, and Pain 
Study Description: 
The purpose of this clinical trial is to investigate the effects of non-invasive 
transcranial alternating current stimulation (tACS) on patients diagnosed 
with lupus. We will recruit up to 72 males and non-pregnant females 
diagnosed with systemic lupus erythematosus (or lupus) and a diagnosis of 
depression. At the initial session, consent will be obtained and eligibility 
will be determined. Eligible participants will undergo a structural MRI as 
part of the screening process, then be randomized and have 5 consecutive 
daily, 40 minute stimulation sessions. Participants will be randomly 
assigned to one of three groups: sham stimulation, individualized alpha-
tACS (usually 8-12 Hz), or individualized theta-tACS (individualized alpha 
frequency minus 4 Hz). Participation will include 1 to 11 visits. 
Neurophysiological measures will be taken before and after the 
stimulation sessions on the first and fifth days of the intervention, as well 
as the 2-week follow-up and 4-week follow-up visits. Psychiatric clinical 
assessments will be performed at baseline (Day 1 of stimulation), Day 5 of 
stimulation, and at both follow-up visits using the HDRS17, the Hamilton 
Anxiety Rating Scale (HAM-A), the Inventory of Depression and Anxiety 
Symptoms (IDAS), and the Comparative Pain Scale Chart. Participants will 
also be asked to complete self-report surveys via REDCap at a 3-month 
time point measured from completion of the intervention.  
Objectives: 
Primary Objective: To investigate the physiological changes in patients with 
systemic lupus erythematosus over the course of a 5-day, 40-minute 
stimulation protocol, specifically changes in alpha oscillation power from 
resting-state EEG recordings from baseline (Day 1) to Day 5 of stimulation. 
Secondary Objectives: To elucidate the relationship between changes in 
EEG and changes in depression and pain symptoms, by comparing the 
changes in symptoms and the change in alpha oscillation power over the 
course of the intervention (baseline to day 5 of stimulation). 
Study Population: 
We will recruit up to 72 males and non-pregnant females aged 18-65 with 
a diagnosis of lupus, free of benzodiazepines and anticonvulsant 
medications. We anticipate having evaluable data from at least 45 
participants. Participants will be recruited in person from the UNC 
Rheumatology Specialty Clinic and through indirect recruitment from the 
surrounding Chapel Hill, Durham, and Raleigh areas. 
Phase: 
 N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
 University of North Carolina at Chapel Hill 

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Description of Study 
Intervention: 
Patients will be randomized with equal allocation into 3 study arms: an 
active sham, individualized alpha-tACS (usually 8-12 Hz), or individualized 
theta-tACS (individualized alpha frequency minus 4 Hz). Active sham 
treatment will include 20 seconds of ramp in to 40 seconds of 10Hz tACS 
with a ramp out of 20 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. alpha-tACS 
and theta-tACS will also have a 20 second ramp in and ramp out with 40 
minutes of stimulation for a total of 2440 seconds. Stimulation waveforms 
are sine-waves with an amplitude of 1mA zero-to-peak.  Participants will 
stay in a relaxed yet experimentally controlled state by watching a nature 
movie such as “Reefscape” during stimulation. 
Study Duration: 
 2 years 
Participant Duration: 
Eligible participants who complete this clinical trial will have a total of 9 to 
11 visits; an initial screening session, a visit for a structural MRI to 
screening for incidental findings and to aid signal processing of EEG data, 5 
days of stimulation, a 2 and a 4 week follow up visit (follow up sessions are 
measured from completion of the intervention). Participants will also be 
asked to complete self-report surveys via REDCap at a 3-month time point 
measured from completion of the intervention. Study visits include clinical 
assessments, patient questionnaires/surveys, neuropsychological 
assessments, and specimen collection including up to 2 blood draws. The 
initial session will take approximately 3 hours, each blood draw will take 30 
minutes (and will be included in other visits when possible), the first and 
last day of stimulation will take approximately 5 hours. Days 2 through 4 of 
stimulation will take 2 hours each day.  The visit for the structural MRI 
takes approximately 45 minutes. The 2-week follow up will take 
approximately 3 hours and the 4-week follow up will take approximately 4 
hours.  The 3-month surveys will take approximately an hour. We estimate 
that total participation to be approximately 28 hours. 
Funding: 
The Fund for Excellence in Lupus and Sjogren’s 
 
1.2 SCHEMA 
1.2.1 ARM ALLOCATION 
  
Up to 72 participants will be equally randomized in to one of three arms (1:1:1): 
 
72 males and females diagnosed 
with SLE, free of benzodiazepines 
and anticonvulsant medications
24 randomized to 
Alpha-tACS
24 randomized to 
Theta-tACS
24 randomized to 
Sham stimulation

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**Randomization is double-blind 
1.2.2 STUDY LAYOUT 
 
 
*Note: Follow-up weeks are counted from the completion of the intervention 
**Note: Prior to the week of stimulation, participants will return for a structural MRI to assist with 
source localization in EEG and screen for incidental findings. 
  
 
 

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Abbreviations: 
• 
American College of Rheumatology (ACR) 
• 
Antinuclear Antibody test (ANA) 
• 
Anti-double stranded DNA (anti-dsDNA) 
• 
Complete Blood Count (CBC) 
• 
C-reactive protein (CRP) 
• 
Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Electroencephalogram (EEG) 
• 
Extractable Nuclear Antigen Antibodies (ENA) 
• 
Fatigue Scale for Motor and Cognitive Functions (FSMC) 
• 
Hamilton Anxiety Rating Scale (HAM-A) 
• 
Hamilton Depression Rating Scale, 17 item (HDRS17) 
• 
Inventory of Depression and Anxiety Symptoms (IDAS) 
• 
Magnetic Resonance Imaging (MRI) 
• 
Mini International Neuropsychiatric Interview (MINI) 
• 
Polymerase Chain Reaction (PCR) 
• 
Positive and Negative Affect Schedule (PANAS) 
• 
Pain Catastrophizing Scale (PCS) 
• 
Resting state EEG (RSEEG) 
• 
Short Form Health Survey (SF-36) 
• 
Structural Magnetic Resonance Imaging (sMRI) 
• 
Systemic Lupus Erythematosus (SLE) 
• 
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) 
• 
Systemic Lupus Collaborating Clinics (SLICC) 
• 
Transcranial alternating current stimulation (tACS) 
• 
WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) 

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• 
Young Mania Rating Scale (YMRS) 
1.3 SCHEDULE OF ACTIVITIES (SOA) 
Procedures 
Screening 
(Initial Session & MRI) 
Day 1 of Stimulation 
(Baseline) 
Days 2 of Stimulation 
Day 3 of Stimulation 
Day 4 of Stimulation  
Day 5 of Stimulation 
2 Week Follow-Up 
4 Week Follow-Up 
3 Month Follow-Up 
Visit Windows (in days) 
- 14 
to 0 
1 
2 
3 
4 
5 
19 
+/- 3 
33 
+/- 3 
93 
+/- 3 
Informed Consent4 
X 
  
  
 
 
  
  
  
 
MRI Screening Form 
X 
 
 
 
 
 
 
 
 
sMRI3 & Neuroradiologist review 
X 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
  
  
 
 
  
  
  
 
Pregnancy Test 
X 
 X 
  
 
 
 
  
  
 
MINI4 
X 
  
  
 
 
  
  
  
 
Handedness4 
X 
  
  
 
 
  
  
  
 
Randomization 
 
X 
 
 
 
 
 
 
 
Suicide assessment4 
  
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS4 
X 
X 
 
 
 
X 
X 
X 
 
YMRS4 
X 
X 
 
 
X 
X 
X 
 
HDRS174 
X 
X 
  
 
 
X 
X 
X 
 
WHODAS 2.04 
  
X 
  
 
 
  
  
  
X 
HAM-A4 
 X 
X 
  
 
 
X 
X 
X 
 
IDAS4 
 X 
X 
  
 
 
X 
X 
X 
X 
PANAS4 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
Comparative Pain Scale4 
  
X 
  
 
 
X 
X 
X 
X 
PCS4 
  
X 
  
 
 
X 
X 
X 
X 
FSMC4 
 
X 
 
 
 
X 
X 
X 
X 
RSEEG 
  
X 
  
 
 
X 
X 
X 
 
Sustained attention task 
 
X 
 
 
 
X 
X 
X 
 
Selective attention task  
 
X 
 
 
 
X 
X 
X 
 
Working memory task 
  
X 
  
 
 
X 
X 
X 
 
Blinding Assessment 
  
  
  
 
 
X 
  
  
 

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Stimulation (alpha-tACS, theta-tACS, 
or sham) 
  
X 
X 
X 
X 
X 
  
  
 
Stimulation Side Effects 
Questionnaire 
  
X 
X 
X 
X 
X 
  
  
 
SLE Requirements 
 
Medical History and Demographics4 
X 
 
 
 
 
 
 
 
 
Physical Exam (Height and Weight) 
X 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Subject Assessments  
 
SLICC/ACR SLE Criteria4 
X 
 
 
 
 
 
 
 
 
SLEDAI-2K1 
X 
 
 
 
 
 
X* 
 
SF-364 
X 
 
 
 
 
 
X 
 
SLICC Damage Index4 
X 
 
 
 
 
 
X 
 
Blood Draw for Laboratory Assessments (UNC McClendon Lab) 
 
CBC with Differential 
X 
 
 
 
 
 
 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
X 
 
Urine protein/creatinine ratio 
X 
 
 
 
 
 
X 
 
Complement C3/C4 
X 
 
 
 
 
 
X 
 
Anti-dsDNA 
X 
 
 
 
 
 
 
X 
 
ANA2  
X 
 
 
 
 
 
 
 
 
ENA panel2  
X 
 
 
 
 
 
 
 
 
CRP 
X 
 
 
 
 
 
X 
 
 
1A SLEDAI-2K assessment will not be conducted at the 4 week follow-up if this visit occurs within 30 days or less of 
the Screening Initial Session. 
2 ANA and ENA panel labs will only be completed if there are no recorded historical values in participant’s medical 
chart. 
3sMRI will be completed if a patient has not undergone a MRI in the past 3 months prior to screening. Reference 
section 5.4 for additional detail. 
 
