Closed-Loop Transcranial Alternating Current Stimulation for the Treatment of Depression (CLACS): Single-Site Open-Label Pilot Study
Phase: NA
Conditions: Depression, Major Depressive Disorder, tACS
Sponsor: Electromedical Products International, Inc.

CLOSED-LOOP TRANSCRANIAL ALTERNATING CURRENT STIMULATION FOR 
THE TREATMENT OF DEPRESSION (CLACS): SINGLE-SITE OPEN-LABEL 
PILOT STUDY 
Protocol Number: 22-3094 
NCT: 05772702 
Principal Investigator: David Rubinow, MD 
Co-Investigator and Biostatistician: Flavio Frohlich, PhD 
Co-Investigator: Crystal Schiller, PhD 
Co-Investigator: Tobias Schwippel, MD 
 
Funded by: Electromedical Products International 
 
16 February 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
 
Summary of Changes from Previous Version: 
 
Protocol Date 
Summary of Revisions Made 
30Jan2023 
Original protocol 
05Jun2023 
Addition of self-scoring surveys up to 12-week post treatment follow-up; 
Addition of EEG at Day 1/ Baseline and at the 2-week post treatment follow-up 
28Nov2023 
2-week post treatment follow up visit must be done in person (no remote option) 
21Dec2023 
Enrollment increase from 20 to 35 participants 
16Feb2024 
Addition of HDRS-17 assessment at the 6-week post treatment follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
1. STATEMENT OF COMPLIANCE​
5 
2. PROTOCOL SUMMARY​
6 
2.1 Schedule Of Activities (SOA)​
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2.2 Synopsis​
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3. INTRODUCTION​
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3.1 Study Rationale​
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3.2 Background​
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3.3 Risk/Benefit Assessment​
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4. OBJECTIVES AND OUTCOME MEASURES​
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5. STUDY DESIGN​
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5.1 Overall Design​
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5.2 Scientific Rationale for Study Design​
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5.3 Justification for Dose​
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5.4 End of Study Definition​
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6. STUDY POPULATION​
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6.1 Inclusion Criteria​
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6.2 Exclusion Criteria​
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6.3 Lifestyle Considerations​
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6.4 Screen Failures​
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6.5 Strategies for Recruitment and Retention​
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7. STUDY INTERVENTION​
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7.1 Study Intervention(s) Administration​
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7.2 Measures to Minimize Bias: Randomization and Blinding​
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7.3 Study Intervention Compliance​
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7.4 Concomitant Therapy​
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8. STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL​
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8.1 Discontinuation of Study Intervention​
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8.2 Participant Discontinuation/Withdrawal from the Study​
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8.3 Lost to Follow-Up​
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9. STUDY ASSESSMENTS AND PROCEDURES​
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9.1 Efficacy Assessments​
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9.2 Safety and Other Assessments​
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9.3  Adverse Events and Serious Adverse Events​
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9.4  Unanticipated Problems​
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10. STATISTICAL CONSIDERATIONS​
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10.1 Statistical Hypotheses​
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10.2 Sample Size Determination​
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10.3 Populations for Analyses​
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10.4 Statistical Analyses​
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11. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS​
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11.1 Regulatory, Ethical, and Study Oversight Considerations​
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11.2 Abbreviations​
33 
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12. REFERENCES​
35 
 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
1.​
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)  
 
All members of the study team have completed Human Participants 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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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
2.​
PROTOCOL SUMMARY 
2.1​
SCHEDULE OF ACTIVITIES (SOA) 
Procedures 
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Waived/ Verbal 
Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Contact 
information, 
MDD diagnosis, 
exclusion/inclu
sion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication & 
psychotherapy 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
Determine 
Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Maudsley 
Staging 
Method 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
M.I.N.I. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS Triage 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
HDRS-17 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Procedures 
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(D1
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(D3
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(D4
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(D6
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(D7
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(D8
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QIDS (S) 
 
 
X 
 
 
 
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ASRM (S) 
 
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SHAPS (S) 
 
 
X 
 
 
 
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DASS-42 (S) 
 
 
X 
 
 
 
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STAI (trait) (S) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
STAI (state) (S) 
 
 
X 
 
 
 
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Q-LES-Q-SF (S) 
 
 
X 
 
 
 
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CGI 
 
 
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CLtACS 
 
 
X 
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CLtACS Side 
Effect 
Questionnaire 
 
 
X 
X 
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X 
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Likert State 
Scale (Mood) 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 (HD)-EEG 
 
 
X1 
 
 
 
 
 
X2 
 
 
 
 
 
AE Structured 
Interview 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Treatment 
Experience 
Questionnaire 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
(S) = RedCap online survey; ASRM: Altman Self-Rating Mania Scale; SHAPS: Snaith-Hamilton Pleasure Scale; DASS-42: Depression Anxiety and 
Stress Scale; QIDS: Quick Inventory of Depressive Symptomatology; STAI: State-Trait Anxiety Inventory; CGI: Clinical Global Impression Scale; 1. 
HD-EEG is performed pre-stimulation and post-stimulation; 2. Visit must be done in person for participants undergoing the EEG assessment 
 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
2.2​
SYNOPSIS 
Title: 
Closed-Loop Transcranial Alternating Current Stimulation (CLtACS) for the 
Treatment of Depression: Open-label Pilot Study 
Study Description: 
The purpose of this clinical trial is to investigate the preliminary efficacy of   
CLtACS for the treatment of major depressive disorder (MDD) in an 
open-label pilot study. We will recruit up to 35 participants with unipolar, 
non-psychotic MDD. Eligible participants will have five up to 40-minute 
stimulation sessions over five consecutive days. All participants will receive 
CLtACS at their individual peak alpha frequency. Participation will include 
13 visits, six of them remotely (with an in-person option as needed), and 
one electronic survey. Potential participants fill-in an electronic 
pre-screening form. If preliminarily eligible, a remote screening visit is 
performed. If eligible, participants attend five consecutive, daily 
stimulation sessions. Clinical assessments will be performed at Baseline/ 
day 1 of stimulation (D1), day 5 of stimulation (D5), at follow-up visit 2 
(FU2)/ 2 weeks after completion of stimulation (D19), and at follow-up 4 
(FU4)/ 6 weeks after completion of stimulation (D47) using the Hamilton 
Depression Rating Scale (HDRS-17). 7 Self-scoring surveys will be sent after 
completion of stimulation (FU1, FU2, FU3/ 4 weeks after completion of 
stimulation, FU4, FU5/ 8 weeks after completion of stimulation, FU6/ 10 
weeks after completion of stimulation, FU7/ 12 weeks after completion of 
stimulation) until 12 weeks after completion of stimulation (D89). 
Eyes-open and eyes-closed resting state recordings will be collected before 
and after CLtACS on D1 and during the FU2 visit to measure changes in 
alpha oscillations. 
Objectives: 
 