4Patient consenting, medical history collection, and SLE indices (SLICC/ACR SLE Criteria, SLEDAI-2K, SLICC Damage 
Index) will be offered to be completed remotely through UNC’s REDCap platform. Patient self-reported 
questionnaires will also be conducted using REDCap’s secure survey function. Patient self-reported questionnaires 
include: CPS, PCS, SF-36, WHODAS2.0, PANAS, and FSMC. Patient assessments include: MINI , HDRS17, HAM-A, C-
SSRS, Suicide Assessment, YMRS, will be offered both in-person and remotely. Remote clinical assessments will be 
conducted over the phone or UNC approved video platform and will be recorded at the approval of the participant. 
All remote activities will adhere to the statement of activities listed above and windows to be completed.   

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2 INTRODUCTION 
2.1 STUDY RATIONALE 
Systemic lupus erythematosus (SLE) is a severe, chronic autoimmune disorder that affects multiple 
organ systems and is characterized by a pro-inflammatory effect (Azizoddin et al., 2018). It is not 
uncommon for patients with SLE to also have several comorbidities, including depression, chronic pain, 
and cognitive impairment (i.e., "brain fog"). Previous research shows that these comorbidities have the 
strongest association with quality of life metrics, demonstrating that alleviation may lead to better 
quality of life (Mackay, 2015). Current treatments for SLE are inadequate and the development of new 
pharmacological therapies has been slow (Dall'Era et al., 2019), indicating the need for more targeted 
therapies. 
 
 
2.2 BACKGROUND 
Mood disorders are the second most frequent neuropsychiatric (NP) manifestation observed in SLE 
occurring in up to 20% of SLE patients (de Amorim et al., 2019). These symptoms may occur 
simultaneously or independently of other clinical indications which negatively affect quality of life. 
Common SLE treatment options such as corticosteroids may be associated with the exacerbation of NP 
symptoms such as mood disorders. Furthermore, suicidal ideation has also been observed in up to 25% 
of SLE patients and lifetime mood disorders emerged as a significant risk factor (de Amorim et al., 2019).  
The experience of pain involves multiple areas of the brain, including the somatosensory and prefrontal 
cortices, as well as several subcortical areas (Ploner, Sorg, & Gross, 2017). Chronic pain can result in 
abnormal neuronal oscillatory activity, including decreased peak alpha frequency (Pinheiro et al., 
2016). Targeted stimulation modalities, such as transcranial alternating current stimulation (tACS), can 
directly engage and modulate oscillatory activity, which would result in symptom changes. tACS utilizes 
sine-wave stimulation waveforms that can enhance specific oscillatory activities (Pinheiro et al., 2016) 
(Herrmann, Rach, Neuling, & Strüber, 2013). In fact, tACS at the alpha frequency can alter the 
experience of pain in induced pain paradigms (Arendsen, Hugh-Jones, & Lloyd, 2018), as well as directly 
target and enhance alpha oscillatory activity over the somatosensory cortex in patients with chronic low 
back pain (Ahn, Prim, Alexander, McCulloch, & Frohlich, 2019). 
 
Furthermore, Cognitive impairment is observed in 20–60% of SLE patients when standard testing is 
performed (de Amorim et al., 2019). The American College of Rheumatology (ACR) defines cognitive 
dysfunction as significant deficits in any or all of the following cognitive functions: simple or complex 
attention, reasoning, executive skills, memory, visual-spatial processing, language, and psychomotor 
speed.  

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Targeting depression in patients with SLE may provide benefit to these patients, as there is a clear 
relationship between chronic pain and depression (Tunks, Crook, & Weir, 2008). Both depression and 
chronic pain can result in cognitive impairment (Gotlib & Joormann, 2010). In our previous trial of tACS 
to target alpha oscillations in the somatosensory cortex (Ahn et al., 2019), we found a relationship 
between the subjective experience of pain and alpha power over the somatosensory cortex, indicating 
that alpha activity can determine how someone experiences their pain. Furthermore, we found that 
tACS enhanced alpha oscillations over this same region, resulting in decreased experience of pain. We 
have also previously targeted frontal alpha oscillations near the somatosensory cortex in patients with 
depression, resulting in clinical improvement and target engagement of alpha oscillations (Alexander et 
al., 2019). We propose that the same stimulation montage that was previously used in depression could 
be beneficial to patients with SLE, resulting in reduced depression symptoms, thus resulting in reduced 
chronic pain and cognitive difficulties. 
 
We propose a 3-arm (tACS at alpha frequency, tACS at theta frequency, and sham stimulation) clinical 
trial to assess the use of tACS to treat depression in patients with SLE. As described in our previous study 
(Alexander et al., 2019), we will use alpha-tACS to directly target alpha oscillations and reduce 
depression symptoms. Previous research in our lab has found that alpha oscillations exist in an 
antagonistic relationship with theta oscillations (Stitt, Zhou, Radtke-Schuller, & Frohlich, 2018), which is 
why we choose to include the individualized theta-tACS as a possible mechanism to engage alpha 
oscillations and potentially treat depression more effectively than alpha-tACS. Furthermore, the choice 
to include a frequency control is to ensure that stimulation is frequency-dependent, rather than 
stimulation-dependent (i.e., that target engagement and therapeutic efficacy is different between the 
two stimulation frequencies). Safety concerns are paramount in a depressed population, which is why 
we have chosen to include daily questionnaires of safety and will exclude participants at risk of suicide, 
as well as employ a DSMB to monitor any safety issues that may arise. 
 
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
  
Risk of Confidentiality Breach: In the unlikely event of a breach of confidentiality, people might discover 
that an individual was involved in this research study. This is especially sensitive because the population 
recruited for this study may be subjected to negative consequences caused by the stigma of diagnosis. 
Furthermore, some 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 document, 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 participant 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 

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methods will be used during communication between investigators. Only study personnel will have 
access to these data. All study staff participate in annual human participant training that includes 
education about responsibilities to the minimize risk of confidentiality breach. For remote assessments 
conducted via UNC approved video platform or phone, sessions may be recorded. Clinical interviews will 
be recorded with the participant’s permission for the sole purpose of reviewing symptoms with other 
trained researchers to reach a consensus on diagnoses. No personally identifying information will be 
included in the recordings. Like all other data, they will be identified by a code number and kept on a 
password protected computer.. Audio and video recordings may be requested to be turned off at any 
time. 
  
Risk of Embarrassment: Self-report assessments contain questions regarding sensitive personal 
information. This risk is necessary in order to assess mood symptoms, self-report pain, and associated 
psychopathology. Participants will be assured upon intake that only study personnel will see any clinical 
information. 
  
Risk of Injury and Discomfort: The side effects of tACS are mild and transient; in fact, low intensity 
transcranial current stimulation, such as tACS, has been used for several years without any report of 
serious side effects (Frohlich & McCormick, 2010). Furthermore, this stimulation mode 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 (Khan, Khan, Shankles, & Polissar, 2002). However, tACS does have some mild side effects, such 
as transient mild tingling, burning, or itching under the electrode sites. In the first part of this study, 
participants from all three groups reported either absent or mild side effects and there was no 
difference between the groups with the exception of “flickering lights” (or phosphenes, p = 0.014) 
(Alexander et al., 2019). In order to monitor these, we will be administering an adverse effects 
stimulation questionnaire after each stimulation session to determine whether these effects were 
experienced and at what intensity. Research personnel present during these sessions will also check in 
with the participant periodically during the stimulation to see whether they are comfortable. If 
participant is experiencing severe discomfort (as determined by the adverse effects questionnaire or by 
self-report), the stimulation will be immediately stopped. 
 
Risks associated with emotional distress in case of incidental findings on structural MRI or a false 
positive pregnancy test. 
 
Risks associated with venous blood draw include minimal discomfort and/or bruising. Infection, excess 
bleeding, clotting, and fainting are also possible, although unlikely. 
  
Patients experiencing depression have a higher risk of suicide. We have no evidence that our treatment 
paradigms will in any way increase this likelihood. In a similar study in patients with major depressive 
disorder (MDD), 4 participants in the sham/placebo stimulation group experienced an increase in 
suicidal thoughts and only one of those 4 participants reported suicidal intent. No participants who 

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received tACS reported an increase in suicidal ideation from baseline.  We will be using the Suicide Item 
included in the HDRS17 to assess suicide risk. Inclusion criteria states that the patient must be low 
suicide risk defined as a score of less than 3 on the HDRS17 suicide item, potential participants that have 
an above “low risk” designation will not be eligible for the study. Additionally, we will administer this as 
a daily questionnaire to assess suicide risk. In the case suicide risk increases after the screening visit, the 
participant will be asked to stop the study and will be provided with a referral to UNC Psychiatry and 
their mental health care or family medical doctor will be contacted. Dr. Schiller, Co-I, will facilitate this 
process. 
  
Research within our lab has shown that alpha and theta oscillations exist in an antagonistic relationship. 
Therefore, an increase in alpha oscillations would result in a decrease in theta oscillations (and vice 
versa). In a previous tACS trial (Alexander et al., 2019), we found that alpha-tACS reduced alpha 
oscillations over the course of 5 days. We propose that alpha-tACS did this through synchronization of 
those two areas. Theta-tACS would theoretically work in an orthogonal mechanism to alpha-tACS, by 
suppressing alpha oscillations, rather than synchronizing it. Theoretically, theta-tACS could exacerbate 
underlying depression and worsen outcomes. Furthermore, traditional treatments for depression (e.g., 
antidepressants) run the risk of exacerbating depression symptoms as well. We will be following 
patients closely throughout the study as well as employ the assistance of a Data Safety and Monitoring 
Board, which we plan to review our blinded data every 6 months.  
 
2.3.2 KNOWN POTENTIAL BENEFITS 
  
Our novel approach of non-invasive brain stimulation as a treatment for neurological illnesses has the 
potential to treat symptoms not only in depression and chronic pain, but also in schizophrenia, and 
anxiety disorders. 
  
This study has not been designed to benefit the individual participants. However, participants in this 
study may experience some degree of relief from the side effects of SLE (such as depression, chronic 
pain, and cognitive impairment) as a result of tACS intervention. There are no serious risks to the 
participant from the treatment used in this study. The chance to understand and develop a new 
treatment for a wide range of psychiatric disorders is an important step in helping the millions of people 
in the world who suffer from mental illness. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
  
The risks and benefits presented above are no more serious than for other clinical trials in this 
population. Based on the need for complementary and alternative treatments for SLE, the potential risks 
are worth the potential benefits. 
 