Primary Objective: To investigate the preliminary efficacy in reducing 
depression symptom severity by CLtACS in people with MDD over the 
course of a 5-day, 40-minute stimulation protocol. 
Secondary Objective: To investigate the preliminary efficacy in terms of 
response and remission rates. To investigate the neurophysiological effects 
of CLtACS on brain activity by means of HD-EEG. 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Endpoints: 
Primary Endpoint:  
Change in HDRS-17 between two-week follow-up (FU2) and Day 1 (D1). 
Secondary Endpoints:  
●​ Change in HDRS-17 between D5 and Baseline/D1. 
●​ Response and remission rates of depression at D5, FU2 
●​ Change in Quick Inventory of Depressive Symptomatology (QIDS) 
at D5, FU1, FU2 
●​ Change in Altman Self-Rating Mania Scale (ASRM) at D5, FU1, FU2 
●​ Change in Snaith-Hamilton Pleasure Scale (SHAPS) at D5, FU1, FU2 
●​ Change in Depression Anxiety and Stress Scale (DASS-42) at D5, 
FU1, FU2 
●​ Change in State-Train Anxiety Inventory (STAI) at D5, FU1, FU2 
●​ Change in Quality-of-Life Enjoyment and Satisfaction 
Questionnaire, short form (Q-LES-Q-SF) at D5, FU1, FU2 
●​ Change in Clinical Global Impression Scale (CGI) at D5 and FU2 
Exploratory Endpoints: 
●​ Feasibility - fraction of participants who complete the 5-day 
course of stimulation 
●​ Change in HD-EEG alpha oscillation power at D1 pre-stimulation, 
D1 post-stimulation, and FU2  
●​ Change in Quick Inventory of Depressive Symptomatology 
(QUIDS) at FU3, FU4, FU5, FU6, FU7 
●​ Change in Altman Self-Rating Mania Scale (ASRM) at FU3, FU4, 
FU5, FU6, and FU7 
●​ Change in Depression Anxiety and Stress Scale (DASS-42) at FU3, 
FU4, FU5, FU6, and FU7 
●​ Change in State-Train Anxiety Inventory (STAI) at FU3, FU4, FU5, 
FU6, and FU7 
●​ Change in Snaith-Hamilton Pleasure Scale (SHAPS) FU3, FU4, FU5, 
FU6, and FU7 
●​ Change Quality of Life Enjoyment and Satisfaction Questionnaire, 
short form (Q-LES-Q-SF) at FU3, FU4, FU5, FU6, and FU7 
●​ Change in HDRS-17 between FU4 and D1 
Study Population: 
We will recruit up to 35 participants (age 18 and older) with a diagnosis of 
unipolar, non-psychotic MDD. Eligible participants will have a HDRS-17 > 8 
and low suicide risk (no active intent as determined by the Columbia 
Suicide Severity Rating Scale, C-SSRS, triage form). Participants will be 
recruited from the 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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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
Description of Study 
Intervention: 
We will use the XCSITE100Pro stimulator designed by Pulvinar Neuro for 
investigational purposes to deliver closed-loop transcranial alternating 
current stimulation (CLtACS). Stimulation waveforms are sine-waves with a 
zero-to-peak amplitude of 2mA delivered to F3 and F4 with a return 
electrode at Cz. Participants will stay in a relaxed yet experimentally 
controlled state by watching a nature movie such as “Reefscape'' during 
stimulation. 
Study Duration: 
12 months 
Participant Duration: 
Participation for each participant will last no longer than 13 weeks total. 
We estimate total participation time to be approximately 13 hours. 
 
3.​
INTRODUCTION 
 
3.1​
STUDY RATIONALE  
 
Major depressive disorder (MDD) is a common, often severe psychiatric illness that affects 6.7% of adults 
every year in the United States [1]. MDD is characterized by depressed mood, loss of interest or pleasure 
in activities that used to be enjoyable (anhedonia), sleep disturbances, cognitive impairment, and other 
symptoms that can severely affect quality of life. Current recommended pharmacological treatments are 
not effective for all people with MDD and can result in undesirable side effects. Prominently, the STAR*D 
trial demonstrated that a large percentage of patients are treatment-resistant, and that remission is less 
likely following multiple drug trials [2]. More effective and safer therapies for the treatment of MDD are 
desperately needed.    
   
3.2​
BACKGROUND  
  
MDD has been associated with hypoactivity in the left dorsolateral prefrontal cortex [3], characterized by 
elevated alpha oscillations [4]. Therefore, targeting and reducing alpha oscillations in the left dorsolateral 
prefrontal cortex could prove beneficial to patients with MDD. Targeted stimulation modalities, such as 
transcranial alternating current stimulation (tACS), can directly engage and modulate oscillatory activity. 
tACS utilizes sine-wave stimulation waveforms that can enhance specific oscillatory activity [5].       
Preclinical and computational studies have contributed to a growing understanding of the mechanism of 
action of tACS [7].  At the center of successful target engagement is the modulation of neuronal network 
oscillations by carefully tuned stimulation waveforms that match the endogenous dynamics. Given the 
low amplitude of the electric field delivered to the brain, modulation of oscillations requires synergistic 
interaction between the rhythmic stimulation waveform and endogenous brain rhythms [8]. Closed-loop 
stimulation allows the adjustment of the stimulation to the fluctuations in individual brain network 
activity patterns and thus is poised to enhance the efficacy in terms of modulating the targeted 
oscillation. Briefly, closed-loop stimulation combines periodic measurement of brain activity patterns 
with EEG and stimulation that is tuned based on the dynamic properties of the measured brain activity. 
Measurement and stimulation are interleaved due to the electric artefacts caused by stimulation. This 
approach has been pioneered by the Frohlich Lab and was demonstrated to successfully modulate 
another, transient thalamo-cortical activity pattern, sleep spindles and associated memory consolidation 
[9]. Closed-loop stimulation is thus expected to ultimately increase efficacy through improved targeting 
[10], [11]. Alternative strategies would include increasing the cumulative dose of the stimulation, which 
would be more burdensome for the participants (longer and or more sessions). Given the promising 
clinical results of the previous 5-day paradigm, increasing the cumulative dose is not a priority. In 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
addition, stimulation could be combined with other therapeutic interventions such as therapy. Examining 
such synergistic effects are outside the scope of this study. 
This current study aims to improve efficacy by delivering targeted, individualized stimulation based on 
closed-loop tACS for which the stimulation waveform is adjusted based on interleaved EEG 
measurements.       
 
3.3​
RISK/BENEFIT ASSESSMENT   
 
3.3.1 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 clinical 
population recruited for this study may be subjected to negative consequences caused by the stigma of 
mental disorders. 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, or stored in pass-word protected 
spreadsheets only accessible to study personnel. All data is stored in locked cabinets inside locked 
offices; electronic data will be stored only on password-protected computers. Interviews will be 
conducted over the HIPAA approved Zoom account at UNC. Only study personnel will have access to the 
data. All study staff participate in annual human participant training that includes education about 
responsibilities to the minimize risk of confidentiality breach. 
 
Risk of Embarrassment: Self-report assessments contain questions regarding sensitive personal 
information, which may lead to emotions of embarrassment. This risk is necessary in order to assess 
mood symptoms and associated psychopathology. Participants will be assured upon intake that only 
study personnel will see any clinical ratings and that self-identifying information will not be collected 
alongside HIPAA protected 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 [12]. 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 [13]. However, tACS 
does have some mild side effects, such as transient mild tingling, burning, or itching under the electrode 
sites.     [6]. To monitor these mild side effects, we will be administering a stimulation questionnaire after 
each stimulation session to determine whether these effects were experienced and at what intensity. 
Research personnel are present during the full experiment.  
 
Patients with MDD have an about 20 times higher rate of suicide than average. We have no evidence 
that our treatment paradigms will in any way increase this likelihood. Rather, active engagement in a 
clinical trial may offer hope and structure to the participants. Regardless, participants with high suicide 
risk (intent or plan) will not be included in this study. If an enrolled participant shows signs of suicide 
risks that were not apparent during enrollment, a referral to UNC Psychiatry will be made. Dr. Schiller, 
Co-I, will facilitate this process. 
 
We will be using the Columbia Suicide Severity Rating Scale (C-SSRS, triage form) [14] to determine 
intent for suicide during D1. Inclusion criteria state that the participant must be low suicide risk and that 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
potential participants with an above “low risk” designation will not be eligible for the study. In the event 
that suicide risk increases during participation in the study, the participant will be asked to stop the 
study. The participant will be provided with a referral to UNC Department of Psychiatry, and their mental 
health care or family medical doctor will be contacted. 
 
3.3.2 KNOWN POTENTIAL BENEFITS  
 
This study has not been designed to benefit the individual participants.       
 
3.3.3 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 MDD, the potential 
risks are worth the potential benefits. Furthermore, this is an open-label study that does not require 
considerations about the risks associated with a placebo group. We also note that the FDA has recently 
confirmed a non-significant risk (NSR) status for a very similar tACS trial in MDD. 
 
4.​
OBJECTIVES AND OUTCOME MEASURES 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To determine the effect of 
CLtACS on depression symptom 
severity 
 
Change in HDRS-17 between 
two-week follow-up (FU2) and 
Day 1 (D1) 
The HDRS-17 is the standard 
clinician-administered 
instrument to measure change 
in symptom severity in people 
with MDD 
Secondary 
 
 
To determine the effect of 
CLtACS on depression symptom 
severity 
 
Change in HDRS-17 between D5 
and Baseline/ D1 
The HDRS-17 is the standard 
clinician-administered 
instrument to measure change 
in symptom severity in people 
with MDD. 
To determine the remission and 
response rate of CLtACS  
 
Response is defined as >= 50% 
reduction rate in HDRS-17 score 
relative to D1 
 
Remission is defined as 
HDRS-17 < 8 
Number of response/remission 
rates at D5 and FU2   
Remission and response rates 
provide additional insights into 
the efficacy of a treatment. 
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NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
To determine time-course of 
symptom change 
Change in Quick Inventory of 
Depressive Symptomatology 
(QIDS) at D5, FU1, FU2 
Battery of self-report measures 
of mood and related constructs 
at the 7-day follow up (digitally 
delivered) provide additional 
insights into the symptom 
changes in between the 
clinician administered 
assessment on Day 5 and at 
FU2. 
Change in Altman Self-Rating 
Mania Scale (ASRM) at D5, FU1, 
FU2 
Change in Snaith-Hamilton 
Pleasure Scale (SHAPS) at D5, 
FU1, FU2 
Change in Depression Anxiety 
and Stress Scale (DASS-42) at 
D5, FU1, FU2 
Change in State-Train Anxiety 
Inventory (STAI) at D5, FU1, FU2 
Change in Quality of Life 
Enjoyment and Satisfaction 
Questionnaire, short form 
(Q-LES-Q-SF) at D5, FU1, FU2 
Change in Clinical Global 
Impression Scale (CGI) at D5, 
FU2 
Exploratory 
 
 
Feasibility 
Fraction of participants who 
complete the 5-day course of 
stimulation 
Since the primary outcome is 
determined from the subgroup 
of people who have completed 
stimulation, 
examining 
the 
fraction 
of 
people 
who 
complete 
the 
stimulation 
paradigm 
is 
important 
to 
minimize bias in case of people 
discontinuing 
study 
participation due to lack of 
perceived efficacy or symptoms 
worsening. 
To determine the effect of 
CLtACS on endogenous EEG 
alpha oscillations 
Change in HD-EEG alpha 
oscillation power at D1 
pre-stimulation, D1 
post-stimulation, and FU2 
The inclusion of EEG endpoints     
provides insights into the 
network-level mechanisms 
underlying the treatment 
effects. 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
To determine time-course of 
symptom change 
 
Change in Quick Inventory of 
Depressive Symptomatology 
(QUIDS) at FU3, FU4, FU5, FU6, 
FU7 
Battery of self-report measures 
of mood and related constructs 
provide additional insights into 
the symptom changes in 
between the clinician 
administered assessment on 
D5, FU2, and FU4. 
 