 

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3 OBJECTIVES AND OUTCOME MEASURES 
OBJECTIVES 
OUTCOME MEASURES 
JUSTIFICATION 
Primary 
To investigate the physiological 
changes in patients with systemic 
lupus erythematosus over the 
course of a 5-day, 40-minute 
stimulation protocol, specifically 
changes in alpha oscillation power 
from resting-state EEG recordings 
from baseline (Day 1) to Day 5 of 
stimulation. 
Resting state EEG 
recordings taken on Day 
1 and Day 5 of 
stimulation. 
The protocol is for a 5-day intervention. 
The primary objective is focused on 
looking at the change in brain activity 
over the course of the intervention. Long-
term effects (2-week follow-up and 4-
week follow-up) will be assessed as 
exploratory outcomes. 
Secondary 
To elucidate the relationship 
between changes in EEG and 
changes in pain and depression 
symptoms, by comparing the 
changes in symptoms and the 
change in alpha oscillation power 
over the course of the intervention 
(baseline to day 5 of stimulation). 
The SF-36 will be evaluated at 
screening and 4-week follow-up. 
Correlations between 
clinical assessments and 
alpha oscillation power 
(as measured by resting 
state EEG recordings) 
from Day 1 and Day 5 of 
stimulation. 
 The objective is to target engagement 
(i.e., if the stimulation paradigm changes 
brain activity); the secondary objective is 
to determine if this engagement resulted 
in behavioral changes. 
Exploratory 
To investigate the outlasting effects, 
if any, of tACS on brain activity and 
clinical assessments.  
  
Resting state EEG 
recordings taken on 2-
week and 4-week follow 
up visits.  
 The objective is to explore if any changes 
in brain activity persist as long-term 
effects. Long-term effects are detected at 
the 2-week and 4-week follow ups.  
To investigate whether tACS 
increases cognitive control signals 
during cognitive tasks that probe 
sustained attention, selective 
attention, and working memory. 
Correlations between 
frontal midline alpha 
and theta activity (as 
measured from EEG 
recordings on D1, D5, 2-
week, and 4-week 
follow up visits) and 
accuracy at cognitive 
We hypothesize that tACS will improve 
cognitive control. In particular, we 
hypothesize that alpha frequency tACS 
will improve performance the most for 
tasks that require attention (sustained 
attention and selective attention tasks), 

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OBJECTIVES 
OUTCOME MEASURES 
JUSTIFICATION 
 
tasks (reaction time for 
attention tasks, 
accuracy for working 
memory task).  
whereas theta frequency tACS will 
improve performance the most for the 
working memory task.  

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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
The design for this study is a pilot, randomized, double-blind, sham-controlled clinical trial which will be 
used to investigate the effects of alpha-tACS on patients with systemic lupus erythematosus (SLE), as 
well as determine the relationship between physiological changes and clinical changes. We are 
recruiting from a clinical population. For this trial, we are seeking up to 72 males and non-pregnant 
females, ages 18-65, with a diagnosis of SLE, free of benzodiazepines and anticonvulsant medication, 
and at a low risk for suicide according to the Hamilton Depression Rating Scale (HDRS17). We anticipate 
having evaluable data from at least 45 participants. 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; nursing or 
pregnant participants will be excluded from participation and all women of child-bearing potential will 
be required to use an appropriate form of birth control throughout their participation. These individuals 
will be outpatients and may seek mental health care from a family practitioner, therapist or psychiatrist. 
  
This is a single-site, pilot clinical trial with 3 arms of equal allocation (1:1:1).  We estimate 2 years to 
complete study enrollment. Participants will be randomly assigned to one of three arms; active sham 
stimulation, individualized alpha-tACS (usually 8-12Hz), or individualized theta-tACS (alpha frequency 
minus 4 Hz). Active sham stimulation will include 20 seconds of ramp-in to 40 seconds of 10 Hz tACS 
with a ramp out of 20 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.  Alpha- tACS and theta-tACS will have a 20 second ramp-in and ramp-out with 40 minutes of 
stimulation for a total of 2440 seconds of stimulation. Stimulation waveform is a sine-wave with an 
amplitude of 1 mA. In each arm, participants will stay in a relaxed and yet controlled state by watching a 
nature movie such as “Reefscape” during stimulation. 
  
Eligible participants who complete this clinical trial will have a total of 9-11 visits; including an initial 
screening session, 5 days of stimulation, a visit for a structural MRI, a 2 and a 4 week follow up 
visit  (follow up sessions are measured from end of stimulation). Participants will also be asked to 
complete self-report surveys via REDCap at a 3-month time point measured from completion of the 
intervention. The initial session will take approximately 3 hours, each blood draw will take 30 minutes 
(and will be included in other visits when possible), the first and last day of stimulation will take 
approximately 5 hours. Days 2 through 4 of stimulation will take 2 hours each day.  The visit for the 
structural MRI takes approximately 45 minutes. The 2-week follow up will take approximately 3 hours 
and the 4-week follow up will take approximately 4 hours.  The 3-month surveys will take approximately 
an hour. We estimate that total participation to be approximately 28 hours.  
 
If a participant is unable to complete his/her blood draws during the indicated sessions, there may be an 
additional 2 sessions. 
 

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As this study requires several days of participation in a row, we will allow participants to miss one 
stimulation session, as long as it is made up at the end of the stimulation week. In addition, follow-up 
sessions will be permitted to be scheduled ± 3 days to account for possible scheduling problems. 
  
Our primary objective is to investigate the physiological changes in patients with SLE over the course of 
a 5-day, 40-minute stimulation protocol, specifically changes in alpha oscillation power from resting 
state EEG recordings over the course of the intervention (Day 1 to Day 5 of stimulation). As a secondary 
objective, we are looking to elucidate the relationship between changes in EEG and changes in clinical 
assays.  
 
In the light of COVID-19, we will offer participants the option to consent and conduct patient self-
reported questionnaires and patient assessments remotely to protect our high-risk patient population. 
This option will continue throughout the remainder of the study. Self-reported questionnaires and SLE 
indices detailed in the schedule of activities will be done using REDCap’s secure survey function. All 
study staff has been vaccinated against COVID-19. 
 
 Patient assessments will be conducted using a UNC approved virtual platform. Participants will meet 
with the study coordinator on the phone or through a UNC approved video platform to conduct the 
following assessments: MINI , HDRS17, HAM-A, C-SSRS, Suicide Assessment, and YMRS. Sessions will be 
recorded only using audio and stored on a password protected computer until we are able to score and 
validate the assessments. All optional remote procedures have been noted in the schedule of 
assessments.  
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This study is a double-blind, randomized, sham-controlled interventional study. The choice of double-
blind and randomized for this study is important for the integrity of our data, especially for the clinical 
assessments. All individuals involved with data collection (as well as all randomized participants) will not 
know participant assignment until all data has been collected. This will reduce implicit and explicit bias 
in the data collection process. 
  
In this study, participants will be randomized in to one of three arms: active sham/placebo stimulation, 
individualized alpha-tACS (usually 8-12Hz), or individualized theta-tACS (alpha frequency minus 4 
Hz). We propose that alpha-tACS will be the therapeutic frequency, based on work in our lab 
demonstrating the effect of 10Hz-tACS on depression (Alexander et al., 2019) and chronic pain (Ahn et 
al., 2019); whereas, previous work from our lab demonstrates that alpha oscillations exist in an 
antagonistic relationship with theta oscillations (Stitt et al., 2018). Therefore, theta-tACS was chosen as 
a control stimulation frequency for this study. 
  

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In this design, our sham/placebo stimulation is active, including 80 seconds of stimulation (20 seconds 
ramp-in to 40 seconds of 10 Hz tACS at 1 mA with 20 seconds of ramp-out). This choice of active 
sham/placebo is important to mimic the skin sensations and other transient side effects associated with 
stimulation. Typically, stimulation side effects only last approximately a minute into stimulation; 
indicating that theoretically sham/placebo stimulation should be difficult to differentiate from verum 
tACS. 
 
 
4.3 JUSTIFICATION FOR DOSE 
In a previous study at the Carolina Center for Neurostimulation, we utilized a 5-day, 40-minute 
stimulation paradigm to treat the mood symptoms of patients with major depressive disorder (MDD) 
(Alexander et al., 2019). In this study, we found that 10Hz-tACS selectively modulated alpha power as 
measured by changes in resting state EEG, which resulted in changes in clinical outcomes. As we are 
looking for long-term changes similar to this previous study, we are choosing to follow the same 
protocol in patients with SLE. 
  
 
 
4.4 END OF STUDY DEFINITION 
The end of this study is defined as when the last participant completes the 3 month follow up survey. In 
this case, we anticipate having evaluable data from at least 45 participants; therefore, enrollment will 
discontinue when 45 participants have completed the entire study duration including the 3-month 
follow up. 
 

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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
• 
Ages 18-65 years 
• 
Meet the 2012 Systemic Lupus International Collaborating Clinics criteria OR the 1997 American College of 
Rheumatology criteria for SLE diagnosis, including testing positive ANA and/or anti-dsDNA and/or anti-
ENA 
• 
Low suicide risk (score of <3 on the Suicide Item on the HDRS17) 
• 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
• 
Not experiencing manic episode; a manic episode is defined as a score > 12 on the YMRS. 
• 
Stable on all SLE-related and psychiatric meds for 4  weeks prior to screening 
 
 
5.2 EXCLUSION CRITERIA 
• 
Drug-induced SLE and any other rheumatologic or autoimmune disease (except for Sjogren’s syndrome 
and mixed connective tissue disease) 
• 
Positive hepatitis B surface antigen or hepatitis C antibody or HIV antibody/antigen in medical history, as 
patients with these illnesses cause also experience depression and cognitive impairment (from the illness 
itself or the treatment) that may not be mitigated by tACS, thus confounding the results. 
• 
Have received intravenous glucocorticoids at a dosage of ≥ 500mg daily within the past month 
• 
Opportunistic infection ≤ 12 weeks before initial study dosing OR currently undergoing treatment for a 
chronic opportunistic infection (TB, pneumocystis pneumonia, cytomegalovirus, herpes simplex virus, 
herpes zoster, or atypical mycobacteria) 
• 
Acute/chronic infection requiring hospitalization ≤ 30 days before screening visit AND/OR administration 
of parenteral (IV or IM) antibacterial, antiviral, antifungal, or anti-parasitic agents ≤ 30 days before 
screening visit 
• 
History of thrombophlebitis or thromboembolic disorders (e.g., blood clots) or serious adverse reactions 
to blood draws 
• 
Medical illness (unstable cardiac disease, AIDS,  liver or renal impairment, or malignant disease within 5 
years before screening visit) or treatment of same that could interfere with study participation 