Time-scale of symptom change 
will provide useful information 
for the design of future, 
large-scale treatment studies. 
 
Change in Altman Self-Rating 
Mania Scale (ASRM) at FU3, 
FU4, FU5, FU6, and FU7 
Change in Depression Anxiety 
and Stress Scale (DASS-42) at 
FU3, FU4, FU5, FU6, and FU7 
Change in State-Train Anxiety 
Inventory (STAI) at FU3, FU4, 
FU5, FU6, and FU7 
Change in Snaith-Hamilton 
Pleasure Scale (SHAPS) FU3, 
FU4, FU5, FU6, and FU7 
Change Quality of Life 
Enjoyment and Satisfaction 
Questionnaire, short form 
(Q-LES-Q-SF) at FU3, FU4, FU5, 
FU6, and FU7 
      
To determine the effect of 
CLtACS on depression symptom 
severity 
Change in HDRS-17 between six 
week follow up (FU4) and D1 
The HDRS-17 is the standard 
clinician-administered 
instrument to measure change 
in symptom severity in people 
with MDD. 
 
5.​
STUDY DESIGN  
 
5.1​
OVERALL DESIGN 
 
The design for this study is a pilot, open-label clinical trial which will be used to investigate the 
preliminary efficacy of closed-loop alpha-tACS for the treatment of depression. We are recruiting from a 
clinical population. Participants will be up to 35 people ages 18-70 with unipolar, non-psychotic MDD, 
who have a HDRS-17 > 8 and are at a low risk for suicide according to the Columbia Suicide Severity 
Rating Scale (C-SSRS). Nursing and 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 or may not seek or receive concurrent 
mental health care from a family practitioner, therapist, or psychiatrist. 
 
This is a single-site, pilot clinical trial with a single arm. We will use the XCSITE100Pro stimulator 
designed by Pulvinar Neuro for investigational purposes to deliver closed-loop stimulation over five 
consecutive days. Participants will stay in a relaxed yet experimentally controlled state by watching a 
nature movie such as “Reefscape” during stimulation. The initial session (D1) and D5 will take 
approximately 2 hours. D2-D4 will take 1 hour. The 2-week (FU2) and 6-week (FU4) follow-up will take 
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approximately 1 hour. Completion of patient-administered surveys at FU1 to FU7 will take about 30 
minutes to complete. We estimate that total participation to be approximately 13 hours. 
 
5.2​
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
  
This study is an open-label pilot interventional study. Given the novelty of the treatment and the 
absence of data to estimate effect sizes, an initial open-label trial is warranted.  
 
5.3​
JUSTIFICATION FOR DOSE 
 
We are utilizing the same dosage as given in a similar pilot study: 5 consecutive days of up to 40-minutes 
of stimulation [6].       
5.4​
END OF STUDY DEFINITION 
 
The end of this study is defined as when the last participant completes the final study visit (i.e., the last 
participant completes the FU7 study visit). 
 
6.​
STUDY POPULATION 
 
6.1​
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
•​
Ages 18-70 years 
•​
DSM-V diagnosis of MDD; unipolar, non-psychotic 
•​
Hamilton Rating Depression Rating Scale (HRDS-17) score >8 
•​
Low suicide risk as determined by the C-SSRS triage form (no intent or plan) 
•​
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
6.2​
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
•​
DSM-5 diagnosis of severe alcohol use disorder (AUD) within the last 12 months 
•​
DSM-5 diagnosis of moderate to severe substance use disorder (excluding tobacco) within the 
last 12 months  
•​
Lifetime history of bipolar disorder, psychotic disorder, schizophrenia, autism  
•​
Current use of benzodiazepines > 20mg diazepam/d equivalent 
•​
Antidepressant dose change within the last 2 weeks  
•​
Initiated new antidepressant within the last 4 weeks 
•​
Initiated psychotherapy within the last 4 weeks 
•​
Initiated other form of non-medication, non-neurostimulation treatment within the last 4 weeks 
•​
Currently or history (3 months) of receiving TMS, ketamine, esketamine, or ECT. 
•​
Previously failed to respond to ECT or TMS 
•​
History of seizure (excluding febrile seizures in childhood or ECT induced seizures) 
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•​
Neurological disorders that would increase risk of participation or present a significant 
confounder in the opinion of the investigator (for example, dementia, history of stroke, 
Parkinson's disease, multiple sclerosis, history of traumatic brain injury with prolonged loss of 
consciousness, ruptured cerebral aneurysm, previous CNS radiation ) 
•​
Unstable medical disorder in the eye of the study physician 
•​
Prior brain surgery and/or brain implants 
•​
Current pregnancy or breastfeeding 
•​
Unwillingness to use appropriate birth control if sexually active 
•​
Currently enrolled in another clinical trial for depression 
•​
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 
6.3​
LIFESTYLE CONSIDERATIONS 
  
People of child-bearing potential who are sexually active are asked to use an appropriate method of 
birth control. 
 
6.4​
SCREEN FAILURES 
 
In the case that a participant does not qualify based on suicide risk, established procedures in the 
Carolina Center for Neurostimulation will be followed to ensure participant safety. 
 
6.5​
STRATEGIES FOR RECRUITMENT AND RETENTION 
This clinical trial will utilize multiple recruitment strategies to communicate this opportunity to as many 
potential participants as possible. First means is through a referral process. Participants can be referred 
to the study through their primary mental health care provider or family doctor during routine visits. This 
type of recruitment will take place in doctors’ offices throughout Chapel Hill, Carrboro, Durham and 
Raleigh areas. Clinicians will be informed of inclusion criteria through email and listserv announcements 
and be asked to mention this clinical trial to appropriate patients and offer them a flyer/ brochure with 
contact information. We will also be using the UNC i2b2 to send request forms to the Carolina Data 
Warehouse to recruit participants who have been seen at UNC Hospitals that meet the inclusion 
criteria. 1 
In addition to referrals through primary care providers, we will advertise the study directly to the public 
on 
websites 
such 
as 
ClinicalTrials.gov, 
Research 
For 
Me, 
frohlichlab.org 
and 
Carolinaneurostimulation.org. We will have contact information and a summary of the clinical trial 
posted on the Frohlich Lab Facebook and Twitter pages. Will we also be launching a Facebook or 
Instagram advertisement to identify potential patients. We will also use radio spots, newspaper ads, 
billboards, and in-person recruitment as needed. We will also be using the UNC Mass email and 
department listserv to send out an email that has the link to the survey. All patient identifiers will be 
stored in REDCap until recruitment is over. When recruitment is over, all patients who do not consent or 
are not eligible for participation in the study will have their responses permanently deleted in REDCap. 
1 
 
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We will send unencrypted emails to facilitate the initial contact to potential participants. Medical 
information is never requested per email. All medical information is recorded through HIPAA conform 
Zoom meetings and RedCap surveys.  
Our retention strategy includes a payment schedule of three times per participant. The participant will 
receive payment in the form of a Visa Card at D1 ($100). This card will be charged again on D5 ($100), 
and the final follow-up session ($100). Thus, completion of the study will result in a financial 
compensation of $300. 
  
Research personnel 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, if 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).  
 
7.​
STUDY INTERVENTION 
 
7.1​
STUDY INTERVENTION(S) ADMINISTRATION 
 
7.1.1 STUDY INTERVENTION DESCRIPTION 
 
We will be using the XCSITE100Pro stimulator designed by Pulvinar Neuro. The device is not implanted 
and has not been designed for or 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 alternating current stimulation 
(tACS).  
 
Previous studies in the Frohlich lab that used the XCSITE 100 and comparable devices (i.e., the 
commercial, CE-certified Neuroconn Plus stimulator) have 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 
pre-programmed for closed-loop, and is not designed for tACS clinical trials. This makes the use of the 
Neuroconn device not appropriate for this study. The XCSITE 100 Pro includes identical stimulation 
hardware, including the safety features listed below, as the XCSITE 100. 
 
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The XSCITE100Pro 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 8 mA (peak-to-peak for tACS). For the purposes of this study, 
this device will be set to deliver closed-loop tACS in the alpha frequency with a peak amplitude of 2 mA. 
For more instructions, please see the submitted instruction manual. 
 
The stimulator includes the following safety features: 
 
Current Sensor Circuit. A 33.2 Ω sense resistor is placed in series with the stimulation electrodes on the 
high side. Since high-side current sensing is used, any short circuit of the electrode terminals to ground 
will be detected. The stimulation current flows through this resistor and creates a voltage. The voltage 
across this resistor is sensed and amplified by the AD628 difference amplifier.  
 
Voltage Sensor Circuit. The differential voltage across the electrodes is measured so that the impedance 
can be calculated. The voltage is measured by buffering the positive electrode and negative electrode 
each with a unity gain op-amp circuit. The voltage output is then shifted before it is read by the 
microprocessor using the same level shifting circuit described in the current sensor section.  
 
The device is equipped with 4 different stages of safety precautions, all of which protect the participant 
from high currents. The stages are as follows: 
1.​ Automatic software current cutoff. The output of the current sensor described above is read by a 
microprocessor, which compares the reading to a value of +4 mA peak. If the current exceeds 
these limits, stimulation is turned off. The user is then given the option to investigate the issue, 
and cancel or resume the test. Since high-side current sensing is used (described above), any 
short circuit of the electrode terminals to ground will be detected.  
2.​ Automatic hardware current cutoff. The output of the current sensor is fed into a pair of 
comparators which detect if the current exceeds + 4.5 mA. If so, the fault is latched such that the 
relay in series with the electrodes is opened. Additionally, the microprocessor is notified of this 
instance through an interrupt. Upon this interrupt, the microprocessor immediately stops 
stimulation  
3.​ Permanent hardware current cutoff. A 5 mA fast-acting fuse is in series with the electrode 
connector. If the above two over-current detection methods fail, the fuse will blow, and the 
stimulator will no longer be electrically connected to the device.  
4.​ Power supply fuse. Finally, if for any other reason the entire device draws too much current, the 
main power supply fuse is triggered. This fuse is sized with a cutoff of 200% of steady-state 
operating current. 
7.1.2 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 
electrodes placed over F3 (left frontal cortex, standard 10-20 EEG coordinated) and F4 (right frontal 
cortex), and one 5x7cm electrode placed over Cz (midline, central). 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 day, for up to 40-minutes. Before each stimulation session, a 
single-channel eyes open and eyes closed resting state EEG will be performed to individualize the 
treatment frequency. 
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The stimulation waveforms used in this study are tACS at the individual peak alpha frequency at 1 mA 
zero-to-peak amplitude both at F3 and F4, achieved via a splitter cable to distribute 2 mA between the 
two sites. Stimulation includes a ramp-in and ramp-out of 20 seconds, with a maximum of 40-minutes of 
stimulation at an amplitude of 1 mA per electrode, for a total of 2440 seconds of stimulation. 
 
Research personnel will be thoroughly trained and have training documented on the transcranial 
stimulation device and will be present during all stimulation sessions. To monitor side effects of 
stimulation a stimulation effects questionnaire will be administered after each stimulation session. At 
D5, a systematic interview for side-effect is administered. 
 
7.2​
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization 
There is no randomization since this is an open-label pilot study. 
 
Blinding 
There is no blinding since this is an open-label pilot study. 
 
7.3​
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 research personnel, compliance can 
be directly observed. 
 
7.4​
CONCOMITANT THERAPY 
  
Eligible participants will be permitted to be receiving concomitant therapy, such as psychotherapy, 
antidepressants, or other medications. However, eligibility for this trial includes a stable antidepressant 
medication dose for the past 2 weeks before the screening visits. Moreover, a new antidepressant must 
not be started during the last 4 weeks before the screening visit. Participants who are not taking 
medication for the treatment of MDD are also included. 
 
To ensure that concomitant therapies are logged appropriately, participants will be requested to report 
any changes to the researchers. Furthermore, concomitant therapies (pharmacotherapy, psychotherapy) 
will be logged at Screening, D1, D5 and follow-up visit. 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. 
  
8.​
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
  
8.1​
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 
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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. 
 
The study intervention (i.e., the 5 consecutive days of stimulation) will be discontinued for the following 
reasons: 
●​ A participant develops significantly increased suicidal risk, as determined by an acute 
assessment by Dr. Schiller or Dr. Rubinow. 
●​ A participant has an ASRM score greater than or equal to 6. 
●​ 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). 
 
If the participant withdraws from the intervention, the participant will be contacted and invited for the 
FU1 survey questionnaires and for the FU2 follow-up assessment including all respective questionnaires. 
These assessments are not intended as a clinical follow-up with the participants but serve research 
purposes only.  
 