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• 
Neurological disorders, including but not limited to history of seizures (except childhood febrile seizures 
and ECT-induced seizures), dementia, history of stroke, Parkinson's disease, multiple sclerosis, cerebral 
aneurysm. 
• 
History of moderate to severe traumatic brain injury (TBI); i.e., TBI that resulted in no or brief 
hospitalization, loss of consciousness of less than 20 minutes, post-traumatic amnesia of less than 24 
hours, and no continuing side effects of the TBI (e.g., seizures, cognitive impairment, headaches) 
• 
Frequent (more than once a week) or severe (requiring a visit to urgent care, hospital, or ED) migraines in 
the past 30 days before the screening visit  
• 
DSM-V diagnosis of alcohol of substance abuse (other than nicotine) within the last month or a DSM-IV 
diagnosis of alcohol or substance dependence (other than nicotine) within the last 6 months 
• 
Prior or current diagnosis of bipolar disorder, manic episodes, hypomanic episodes, or mixed episodes 
• 
Prior or current diagnosis of a psychotic disorder  
• 
Current use of benzodiazepines or anti-epileptic drugs 
• 
Prior brain surgery 
• 
Any brain devices/implants, including cochlear implants and aneurysm clips or other factors that are 
contraindicated for undergoing an MRI 
• 
Non-English speakers 
• 
Pregnancy, nursing, or if female and fertile, unwilling to use appropriate birth control measures during 
study participation 
• 
Concurrent medical condition or treatment for a medical disorder that, in the opinion of the investigator, 
could confound interpretation of results or affect the patient’s ability to fully participate in the study. 
• 
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 
 
 
5.3 LIFESTYLE CONSIDERATIONS 
Benzodiazepine use will be prohibited during this study, unless used as needed. If participants are 
prescribed benzodiazepines as needed (PRN), they will be requested not to use benzodiazepines within 
48 hours of a study session.  
 
 

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5.4 SCREEN FAILURES 
In the design of this study, all participants will be screened by a clinician (Dr. Sheikh) who will determine 
eligibility based on diagnosis of SLE. However, this process does not necessarily account for all exclusion 
criteria. 
  
In the case that a participant enrolls to participate in the trial, but does not meet criteria, the study 
coordinator completing the screening process will clearly explain why the participant does not meet 
criteria. However, in the case that a participant does not qualify based on suicide risk, procedures 
outlined below must be followed to ensure participant safety. 
  
After obtaining participant informed consent, the HDRS will be administered, which contains a question 
related to suicidal thoughts/actions. If someone answers greater than 2 (i.e., either "suicidal ideas or 
gesture" or "attempts at suicide"), their participation in the study will be immediately stopped and Dr. 
Schiller (Co-I, responsible for participant safety) will be contacted for acute assessment. In the case that 
they do not see anyone for their depression, Dr. Schiller will assist the participant in seeking medical 
care.  
 
This may include facilitating contact with the subject’s psychiatrist/primary care physician in order to 
establish a plan for safety, continued care, and follow-up. If the patient does not have an established 
provider, Dr. Schiller will assist the patient in establishing care. If at any point in the assessment, the 
patient is deemed to be an imminent risk of harm to self or others, study personnel will enlist the aid of 
campus security to ensure that the patient is safely escorted to the Emergency Department for further 
care. 
 
Dr. Lee will review sMRIs for incidental findings of malignancy prior to randomization and tACS 
stimulation. In cases of incidental findings, the patient will be disqualified from the study and the study 
team will follow Dr. Lee’s recommendations regarding facilitating contact with appropriate providers for 
medical care. If a patient has received a clinical or research MRI in the 3 months before screening and 
had been found to have no evidence of malignancy, then they would not need to undergo an MRI for 
this study given there has been no change in clinical status or symptoms during that time. 
 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
This clinical trial will utilize multiple recruitment strategies in order to communicate this opportunity to 
as many potential participants as possible, including posting ads in the local newspapers, including the 
Independent Weekly (free). In addition to newspapers we will have postings on websites such as 
ClinicalTrials.gov. We will have contact information and a brief summary of the clinical trial posted on 
the Carolina Center for Neurostimulation website, Thurston Arthritis Research Center Website, and on 
the Frohlich Lab Twitter page.  These strategies will assist in recruiting patients. Finally, in addition to 

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these recruitment strategies, we will have information about our study with study coordinator contact 
information on Join the Conquest, ClinicalTrials.gov. Interested individuals need simply to read the 
information about the study and contact the study coordinator to complete the phone screening.  
 
Furthermore, Dr. Saira Sheikh, principal investigator, is an expert in SLE and will be able to identify 
potential candidates and provide materials for those interested in enrolling among the patients seen at 
the UNC Rheumatology Specialty Clinic. 
 
Our retention strategy includes a payment schedule of four times per participant. The participant will 
receive payment at the initial session, Days 1 through 5 of stimulation, both follow up sessions, and the 
final 3-month follow up. The research staff will also give each participant a reminder call for the initial 
session, the MRI visit, the first day of stimulation, and each follow up session. Each research staff 
member will be easily available for the participants to contact via email or phone. 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. However we will not require the same researcher to be present during stimulation sessions 
2 through 4.  The study team will work hard at forming rapport with the participant so 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). 
  
As this study requires several days of participation in a row, we will allow participants to miss one 
stimulation session, as long as it is made up at the end of the stimulation week. If two consecutive 
stimulation sessions are missed, the participant will be withdrawn from participation. This schedule 
would permit the participant to still receive the full intervention (5 days of stimulation) without being 
withdrawn from the study due to unforeseen circumstances (e.g., inclement weather, car trouble). In 
addition, follow-up sessions will be permitted to be scheduled ± 3 days to account for possible 
scheduling problems; this would permit the two-week follow-up to occur 11-17 days after completion of 
the intervention and the four-week follow-up to occur 25-31 days after completion of the intervention. 
 
 

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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
  
We will be using the XCSITE100 stimulator designed by PulvinarNeuro 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. While the Neuroconn device is 
commercially available, it cannot be preprogrammed for 10Hz-tACS, cannot be monitored remotely, and 
is not designed for tACS clinical trials. This makes the use of the Neuroconn device not appropriate for 
this study. 
  
The XSCITE100 stimulator may apply 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. tACS may be applied 
for currents between 100 μA and 2 mA (peak-to-peak for tACS). For the purposes of this study, this 
device will be set to deliver either sham stimulation, alpha-tACS, or theta-tACS. 
  
The XCSITE100 device runs on a single 9V rechargeable battery. The device itself is run through a device 
on a tablet. For more instructions, please see attached instruction manual. 
  
The stimulator has two main components: 
1. Android tablet with user interface application (i.e., App) 
2. Stimulator with:  
1. Microprocessor 
2. Function generator chip 
3. Voltage controlled current source 
4. Safety circuitry 
6.1.2 DOSING AND ADMINISTRATION 
  
The research team will first measure each participant's head using the 10-20 system to determine the 
electrode locations.  Participants will then be fitted with the 3 electrodes for stimulation: two 5x5cm 

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electrodes placed over F3 and F4, and one 5x7cm electrode placed on Cz. Electrodes will be carbon 
rubber, with Ten20 conductive paste applied. During stimulation, the participant will be in a relaxed and 
experimentally-controlled state by watching a nature movie (such as Reefscapes). One session of 
stimulation will be performed per patient per day, for 40 minutes. Before and after the stimulation on 
Day 1 and Day 5 of stimulation, an eyes open resting state EEG will be performed. 
  
Participants will be randomly assigned to one of three arms; active sham stimulation, individualized 
alpha-tACS (usually 8-12Hz), or individualized theta-tACS (alpha frequency minus 4 Hz). Active sham 
stimulation will include 20 seconds of ramp-in to 40 seconds of 10 Hz tACS with a ramp out of 20 
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.  Alpha- tACS and theta-
tACS will have a 20 second ramp-in and ramp-out with 40 minutes of stimulation for a total of 2440 
seconds of stimulation. Stimulation waveform is a sine-wave with a zero-to-peak amplitude of 1 mA. In 
each arm, participants will stay in a relaxed and yet controlled state by watching a nature movie such as 
“Reefscape” during stimulation. 
  
Stimulation devices will be preprogrammed and codes will be randomized to one of the two 
experimental arms. Researchers will enter the participant-specific code into the Asus tablet that controls 
the XCSITE100 device and will monitor participants during the 40 minutes of the 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 an adverse events questionnaire will be administered after each stimulation 
session. 
  
Adverse Effects Questionnaire: 
  
Transcranial Current Stimulation Questionnaire 
_____________________________________________________________________________________ 
Did you experience any of the following? Please circle the appropriate number for each (1-4). In the last 
column, indicate how related the symptom is to transcranial current stimulation 
1 = no relation; 2 = remote; 3 = possible; 4 = probable; 5 = definite 
  
  
Absent 
Mild 
Moderate 
Severe 
Related to Stimulation? 
Headache: 
1 
2 
3 
4 
  
Neck pain: 
1 
2 
3 
4 
  
Scalp pain: 
1 
2 
3 
4 
  
Tingling: 
1 
2 
3 
4 
  
Itching: 
1 
2 
3 
4 
  
Ringing/Buzzing Noise: 
1 
2 
3 
4 
  
Burning sensation: 
1 
2 
3 
4 
  
Local redness: 
1 
2 
3 
4 
  

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Sleepiness: 
1 
2 
3 
4 
  
Trouble concentrating: 
1 
2 
3 
4 
  
Improved mood: 
1 
2 
3 
4 
  
Worsening of mood: 
1 
2 
3 
4 
  
Dizziness: 
1 
2 
3 
4 
  
Flickering lights: 
1 
2 
3 
4 
  
Other (specify): 
1 
2 
3 
4 
  
 
 
6.2 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
6.2.1 RANDOMIZATION 
  
Angel Huang will randomize 72 6-digit codes which will be used by the study coordinator and research 
assistants.  These codes are directly linked to which treatment participants receive (sham/placebo, 
individualized alpha-tACS at 1 mA, or theta-tACS at 1 mA) and will be entered into the XCSITE tablet. The 
assignment of each participant cannot be determined by looking at the codes (e.g., codes are not 
sequential, code assignment is not based on “odd” or “even” numbers). Angel Huang has no other 
responsibility in the study other than providing these randomized codes. In the case that Angel Huang 
leaves the Frohlich Lab, another equivalent researcher who does not work with human participants will 
perform this task.  
 
In case of attrition, previously used codes will be used for newly randomized participants. If a participant 
withdraws, is withdrawn, or is lost to follow up, the codes will be reassigned. 
  