8.2​
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time and without having to give a 
reason. If the participant is willing to give a reason for discontinuation or withdrawal from the study, it 
will be recorded with the participant files. Participants who sign the informed consent form and do not 
receive stimulation will be replaced. Participants who sign the informed consent form and receive only 
part of the study intervention OR withdraw or are withdrawn or discontinue from the study prior to the 
2-week follow-up will not be replaced. The maximum number of participants consented will be 35.  
 
8.3​
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if they fail to return for the scheduled follow-up visit 
and are unable to be contacted by the study site staff. 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 the follow-up session, research personnel 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. 
 
9.​
STUDY ASSESSMENTS AND PROCEDURES 
 
9.1​
EFFICACY ASSESSMENTS  
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Inclusion and exclusion criteria will be determined by the electronic pre-screening form and the virtual 
screening visit, including documentation of concomitant therapies, medical history, and diagnoses, to 
ensure that participants are diagnosed with MDD, and with low suicide risk. 
9.1.1​
CLINICAL EVALUATIONS 
  
1.​ The M.I.N.I is a diagnostic tool that will be used during the screening session to confirm 
diagnosis of MDD. 
2.​ The Hamilton Depression Rating Scale 17-item (HDRS17) [15] is a scale is used to determine 
eligibility and to monitor the severity of the participant’s depressive symptoms. 
3.​ The C-SSRS (triage form) is a standardized method to assess suicide risk.  
4.​ The Maudsley Staging Method is a method of measuring treatment resistance in participants 
with depression on a scale of 3 to 15 (mild = 3-6; moderate = 7-10; severe=11-15) [16]. 
5.​ The Altman Self-Rating Mania Scale (ASRM) is a method to detect symptoms of mania and 
hypomania during the study.  
9.1.2​
SELF-REPORT ASSESSMENTS 
  
1.​ The Quick Inventory of Depressive Symptomatology (QIDS) is a 16-item, self-report rating 
inventory that measures characteristic attitudes and symptoms of depression and will be used to 
monitor the severity of the patient’s depression throughout the study. 
2.​ The Quality of Life Enjoyment and Satisfaction Questionnaire, short form (Q-LES-Q-SF)[17] is a 
self-report questionnaire that assesses quality of life. 
3.​ Stimulation side-effect questionnaires are administered after every stimulation session. 
Systematic query of side effects across all major organ systems is administered at D5. 
 
9.1.3​
HIGH-DENSITY (HD) EEG 
Eyes-open and eyes-closed resting state recordings will be collected before and after CL-tACS on D1 and 
during the FU2 visit to measure changes in alpha oscillations. High-Density (HD)-EEG will be performed 
using a HydroCel Geodesic Sensor Net (128 channel) with a Net Amps 400 series amplifier (Magstim EGI, 
Eugene, OR, USA) with whole scalp coverage. 
9.2​
SAFETY AND OTHER ASSESSMENTS 
9.2.1​
SUICIDAL IDEATIONS AND SUICIDAL BEHAVIOR 
 
Only participants deemed at low suicide risk based on the C-SSRS (ideation allowed, however intent, plan 
or attempt excluded) are enrolled in this study. The C-SSRS [14] will be administered by trained research 
personnel at screening and the follow-up session to thoroughly assess suicide risk. In addition, the 
answers to suicide-related questions on the HRDS-17 and on the QIDS will be monitored. Based on these 
sources of information, clinical personnel will decide if an acute assessment is required. Acute 
assessment may include facilitating contact of the participant with their psychiatrist or primary care 
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physician to establish a plan for safety, continued care, and follow-up. If the participant does not have an 
established provider, Dr. Schiller or Dr. Rubinow will assist in establishing a care plan. If at any point 
during the assessment, the participant is deemed an imminent risk of harm to self or others, study 
personnel will enlist the aid of security at the facility or first responders to ensure that the participant is 
safely escorted to the Emergency Department for further care. Dr. Schiller and/or Dr. Rubinow will decide 
if participation should be stopped after the acute assessment. If the participant is hospitalized, their 
participation will end. 
9.2.2​
DEVELOPMENT OF MANIA 
​
The Altman Self-Rating Mania Scale (ASRM) was designed to assess the severity of manic symptoms at 
enrolment, with the ability to track changes over the duration of participation. When undergoing 
treatment for depression, a possible side effect (as inferred from clinical trials with antidepressant 
medications) is to alter levels of serotonin, potentially associated with mania [18], [19]. Although we do 
not expect such an event to occur since there are no reports of inducing mania by tACS and we are not 
using a medication that targets serotonin levels, we will be conducting this assessment as a 
precautionary measure. If a participant develops any sign of mania (ASRM > 6), Dr. Schiller or Dr. 
Rubinow will conduct an acute assessment to determine if the participant is experiencing mania. If this 
occurs during the week of stimulation, 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 mental health concerns, Dr. Schiller or Dr. Rubinow will assist in creating a medical care 
plan. 
9.2.3​
ADVERSE EVENT ASSESSMENT 
A self-report form of sensory experiences associated with stimulation and side-effects will be 
administered at D1-D5. In addition, a structured interview probing for the experience of adverse events 
will be administered at D5. Dr. Schiller or Dr. Rubinow will use the completed interview to assess the 
severity of the adverse event and its potential relationship to the study intervention.  
  
9.3​
 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
9.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether considered intervention-related (21 CFR 312.32 (a)).  
 
9.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of the 
investigator, 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.  
 
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9.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
9.3.3.1 SEVERITY OF EVENT 
 All adverse events (AEs) will be assessed by the principal investigator and/or co-investigator(s) 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”. 
 
9.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the principal 
investigator and co-investigator(s) who examines and evaluates the participant based on temporal 
relationship and their 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 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. 
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9.3.3.3 EXPECTEDNESS  
 
The principal investigator (Dr. Rubinow), with input from the co-investigator (Dr. Schiller) when 
necessary, will determine whether an adverse event (AE) is expected or unexpected in this population. 
The co-investigators (Dr. Flavio Frohlich and Dr. Tobias Schwippel) are experts in non-invasive brain 
stimulation and will provide their expert opinion regarding this as well. 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. 
9.3.4 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.  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.   
 
Research personnel will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. Events will be followed for outcome information until resolution or stabilization. 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. 
 