6.2.2 BLINDING 
  
This study is designed to be double-blind. This means that the participant and the researchers do not 
know of each participant's assignment until the completion of all data collection. This is accomplished by 
the use of the randomization codes described above. 
  
Furthermore, this study utilizes an active sham stimulation. This means that the sham/placebo condition 
includes some stimulation, mimicking the skin sensations associated with tACS. In our previously 
concluded trial (Alexander et al., 2019), participants in the sham and 10 Hz tACS groups responded 
similarly to the blinding questionnaire, indicating that our active sham stimulation successfully blinded 
the participants. 
 

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Additionally, during the initial data analysis phase, Dr. Frohlich will be blinded to whether data and 
results are from sham vs active treatment in compliance with the UNC School of Medicine Conflict of 
Interest Committee proposed financial conflict of interest management plan. 
 
 
6.3 STUDY INTERVENTION COMPLIANCE 
Full compliance with the intervention is defined as completing all 5 daily stimulation sessions for 40 
minutes each day. As the intervention is applied and monitored by the study coordinator(s) and 
research assistants, compliance can be directly observed. 
 
 
6.4 CONCOMITANT THERAPY 
Eligible participants will be permitted to be receiving concomitant therapy. The only medications not 
permitted during this trial are anticonvulsants and benzodiazepines. While the use of antidepressants, 
anti-inflammatories, or other therapies may improve the symptoms of SLE during the course of this 
study, we anticipate that this bias will be reduced by two factors: (1) prior to entry to the study, all 
participants will be required to be on stable SLE and psychiatric related medications (i.e., no change in 
administration or dose) for at least 4 weeks, and (2) the design of this study includes a control 
stimulation (placebo/sham). Both of these design choices will reduce the potential outside influence of 
concomitant therapies.  
  
To ensure that concomitant therapies are logged appropriately, participants will be requested to report 
any changes to the researchers. Furthermore, concomitant therapies will be logged at the Initial Session, 
Day 1 of stimulation (baseline), day 5 of stimulation, and at both follow-up visits. Participants will be 
requested to include the dosing for these therapies (i.e., how often per day, how much in each pill, how 
many pills) as well as when they were first prescribed the medication. 
 
 

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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from the week of stimulation does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol.  If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, the 
investigator or qualified designee will determine if any change in participant management is needed. 
Any new clinically relevant finding will be reported as an adverse event (AE). 
  
The study intervention (i.e., the 5 consecutive days of stimulation) will be discontinued for the following 
reasons: 
• 
A participant develops increased suicidal risk, as determined by an acute assessment by Dr. Schiller. 
• 
A participant has a YMRS score greater than to 12. 
• 
The participant misses two consecutive days of stimulation. 
• 
The participant misses a single day of stimulation and is unable to make it up at the end of the stimulation 
week. 
• 
Any clinical adverse event (AE), laboratory abnormality, intercurrent illness or other medical condition, or 
situation occurs such that continued participation in the study would not be in the best interest of the 
participant. 
• 
The participant meets any exclusion criteria (either newly developed or not previously recognized). 
• 
A participant wishes to withdraw from further participation for any reason. 
If the participant withdraws from the intervention, he/she will be followed through the 4 week follow-
up with the designated clinical assessments to ensure participant safety: 
• 
HDRS 
• 
YMRS 
• 
Suicide Questionnaire 
Additional measures may be continued if deemed appropriate (e.g., EEG, cognitive tasks, Comparative 
Pain Scale, Pain Catastrophizing Scale). 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A study participant will be discontinued from further participation if: 

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• 
Any clinical adverse event (AE), serious adverse event (SAE), laboratory abnormality, intercurrent illness 
or other medical condition, or situation occurs such that continued participation in the study would not 
be in the best interest of the participant. 
• 
The participant meets any exclusion criteria (either newly developed or not previously recognized). 
• 
A participant wishes to withdraw from further participation for any reason. 
The reason for participant discontinuation or withdrawal from the study will be recorded with the 
participant files. Participants who sign the informed consent form and are not randomized will be 
replaced. Participants who sign the informed consent form, and are randomized and receive the full 
study intervention (5 consecutive days of 40 minutes of stimulation), and subsequently withdraw or are 
withdrawn or discontinue from the study will not be replaced. However, participants who sign the 
informed consent form, and are randomized and receive only part of the study intervention, and 
subsequently withdraw or are withdrawn or discontinue from the study will be replaced. 
 
 
7.3 LOST TO FOLLOW-UP 
All efforts will be made to ensure participants are not lost to follow-up, including developing rapport 
and ensuring enrolled participants are reminded of their session dates. To ensure that participants 
attend both follow-up sessions, study coordinators and research assistants will be flexible in timing, 
including offering sessions later in the day as well as some weekends. 
  
Every effort will be made to contact participants who are lost to follow-up, including contacting via 
email and phone. However, if a participant is lost to follow-up, the missed sessions will be labeled as 
missing data and our pre-determined analysis plan takes into consideration missing data. 
 
 
7.4 SUSPENSION OR TERMINATION OF STUDY 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
2 SAEs for up to 10 participants or 20% SAE if more than 10 (see SAE stopping rules below) 
• 
6 TEAEs for up to 10 participants or 40% TEAE if more than 10 (see TEAE stopping rules below) 
 

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If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
research staff, study participants, the DSMB and the IRB and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed. 
 
7.4.1 SERIOUS ADVERSE EVENT (SAE) STOPPING RULES 
 
In the event of 2 SAEs (if enrollment is less than 10 subjects), possibly or definitely associated with the 
study intervention, the study will be suspended and the DSMB will be notified. If enrollment is more 
than 10 subjects, in the event of the equivalent SAEs to 20% of study enrollment, possibly or definitely 
associated with the study intervention, the study will be suspended and the DSMB will be notified.  
 
7.4.2 TREATMENT EMERGENT ADVERSE EVENT (TEAE) STOPPING RULES 
 
The use of tACS is known to have transient, mild to moderate AEs, including phosphene perception, 
dizziness, skin sensation, mild headache, vertigo, pressure perception, and back pain and neck stiffness. 
 
For the purposes of this study, a treatment-emergent adverse event (TEAE) is defined as a new event 
that occurs during or after first dose of study treatment that persists for 14 days or more (ie: event 
occurs during stimulation week and continues to persist at 2 week follow up) and is determined to be 
related to the study intervention. 
  
The study will be suspended and the DSMB will be notified for TEAEs possibly or definitely related to 
intervention: 
• 
in the event of 6 TEAEs (for enrollment up to 10 subjects);   
• 
in the event of the equivalent TEAEs to 40% of study enrollment, if enrollment is more than 10 
subjects 
 
 

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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
Inclusion and exclusion criteria will be determined at the initial session, including concomitant therapies, 
medical history, and diagnosis, to ensure that participants are diagnosed with SLE, with low suicide risk, 
and free of benzodiazepines and anticonvulsant medications. 
8.1.1 PHYSIOLOGICAL CHANGES 
1.  Resting state EEG (RSEEG) recordings will be completed at several times during the course of the study. 
On Day 1 and Day 5 of the intervention week, participants will complete an eyes open RSEEG immediately 
before and after the 40 minutes of stimulation. This measure is used to determine the immediate after-
effects of tACS on brain activity, specifically on alpha oscillation power, as well as provide a before-
stimulation RSEEG on these dates to compare the baseline (Day 1) to the final day of stimulation. RSEEG 
will also be recorded at both follow-up visits, to determine the outlasting effects of stimulation, if any. An 
eyes closed RSEEG will also be collected on Day 1, Day 5, and at both follow-up visits. 
2. Sustained attention task will be performed with EEG recorded. The simple reaction time task requires 
participants to initiate a trial by pressing a button and then when prompted push a different button. In 
the five-choice serial reaction time task, the task is identical except that the participant is prompted to 
push one of five different buttons. This task measures sustained attention during the delay period of the 
task between task initiation and the probe appearing. 
3. Selective attention task will be performed with EEG recorded. In this task, participants are instructed to 
orient attention to either the left or right visual field, or to both. Then, two low contrast Gabor wavelet 
stimuli are displayed on the screen in the left and right visual field. Each Gabor wavelet is oriented to the 
left or right. Finally, participants are probed as to the orientation (left or right) of the Gabor wavelet in 
one visual field. The attention cue to the left or right visual field is 80% predictive of which stimuli will be 
texted by the probe. Selective attention is the ability to improve performance with a predictive cue 
relative to an informative cue or an incongruent cue. 
4. Working memory EEG task will be completed prior to stimulation on Day 1 and Day 5 of stimulation, as 
well as at both follow-up visits. In the working memory task (WM), participants must encode the color and 
spatial location of centrally presented squares. After a delay period with a centrally presented fixation 
cross, a colored square is displayed at a spatial location and participants must determine if this probe 
stimuli matches the encoded stimuli. By varying the number of stimuli that must be encoded, we will drive 
WM capacity demands that have been previous demonstrated to evoke a systematic increase in frontal 
theta oscillations (Jensen & Tesche, 2002) This is to assess if there are any changes in cognition from the 
intervention. 
8.1.2 PAIN EVALUATIONS 
1. The Pain Catastrophizing Scale will be assessed at baseline on Day 1 of stimulation and the 3 month 
follow-up. This is a questionnaire to assess self-reported pain.  

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2. The Comparative Pain Scale Chart will be administered at baseline, Day 1 through Day 5 of stimulation,  
both follow-up visits, and the 3 month follow up. This is a visual scale to assess self-reported pain.  
 
To protect our participants during COVID-19, the assessments listed above are offered to be completed using the 
remote REDCap survey function (PCS and PSC). 
8.1.3 CLINICAL EVALUATIONS 
1. The Mini International Neuropsychiatric Interview (MINI) is a diagnostic assessment that will be 
administered at the initial session to determine any psychological comorbidities.  
2. The Hamilton Depression Rating Scale 17-item (HDRS17) (Leentjens, Verhey, Lousberg, Spitsbergen, & 
Wilmink, 2000; Williams, 2001)  will be administered during the initial session, day 1 of stimulation 
(baseline), day 5 of stimulation and at both follow-up visits. This scale is used to monitor the severity of 
the participant’s depression symptoms, as well as determine suicide risk.  
3. The Hamilton Anxiety Rating Scale (HAM-A) will be administered at baseline, day 5 of stimulation, and at 
both follow-up visits. This scale will be used to measure any changes in (possible) comorbid anxiety.  
4. The Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at the screening session, 
baseline, day 5 of stimulation, and at both follow-up visits. The C-SSRS is the gold-standard for assessing 
suicide risk and will be used, alongside self-report measures, to determine if a patient is at risk of suicide.  
To protect our participants during COVID-19, some of the assessments listed above are offered to be 
collected remotely over the phone or through a UNC approved video platform. These assessments include 
MINI , HDRS17, HAM-A, and C-SSRS.  
 
8.1.4 PHYSICIAN ASSESSMENTS OF SLE DISEASE ACTIVITY 
1. The 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria for the classification of SLE is 
used to diagnose lupus based on a weighted scoring system for assessments in the following areas: acute 
and chronic cutaneous lupus, alopecia, mucosal ulcers, arthritis, serositis, renal, neurologic, hemolytic 
anemia, thrombocytopenia, leukopenia or lymphopenia, as well as immunologic criteria including ANA, 

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low complement, Direct Coombs’ test, and immunologic disorders as indicated by Anti-dsDNA, Anti-Sm, 
and Antiphospolipid tests. A participant is eligible if 4 of 17 criteria, including at least one clinical criterion 
and one immunologic criterion OR biopsy-proven lupus nephritis alone are present. The 1997 America 
College of Rheumatology (ACR) criteria for the classification of SLE is used to diagnose lupus based on a 
weighted scoring system for assessments in the following areas: malar rash, discoid rash, photosensitivity, 
mucosal ulcers, arthritis, serositis, renal disorders, neurologic disorders, hematologic disorders, abnormal 
ANA, and immunologic disorders. A participant is eligible if 4 of 11 criteria are present. These will be 
conducted at screening to verify patient eligibility. The patient only has to meet the threshold of the SLICC 
criteria OR the ACR criteria to be considered eligible for this study. 
2. The Systemic Lupus International Collaborating Clinics (SLICC) SLE Damage Index assesses lupus related 
damage on a weighted scoring system for assessments in the following areas: ocular, neuropsychiatric, 
renal, pulmonary, cardiovascular, peripheral vascular, gastrointestinal, musculoskeletal, skin, gonadal, 
endocrine, and malignancy. Damage is defined as nonreversible change, not related to active 
inflammation, occurring since the onset of lupus as ascertained by clinical assessment and present for at 
least 6 months unless otherwise stated. Repeat episodes must occur at least 6 months apart to score 2. 
The same lesions cannot be scored twice. This assessment will be completed by a trained investigator at 
screening and the 4 week follow-up. 
3. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) will be completed by a trained 
Investigator at screening and at the 4 week follow-up. If the 4 week follow-up visit occurs within 30 days 
of the screening visit, then a SLEDAI-2k will not be completed at the 4 week follow-up. This questionnaire 
requires a complete history, physical exam, and lab tests, to measure disease activity in SLE patients. It 
has 24 items covering 9 organ systems. Scores can range from 0-105 points. A score of 6 is considered 
clinically important and affects decision to treat.  
To protect our participants during COVID-19, some of the assessments listed above are offered to be 
collected remotely using UNC REDCap database and verified with the study PI during the physical exam. 
These assessments include the SLICC and SLICC SLE damage index.  
8.1.5 SELF-REPORT ASSESSMENTS 
1. The 36-Item Short Form Health Survey (SF-36) measures general health using 36 questions. There are 8 
individual health “domains” or categories that each receive their own score, and from these 8 individual 
scores an overall score can be obtained. Overall scores can range from 0-100, with higher scores 
indicating better overall health.  
2. The WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) will be administered at baseline and the 3-
month follow up to assess any comorbid disability, which could potentially affect quality of life and/or 
response to stimulation. 
3. The Inventory of Depression and Anxiety Symptoms (IDAS) will be administered at baseline, Day 5 of 
stimulation, and at both follow-up visits to assess current levels of anxiety and depression. 
4. The Positive and Negative Affect Schedule (PANAS) will be administered at every single study session to 
assess current levels of affect.  

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5. A blinding questionnaire will be administered on Day 5 of stimulation (Yes or No) to determine if the 
participant felt that they had received stimulation. Similarly, the study coordinator will also complete a 
blinding assessment at this point (Yes or No with a free-response space to explain why) to determine if 
the study coordinator believed the participant received stimulation. 
  
To protect our participants during COVID-19, some of the assessments listed above are offered to be collected 
remotely using UNC REDCap database. Those assessments include: SF-36, WHODAS 2.0, IDAS, PANAS, and day 5 
blinding questionnaire.  
8.2 SAFETY AND OTHER ASSESSMENTS 
8.2.1 SAFETY 
1. A suicide questionnaire previously used in IRBs #14-0600 and #14-1622 will be used at each session of this 
study. This questionnaire tracks suicidal ideation and behavior. Participants will be asked to answer 
whether they have had any thoughts of hurting themselves within the past 24 hours (suicidal ideation, SI) 
and whether they have hurt themselves within the past 24 hours (suicidal behavior, SB). If a participant 
admits to experiencing either SI or SB their participation will be stopped immediately and their primary 
mental health care provider or family physician will be contacted.  In the case that they do not see anyone 
for their depressive symptoms, Dr. Schiller will assist the participant in seeking medical care  
2. The structural MRI to be used for source localization during EEG analysis will be conducted prior to 
randomization. The results of the T1 weighted sMRI will be reviewed by Dr. Yueh Lee for incidental 
findings of malignancy. If any are found, the study team will disqualify patient from study participation 
and will facilitate contact with providers for medical care per Dr. Lee’s recommendations. Patients will 
complete the provided MRI screening form provided by the Biological Research Imaging Center (BRIC) 
prior to the sMRI screening visit. 
3. A stimulation adverse effects questionnaire 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. This 
questionnaire has been used in all our previous tACS studies. 
4. The Young Mania Rating Scale (YMRS) (Young, Biggs, Ziegler, & Meyer, 1978)was designed to assess the 
severity of manic symptoms at baseline, with the ability to reassess the individual’s symptoms over time. 
When undergoing treatment that may affect depression symptoms, a possible effect of treatment is to 
alter the serotonin levels, potentially causing a manic episode. Although we do not expect such an event 
to occur since we are not using a medication that targets serotonin levels, we will be conducting this 
assessment at each evaluation as a precautionary measure. In the case a participant develops any sign of 
mania (YMRS > 12), Dr. Schiller will conduct an acute assessment to determine if the participant is 
experiencing mania. In the case that a participant develops mania during the week of stimulation, their 
participation in the study will be stopped and their primary mental health care provider or family 
physician will be contacted. In the case that they do not see anyone for their depression, Dr. Schiller will 
assist the participant in seeking medical care.  

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5. Urine pregnancy tests will be conducted for all female participants of reproductive age at screening and 
prior to stimulation on the day 1/baseline session, a negative result will be verified and documented OR a 
positive result will be documented and the patient will be withdrawn from the study. 
To protect our participants during COVID-19, some of the assessments listed above are offered to be collected 
remotely over the phone or through a UNC approved video platform. These assessments include the YMRS.  
 
8.2.2 COGNITION 
1. A battery of cognitive assessments, designed to assess the cognitive deficits common in lupus, will be 
administered at baseline (day 1 of stimulation), day 5 of stimulation, and at both follow-up visits. This 
battery will be used to assess any changes in cognition following the intervention and will also be used to 
determine if tACS has any negative effect on cognitive abilities. 
8.2.3 LABORATORY ASSESSMENTS 
• 
**At the initial session, blood samples will be taken. These will be used to complete hematology 
(complete blood count, or CBC, with differential; includes white blood count, hemoglobin, hematocrit, 
and platelet count, which are used to score the SLEDAI 2000 assessment), as well as to assess levels of 
anti-dsDNA (measures levels of antibodies of double-stranded DNA, which is a diagnostic assessment of 
SLE) and measures of inflammation (C-reactive protein or CSR, and a complement C3/C4 panel). This same 
blood testing will be completed at the 4-week follow-up as well. 
• 
**On day 1 of stimulation and at the 4-week follow-up, participants will provide a urine sample. 
Urinalysis, including protein/creatinine ratio and a pregnancy test (urine pregnancy lab or dipstick 
reading) will be assessed with this urine sample. This is for a basic assessment of overall health and is also 
used for the SLEDAI 2000 assessment. 
**These specific assessments are imperative for completing the SLEDAI 2000. These laboratory assessments are 
valid for 28 days prior to the visit, so if any of these laboratories were obtained as part of routine clinical care in 
the preceding 28 days, they could be used to calculate the SLEDAI 2000. In clinical use, they are obtained every 3 
months. 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
  
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
  

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An adverse event (AE) or suspected adverse reaction is considered "serious" if it results in any of the 
following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. An SAE is define as an adverse event of grade 3 or 
higher as determined by the U.S. Department of Health and Human Services’ Common Terminology 
Criteria for Adverse Events (CTCAE Version 5.0 Published: November 27th, 2017). 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
  
All AEs will be graded for severity using the following guidelines. 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the term 
“severe” does not necessarily equate to “serious”. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
  
All adverse events (AEs) must have their relationship to study intervention assessed by the principal 
investigator and co-investigator who examines and evaluates the participant based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be graded using 
the categories below. In a clinical trial, the study product must always be suspect. 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to study intervention administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. The clinical event, including an abnormal laboratory test result, occurs within a reasonable time 
after administration of the study intervention, is unlikely to be attributed to concurrent disease or other 

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drugs or chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred 
within a reasonable time after administration of the trial medication). However, other factors may have 
contributed to the event (e.g., the participant’s clinical condition, other concomitant events). Although an 
AE may rate only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to study intervention administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the study intervention) and in which other 
drugs or chemicals or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, definitive 
etiology documented by the clinician. 
8.3.3.3 EXPECTEDNESS 
  
The principal investigators (Dr. Saira Sheikh, expert in SLE and Dr. Flavio Frohlich, expert in non-invasive 
brain stimulation) will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
  
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits or the study participant may report AE or SAEs outside of a 
scheduled study visit. 
  
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
  
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. 
  