Of note, common experiences associated with the application of low-amplitude electric current to the 
scalp such as phosphenes and tingling sensation are captured with a daily questionnaire. These events 
are only considered AEs if they are reported as bothersome or untoward by the participant. 
 
9.3.5 ADVERSE EVENT REPORTING 
 
We will be adopting the following reporting procedures:  
 
What 
event 
is 
reported 
When 
is 
event 
reported 
By whom is event 
reported 
To whom is event 
reported 
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Fatal or life-threatening 
unexpected, suspected 
serious adverse 
reactions 
Within 24 hours of 
initial receipt of 
information 
Investigator 
●​ Local/internal 
IRB 
●​ Sponsor 
Non-fatal, 
non-life-threatening 
unexpected, suspected 
serious adverse 
reactions 
Within 48 hours of 
initial receipt of 
information 
Research Personnel 
●​ Local/internal 
IRB 
●​ Sponsor 
 
Unanticipated adverse 
device effects 
Within 10 working days 
of investigator first 
learning of effect  
Investigator 
●​ Local/internal 
IRB 
●​ Sponsor 
 
Unanticipated Problem 
that is not an SAE 
Within 7 days of the 
investigator becoming 
aware of the problem 
Investigator 
●​ Local/internal 
IRB 
●​ Sponsor 
 
  
9.3.6 REPORTING OF PREGNANCY  
 
Women of child-bearing potential are asked if they are pregnant or plan to become pregnant before the 
stimulation session. Furthermore, they are asked to use an appropriate method of birth control for the 
duration of trial participation. Importantly, there is no evidence that suggests tACS would interfere with 
pregnancy [20]. However, should a participant become pregnant during the five days of stimulation, their 
participation stimulation will be immediately terminated and the participant will be followed until giving 
birth. 
 
9.4 ​
UNANTICIPATED PROBLEMS 
 
9.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) 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 Institutional Review Board 
(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 (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
•​
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
9.4.2 UNANTICIPATED PROBLEM REPORTING  
 
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If a UE occurs, the IRB and the sponsor 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.   
 
9.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Any new information gained during the study that may affect a participant’s willingness to continue in 
the study will be reported to all currently enrolled participants. 
 
10.​
STATISTICAL CONSIDERATIONS  
 
10.1​
STATISTICAL HYPOTHESES 
 
Primary Efficacy hypothesis: 
●​ Null: There is no difference in depression severity measured by the HDRS-17 between FU2 and 
Day 1. 
●​ Alternate: There is a difference in depression severity measured by the HDRS-17 between FU2 
and Day 1. 
 
10.2​
SAMPLE SIZE DETERMINATION 
A recently concluded pilot clinical trial compared the effects of 10 Hz tACS (therapeutic frequency) 
against 40 Hz tACS (control frequency). A total of 32 participants enrolled, 30 completed the 5-day 
intervention, and 26 completed both a 2 and a 4-week follow-up session. With approximately 9 
participants in each group, a significant reduction was found in alpha oscillation power on the fifth day of 
stimulation (p < 0.05) [6], which is the presumed mechanism of action of closed-loop tACS. Therefore, 
with a total of 35 participants we anticipate we will find a significant difference. Further support for this 
sample size from this previous study derives from a Cohen’s dz = 1.58 for change in HDRS-17 score from 
baseline to the 2-week follow up. For an alpha = 0.05 (two-sided) and a power of 0.95, the required 
sample size is N=8 based on calculation by G*power 3.1.9.7. The plot below shows how power changes 
as a function of effect size for a sample size of N=10. As can be seen, the current design is well-powered 
for the expected effect size for clinical outcomes, and adequately powered (i.e. 80%) for effects as low as 
dz = 1 for any given outcome measure. 
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However, the expected effects of stimulation for secondary outcome measures at FU2 are currently 
unclear, and self-report measures tend to have more variability and thus reduced effect sizes when 
compared to clinician-administered measures like the HDRS-17. Moreover, studies looking to replicate 
prior findings are known to require larger sample sizes compared to the original study. To that end we 
conducted design sensitivity analyses. We reason that a target of N = 28 for a complete dataset allows 
for a sound evaluation of any given effect down to dz = 0.55 which is traditionally considered in 
psychological research to be a medium-sized effect for two-tailed ɑ = 0.05 at 80% power.  
 
In the previous trial, 80% of the participants completed all study sessions. We are thus anticipating 
consenting around 35 people to reach the goal of 28 people for analysis. The power calculation above 
demonstrates what statistical conclusions will be feasible with a sample size of 28 completers. 
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10.3​
POPULATIONS FOR ANALYSES 
 
Every effort will be made to ensure all enrolled participants complete all study sessions as described in 
this protocol.  
 
As 
previously 
stated 
in 
Section 
7 
Study 
Intervention 
Discontinuation 
and 
Participant 
Discontinuation/Withdrawal, enrolled participants who do not complete the full intervention will be 
replaced. Therefore, with this population for analysis plan, we anticipate having data from 35 
participants that are eligible for analysis. 
 
10.4​
STATISTICAL ANALYSES 
 
10.4.1 GENERAL APPROACH 
 
All testing described below assumes a significance threshold of alpha = 0.05. Continuous data will be 
described using means and standard deviations, while categorical data will be described using 
counts/percentages.  
 
There will be no pre-specified covariates described in this protocol. Data will be assessed for normality 
and, if deemed necessary, corrective procedures will be applied (e.g., log normalization). 
 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT (DEPRESSION SEVERITY) 
 
We will perform a paired t-test to establish the statistical significance of the change in depression 
symptom severity (two-sided, alpha = 0.05). Additional, strictly exploratory analyses will take into 
account baseline scores as covariates (e.g., degree of treatment resistance measured by the Maudsley 
scale). 
 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT (RESPONSE AND REMISSION RATE, FEASIBILITY) 
 
We will compute the response and remission rates for the sample. There is no statistical testing 
applicable for this outcome since there are no groups to compare. 
 
We will compute the fraction of participants who complete stimulation by dividing the number of people 
who received 5-days of stimulation by the total number of participants who received any amount of 
stimulation. 
 
As applicable, 95% confidence intervals will be computed to describe precision of the estimate. 
 
10.4.4 SAFETY ANALYSES 
 
As discussed in Section 8.2, Safety and Other Assessments safety will be assessed with the C-SSRS, an 
adverse effects questionnaire, and the Altman Self-Rating Mania Scale (ASRM). 
 