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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
  
The study coordinator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the 3-month follow 
up (end of study participation).  At each study visit, the study coordinator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution or stabilization. 
8.3.5 ADVERSE EVENT REPORTING 
  
We will be adopting the following table for reporting procedures: 
  
What Event is Reported 
When is Event Reported 
By Whom is Event 
Reported 
To Whom is Event 
Reported 
Fatal or life-threatening 
unexpected, suspected 
serious adverse reactions 
Within 24 hours of initial 
receipt of information 
Investigator 
• 
Local/internal IRBs, 
DSMB 
      
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 7 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, 
 
  
8.3.6 REPORTING OF PREGNANCY 
  
Pregnancy tests will be administered at the initial screening session as well as before treatment on the 
first stimulation visit 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 Co-I.  
Following withdrawal, the patient will be followed through the 4 week follow-up with the designated 
clinical assessments to ensure participant safety: HDRS, YMRS, Suicide Questionnaire. Additional 
measures may be continued if deemed appropriate (e.g., EEG, cognitive tasks, Comparative Pain Scale, 
Pain Catastrophizing Scale) 

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8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
  
The Office for Human Research Protections considers unanticipated problems involving risks to 
participants 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 participant population being studied; 
• 
Related or possibly related to participation in the research 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
  
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.  
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
  
Any new information gained during the study that may affect a participant's willingness to continue 
participating will be reported to all currently enrolled participants. 
 
 

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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
9.1.1 PRIMARY EFFICACY HYPOTHESIS  
  
Null hypothesis: There is no difference in changes of alpha frequency power between baseline (Day 1) 
RSEEG and RSEEG at completion of stimulation (Day 5) between treatment regimens. 
  
Alternate hypothesis: There is a difference in changes of alpha frequency power between baseline (Day 
1) RSEEG and RSEEG at completion of stimulation (Day 5) between treatment regimens. 
  
9.1.2 SECONDARY EFFICACY HYPOTHESIS 
  
Null hypothesis: There is no relationship between the changes in alpha frequency power and the 
changes in depression (using the IDAS and HDRS), pain (using the comparative pain scale and pain 
catastrophizing scale), and cognition (using the sustained attention task, selective attention task, 
working memory task, and FSMC). 
  
Alternate hypothesis: There is a relationship between the changes in alpha frequency power and the 
changes in depression (using the IDAS and HDRS), pain (using the comparative pain scale and pain 
catastrophizing scale), or cognition (using the sustained attention task, selective attention task, and 
working memory task, and FSMC). 
 
 
9.2 SAMPLE SIZE RATIONALE 
At this point in time, no clinical trial has been completed using tACS to treat SLE. However, the Carolina 
Center for Neurostimulation has run several trials similar to this, including a clinical trial assessing the 
use of tACS to treat depression over the course of a 5-day, 40-minute stimulation paradigm (Alexander 
et al., 2019).  
 
This study is a critically necessary preliminary step in this line of research. The most important aspects of 
the study are its exploratory analyses, its provision of point- and interval-estimates of parameters of 
interest, and the logistical feasibility and tolerability information it will provide.  The levels of precision 
of the estimators of interest are important; e.g., based on a previous tACS intervention study (Alexander 
et al., 2019)with a mean alpha oscillatory difference of ~2 and SD≈1.2 and alpha set at .05, we anticipate 
N=20 per group will provide more than 80% power. The effect size was based off the difference between 
active tACS and sham stimulation. This study will also provide an initial indication of whether it is 
plausible that tACS may have beneficial effects for the target lupus population. Based on the anticipated 

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precision of estimators, power levels of test procedures, availability of research subjects, and stage of 
this line of research, we believe the study is likely to achieve its specific aims; i.e., there is low risk the 
study will be uninformative/inconclusive. 
 
 
9.3 POPULATIONS FOR ANALYSES 
Every effort will be made to ensure all enrolled and randomized participants complete all study sessions 
as described in this protocol. However, a priori, we determine that our population for analysis will be a 
per-protocol analysis dataset, indicating that only those who complete the intervention (i.e., the 5 days 
of stimulation) will be included in the analysis. For this study, enrolled eligible participants will be 
randomized to receive 5 consecutive days of stimulation. If a participant completes the intervention 
(i.e., receives all 5 consecutive days of stimulation), they will be included in all analyses moving forward.  
 
Reasons for missing data (e.g., missing follow-up sessions) and reasons for participant withdrawal will be 
documented within the master list. 
  
As stated previously in Section 7 Study Intervention Discontinuation and Participant 
Discontinuation/Withdrawal, enrolled participants who do not complete the full intervention will not be 
included in this analysis. Therefore, with this population for analysis plan, we anticipate having data 
from at least 45 participants that are eligible for analysis. 
 
 
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
  
All testing described below assumes a significance threshold of p = 0.05. All hypothesis tests that are 
observed to not be statistically significant will be reported as being inconclusive. Continuous data will be 
described using means and standard deviations, while categorical data will be described using 
counts/percentages. All statistical estimates of population parameters will be tabulated along with their 
corresponding confidence intervals (CIs). 
  
Sensitivity analyses will be used to evaluate the robustness of the main results to reasonable 
perturbations of the statistical models and assumptions used.  
 
Dr. Flavio Frohlich will be responsible for statistical computations for data analyses. During the initial 
data analysis phase, Dr. Frohlich will be blinded to whether data and results are from sham vs active 
treatment in compliance with the UNC School of Medicine Conflict of Interest Committee proposed 
financial conflict of interest management plan. 
 

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9.4.2 ANALYSIS OF THE PRIMARY EFFICACY OUTCOME MEASURE(S) 
  
We will perform spectral analysis of resting state EEG from day 1 of stimulation (baseline) to day 5 of 
stimulation. We will use a general linear mixed-effects model (GLMM) to assess if there is statistically 
significant interaction between treatment (sham/placebo, theta-tACS and alpha-tACS) and session 
(baseline/Day 1 of stimulation, day 5 of stimulation, 2-week follow-up, 4-week follow-up). Spectral 
analysis will be performed with multitapered estimation of the frequency spectrum followed by 
integration over the classical alpha EEG band (usually 8-12 Hz). In a separate analysis, we will perform 
spectral analysis of resting state EEG before and after each separate stimulation session. These analyses 
will be completed on the per-protocol dataset. 
 
In our previous study, which used a 5-day protocol in patients with depression (Alexander et al., 2019), 
we found that a correlation between the log-transformed baseline alpha power (dB) and the alpha 
power changes at the end of the intervention (Day 5) in all regions. We chose to use the log-transformed 
baseline alpha power as a covariate. We will use this same covariate in these analyses as well. 
  
Results from this section will be described in mean decibel (dB) change and presented using spectral 
images for visualization. 
9.4.3 ANALYSIS OF THE SECONDARY OUTCOME MEASURE(S) 
  
Using the EEG results described in 9.4.2, mean dB change from baseline will be correlated with 
normalized change in HDRS* as well as the other described measures. Correlations will be assessed 
using Pearson's r and data will be plotted against the best fit line to visualize the results. 
  
*HDRS normalization: 
[HDRS score at Visit #] - [HDRS score at baseline] 
[HDRS score at baseline] 
9.4.4 SAFETY ANALYSES 
  
Safety will be assessed with a suicide questionnaire, the Columbia-Suicide Severity Rating Scale (C-SSRS), 
an adverse effects questionnaire, and the Young Mania Rating Scale (YMRS). 
  
The suicide questionnaire is used as a screening to assess increase in suicidal ideation (SI) or suicidal 
behavior (SB). If a participant's responses indicate SI or SB, the participant will be contacted and an 
acute assessment will be completed if necessary by Dr. Schiller. Any verified increases in suicidal 
ideation will be described in counts/percentages and compared between groups using chi-square tests. 
  
The adverse effects questionnaire will be administered following every stimulation session, for a total of 
5 administrations per participant. The adverse effects questionnaire inquires about 14 possible adverse 
effects associated with electrical stimulation, rated on a scale of 1 (absent) to 4 (severe). Paired t-tests 

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with random effect "participant" will be calculated per adverse effect to determine if there are any 
differences in adverse effect severity between groups (sham/placebo, alpha-tACS, theta-tACS). Severity 
per adverse effect will be described with mean and standard deviation. 
  
The Young Mania Rating Scale (YMRS) will be used to assess any development of mania over the course 
of treatment. A YMRS score of greater than 12 indicates the possible development of a manic episode. 
Any participant who scores greater than 12 on the YMRS will be assessed by Dr. Schiller. Any verified 
manic episode will be described in counts/percentages and compared between groups using a chi-
square test. 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
  
All baseline descriptive statistics will be described in terms of counts (where applicable) and 
means/standard deviations (where applicable). 
9.4.6 PLANNED INTERIM ANALYSES 
  
Blinded interim descriptive analyses on the safety measures (blinded adverse effects, responses to the 
suicide assessment, cognitive scores from the cognitive battery, as well as any adverse events) will be 
provided to the Data Safety and Monitoring Board (DSMB) every 6 months. 
 
Additionally, in the event of 2 SAEs (if enrollment is less than 10 subjects), possibly or definitely 
associated with the study intervention, the study will be suspended and the DSMB will be notified. If 
enrollment is more than 10 subjects, in the event of the equivalent SAEs to 20% of study enrollment, 
possibly or definitely associated with the study intervention, the study will be suspended and the DSMB 
will be notified.  
 
 If there is reason to view unblinded information, the DSMB will directly receive the list of participants’ 
identification numbers from Angel Huang. Participant identification number will be displayed in a table 
according to the three arms of the study; however, the specific treatment of each arm will not be 
disclosed. This will allow the DSMB to compare the three intervention groups. 
  
There are no other planned interim analyses. 
9.4.7 SUB-GROUP ANALYSES 
  
Sub-group analyses will not be used in this study, as the sample size is too small to conduct analyses 
based on age, sex, race/ethnicity or other demographic characteristic(s).  
9.4.8 EXPLORATORY ANALYSES 
  
 We have previously described two exploratory outcomes: 

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1. To investigate the outlasting effects, if any, of tACS on brain activity and clinical measures. 
2. To investigate whether tACS increases cognitive control signals during cognitive tasks that probe 
sustained attention, selective attention, and working memory. 
For (1), we will follow the same analyses as described in 9.4.2 through the two follow-up visits. For (2), 
we will calculate correlations between frontal midline alpha and theta activity (as measured from EEG 
recordings) and accuracy at cognitive tasks (reaction time for attention tasks, accuracy for working 
memory task). The resulting data may be used as covariates (if deemed appropriate) or may just be used 
as preliminary data for future studies. 
 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
  
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
  
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 
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. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
  
Together, the researcher and potential participants will review the clinical trial in its entirety. 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 signed 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. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
  
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform research staff, study participants, and the IRB and will provide the reason(s) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 

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• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
  
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 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 and there is no risk of deductive disclosure. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
  
Data collected for this study will be analyzed and stored within the Carolina Center for 
Neurostimulation/Frohlich Lab. After the study is completed, the data will be fully de-identified and 
archived within a locked file cabinet within the Thurston Arthritis Research Center.  
 
Electronic files will be stored on secure UNC servers using either restricted access departmental drives 
or the REDCap database for this study. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE  
Principal Investigator 
Saira Sheikh, MD 
The University of North Carolina at Chapel Hill - 
Department of Rheumatology 
szsheikh@email.unc.edu 
(984) 974-4191 
Co-Principal Investigator 
Flavio Frohlich, PhD 
The University of North Carolina at Chapel Hill - 
Department of Psychiatry 
flavio_frohlich@med.unc.edu 
(919) 966-4584 
Co-Investigator 
Crystal Schiller, PhD 
The University of North Carolina at Chapel Hill - 
Department of Psychiatry 
crystal_schiller@med.unc.edu 
(919) 966-4810 
Co-Investigator 
Yueh Lee, MD, PhD 

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The University of North Carolina at Chapel Hill –  
Department of Radiology 
yueh_lee@med.unc.edu  
(919) 537-3730 
  
10.1.6 SAFETY OVERSIGHT 
  
Safety oversight will be under the direction of a DSMB under the direction of the NC TraCS Institute. 
Members of the DSMB will be independent from the study conduct and free of conflict of interest. The 
DSMB will review AEs every 6 months whereas the PI and/or Co-I will review AEs in real time and make 
decisions as of participant’s continuation of the clinical trial. The PI will review AEs as appropriate with 
research team and may request additional review by Co-I on a case-by-case basis. 
10.1.7 CLINICAL MONITORING 
  
The Purpose of the monitoring plan is to present the Carolina Center for Neurostimulaton's approach to 
monitoring clinical trials.  The plan facilitates compliance with good clinical practice. 
(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. 
  
10.1.7.1 THE CAROLINA CENTER FOR NEUROSTIMULATION MONITORING PLAN 
  
The latest version of the approved IRB application for this clinical trial will be followed at all times. This 
responsibility falls in 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. Deviations will be sent to IRB every 4-6 weeks (if necessary). 
  
Data will be verified for completeness following every study session and all data will be entered into 
REDCap, a secure online database. After a participant has completed his/her participation (full 
completion through the 3-month follow-up visit or because he/she withdrew prior to completion), data 
will be re-reviewed for completeness and accuracy. After all data have been collected, data will be re-
reviewed by another study coordinator or research assistant who was not involved with the data 
collection process. 

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AE and SAE are clearly defined in the Master Protocol.  Documents of AE and SAE can be found in the 
study binder on file within Medical School Wing C, Room 233.  It is responsibility of the study 
coordinator to report all events to the PI. Reporting of AEs and SAEs is described within Section 8.3. 
  
The PIs and Co-I will have read-only access to the REDCap database.  This allows the PIs and Co-I to view 
reports that provide information on any missing data on an individual participant basis, but does not 
allow them to add, change or input any data. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
  
The Carolina Center for Neurostimulation will conduct internal quality management of study conduct, 
data and biological specimen collection, documentation and completion. Following written Standard 
Operating Procedures (SOPs), the study coordinators and research assistants will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on Harmonisation 
Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory 
Practices (GLP), Good Manufacturing Practices (GMP)). 
10.1.9 DATA HANDLING AND RECORD KEEPING 
  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
  
The study coordinator and research assistants will be responsible for the informed consent process, 
review for eligibility, questionnaire administration, data entry, device administration, EEG 
administration, and CRF entries. 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.  
  
REDCap will serve as a secure data management tool for this study. 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. The study 
coordinator and research assistants will have complete access to the REDCap system, while the PIs and 
Co-I will have read only ability. This will enable the researchers to enter the data and the PIs and Co-I to 
review. 
10.1.9.2 STUDY RECORDS RETENTION 
  

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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.  
10.1.10 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. 
10.1.11 PUBLICATION AND DATA SHARING POLICY 
  
This study will be registered on ClinicalTrials.gov once IRB approved. The aim is to publish the results of 
this study in a peer-reviewed, highly-ranked journal.  
 
The raw data will be preserved and available upon request after any publication submission or public 
presentation. 
10.1.12 CONFLICT OF INTEREST POLICY 
  
The independence of this study from any actual or perceived influence is critical. Any conflict of interest 
for any persons who have a role in the design, conduct, analysis, publication or any aspect of this trial 
will be disclosed and managed by the UNC Conflict of Interest Office. If necessary, for persons who have 
a perceived conflict of interest, management will be provided again by the UNC Conflict of Interest 
office.  
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
 
10.3 ABBREVIATIONS 
AE 
Adverse Event 
ACR 
American College of Rheumatology  
ANA 
Antinuclear antibody test 
ANOVA 
Analysis of Variance  
Anti-dsDNA 
Anti-double stranded DNA 

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CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CONSORT 
Consolidated Standards of Reporting Trials 
COC 
Certificate of Confidentiality 
CRP 
C-reactive protein 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual, 5th Edition 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
EEG 
Electroencephalogram 
ENA 
Extractable Nuclear Antigen Antibodies 
FSMC 
Fatigue Scale for Motor and Cognitive Functions 
GCP 
Good Clinical Practice 
HAM-A 
Hamilton Anxiety Rating Scale 
HDRS 
Hamilton Depression Rating Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IDAS 
Inventory of Depression and Anxiety Symptoms 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
MINI  
Mini International Neuropsychiatric Interview  
MRI 
Magnetic Resonance Imaging 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PCS 
Pain Catastrophizing Scale 
PI 
Principal Investigator 
PNAS 
Positive and Negative Affect Schedule 
QA 
Quality Assurance 
QC 
Quality Control 
RSEEG 
Resting state EEG 
SAE 
Serious Adverse Event 
SF-36 
36-Item Short Form Health Survey 
SLE 
Systemic Lupus erythematosus  
SLEDAI-2K 
Systemic Lupus Erythematosus Disease Activity Index 2000 
SLICC 
Systemic Lupus International Collaborating Clinics 

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sMRI 
Structural Magnetic Resonance Imaging 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
tACS 
Transcranial alternating current stimulation 
TEAE 
Treatment Emergent Adverse Event 
UP 
Unanticipated Problem 
US 
United States 
WHODAS 
WHO Disability Assessment Schedule 
YMRS 
Young Mania Rating Scale 
 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
 1.1 
 5/30/19 
 Addition of Dr. Yueh Lee as Co-
investigator 
 Dr. Lee, a neuroradiologist, will 
review MRI scans and handle 
incidental findings as needed.  
 1.2 
 7/25/19 
 Clarifying sMRI timing and safety 
review process 
 
 
Updating urine pregnancy test 
timing per UNC IRB stipulation 
 
Updating data blinding procedures 
and data sharing policy per UNC 
SOM COI Committee FCOI 
management plan for Dr. Frohlich 
 
Adjusted CANTAB to be 
computerized for EEG recording 
 Bringing protocol in compliance 
with UNC IRB stipulations and COI 
Committee management plan 
 
Editing for clarity and typos 
 
 
Leverages additional scientific value 
from the dataset 
 1.3 
9/4/19 
Updating personnel 
responsibilities 
 
Updating urine pregnancy test 
timing 
 
Updating study layout 
 
Adding cheek swab for bartonella 
testing  
 
Remove NAMI from recruitment 
 
Remove pressure pain threshold 
Adding Pain Catastrophizing Scale 
 
Replacing FSS with FSMC 
 
 
 
Replacing STAI with IDAS 
 
 
 
Removed SLAQ, PROMIS, and ESR 
Charles Zhou has left the lab, his 
responsibilities have been given to 
Angel Huang.  
 
 
 
 
 
 
 
 
 
 
 
 
 
FSMC is a more comprehensive 
measure for self-reporting of 
cognitive fog. 
 
The IDAS is a better measure to 
assess the change in depression and 
anxiety symptoms over time. 
 
These assessments were not 
necessary for evaluating objectives. 

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 1.4 
 11/14/19 
 clarifying inclusion criteria and 
discontinuation criteria for YRMS, 
a score of greater than (>) 12 is 
considered a manic episode and is 
sufficient for screen-failure or 
discontinuation. 
clarifying secondary objective, the 
SF-36 will be evaluated at 
screening and 4 week follow-up, 
all other measures will be 
evaluated at baseline to Day 5 as 
previously approved. 
 Clarifying protocol 
1.5  
11/25/19 
Removing blood draws to test for 
Bartonella 
We have removed Bartonella as an 
exploratory outcome – thus, the 
data is not needed 
1.6 
01/24/2020 
 Correcting HDRS17 language in 
study assessments and procedures 
to match eligibility criteria.  
Providing clarification for 
discrepancies 
1.7 
2/28/2022 
Clarification of sMRI imaging  
Updated and specified study 
suspension/termination rules for 
probably or definitely related AEs 
Added DSMB to adverse event 
reporting for Fatal or life 
threatening unexpected, 
suspected serious adverse 
reactions  
Added optional remote 
completion for consent through 
REDCap, patient self-report 
questionnaires, and clinical 
psychological assessments through 
the REDCap database and 
phone/UNC approved video 
platform 
 
Clarification  
 
Per DSMB request 
description and 
 
 
Per DSMB request 
 
 
 
 
 
Protection of high-risk patients 
during COVID-19 and to be continue 
throughout the remainder of the 
study 
 
 
 

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11 REFERENCES 
Ahn, S., Prim, J. H., Alexander, M. L., McCulloch, K. L., & Frohlich, F. (2019). Identifying and Engaging 
Neuronal Oscillations by Transcranial Alternating Current Stimulation in Patients With Chronic 
Low Back Pain: A Randomized, Crossover, Double-Blind, Sham-Controlled Pilot Study. J Pain, 
20(3), 277 e271-277 e211. doi:10.1016/j.jpain.2018.09.004 
Alexander, M. L., Alagapan, S., Lugo, C. E., Mellin, J. M., Lustenberger, C., Rubinow, D. R., & Frohlich, F. 
(2019). Double-blind, randomized pilot clinical trial targeting alpha oscillations with transcranial 
alternating current stimulation (tACS) for the treatment of major depressive disorder (MDD). 
Transl Psychiatry, 9(1), 106. doi:10.1038/s41398-019-0439-0 
Arendsen, L. J., Hugh-Jones, S., & Lloyd, D. M. (2018). Transcranial Alternating Current Stimulation at 
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