The C-SSRS will be used to assess suicide risk. If a participant's responses have an elevated risk, the 
participant will be contacted, and an acute assessment will be completed if deemed necessary by Dr. 
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Schiller or Dr. Rubinow (as described above). Any verified increases in suicidal ideation will be described 
in counts/percentages. The C-SSRS is administered at the screening visit and at the 14-day follow up. 
 
The stimulation questionnaire will be administered at D1-D5 after stimulation. This questionnaire solicits 
ratings of 11 possible sensory experiences (“flickering light”) and adverse effects (“scalp pain”) 
associated with electrical stimulation, on a scale of 0 (absent), 1 (low), 2(medium), and 3 (high). Intensity 
of sensory experiences and adverse effects will be described with mean and standard deviation. 
 
The Altman Self-Rating Mania Scale (ASRM) will be used to assess any development of mania over the 
course of treatment. A ASRM score of greater than 6 indicates the possible development of a manic 
episode. Any participant who scores greater than 6 on the ASRM will be assessed by Dr. Schiller or Dr. 
Rubinow. Any verified manic episode will be described in counts/percentages. 
 
The Adverse Events Structured Interview will be administered by research personnel at D5 and whenever 
a participant spontaneously reports a potential AE during trial participation. This interview solicits 
open-ended descriptions of 13 possible adverse effects a participant may experience in any clinical trial 
as well as one question of ‘any other experiences’. Responses will be reviewed by the clinician and rated 
as described in Section 8.3. Severity per adverse effect will be described with mean and standard 
deviation. 
 
10.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
All baseline descriptive statistics will be described based on the General Approach described in 9.4.1. 
 
10.4.6 PLANNED INTERIM ANALYSES  
 
There are no planned interim analyses. 
 
10.4.7 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). 
 
11.​
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
11.1​
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
11.1.1​ INFORMED CONSENT PROCESS 
 
11.1.1.1​
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. We apply for a waiver for written 
consent for our pre-screening survey and our screening visit. For the pre-screening survey, interested 
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potential participants will indicate their consent to answering the questions as part of the survey. For the 
screening visit, verbal consent by the participant will be obtained and documented. Written consent for 
study participation will be obtained at D1. All consent forms will be IRB-approved and updated with any 
new information as modifications are made throughout the study. 
 
11.1.1.2​
CONSENT PROCEDURES AND DOCUMENTATION 
 
At the beginning of D1, the researcher and potential participants will review the clinical trial in its 
entirety. At several intervals during the consent review, the researcher will ask 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 further explain the information. We will especially ensure that 
stimulation related side effects and the possibility to withdraw from the study at any given moment 
without prejudice are well understood.  
 
The rights and welfare of the participant 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. 
11.1.2​ 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 the sponsor, 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 
●​ 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, and 
satisfy the IRB and the sponsor. 
 
11.1.3​ CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the research team. This confidentiality is extended to cover the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information generated 
will be held in strict confidence. In addition, all research activities will be conducted in an as private as 
possible setting. 
 
All data will only be referenced by dummy identifier code. Data will be stored on a password protected 
computer. A key connecting names and identifier code numbers will be kept in a password-protected 
spreadsheet. 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 
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and there is no risk of deductive disclosure. At the end of the study, all records will continue to be kept in 
a secure location for as long a period as dictated by the IRB. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be entered into NCTraCS Clinical Research Data Management Service (REDCap). The database system 
provides secure web-based data entry with the data stored on servers that are maintained by NCTraCS. 
The data is encrypted during transmission. The servers are located in a secure campus area with all 
appropriate physical security measures in place. The web and database servers are monitored by the 
TraCS IT staff, patched frequently, and scanned by a third-party vendor to ensure that they are protected 
against known vulnerabilities. Access is by individual user id and is restricted to the forms and/or 
functions that the user needs to have.   
 
11.1.4​ 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 Carolina Center for Neurostimulation for the duration 
requested by applicable law. 
 
11.1.5​ KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Co-Investigator 
Co-Investigator 
Co-Investigator 
 
David Rubinow, MD 
 
Flavio Frohlich, PhD 
Crystal Schiller, PhD 
Tobias Schwippel, MD 
The 
University 
of 
North 
Carolina 
at 
Chapel 
Hill 
- 
Department 
of 
Psychiatry 
 
919-445-0212 
The 
University 
of 
North 
Carolina 
at 
Chapel 
Hill 
- 
Department 
of 
Psychiatry 
 
919-966-4584 
The 
University 
of 
North 
Carolina 
at 
Chapel 
Hill 
- 
Department 
of 
Psychiatry 
 
919-966-4810  
The University of North 
Carolina at Chapel Hill - 
Department 
of 
Psychiatry 
 
 
919-966-4584 
david_rubinow@med.
unc.edu 
Flavio_frohlich@med.
unc.edu 
crystal_schiller@med.
unc.edu 
Tobias_schwippel@med.
unc.edu 
  
11.1.6​ SAFETY OVERSIGHT 
  
Safety oversight will be under the direction of the Principal Investigator Dr. Rubinow. He will review all 
adverse events timely and serious adverse events and changes in the suicidality and mania ratings as fast 
as possible. Based on his review, continuation of participant’s participation is decided. All SAE or 
unanticipated AE will be reported to the local IRB and the sponsor.  
11.1.7​ CLINICAL MONITORING 
 
The purpose of the monitoring plan is to present the approach of the Carolina Center for 
Neurostimulation to monitoring clinical trials. The plan facilitates compliance with good clinical practice. 
 
(a) The rights and well-being of human participants are protected. 
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(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. 
 
11.1.7.1​
THE CAROLINA CENTER FOR NEUROSTIMULATION MONITORING PLAN 
 
The latest version of the approved IRB application for this clinical trial will be always followed. This 
responsibility falls in the hands of the trained research personnel.  If at any time there is a deviation from 
protocol, the deviation log will be filled out. All team members will be trained on how and when to use 
this log.  
 
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 their participation (full completion 
through the FU7 visit or because they withdrew prior to completion), data will be rereviewed for 
completeness and accuracy.  
 
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 Dawson Hall Building, 77 Villcom Center Drive, Chapel Hill. It is the 
responsibility of trained research personnel to report all events to the PI. Note that the study binder may 
assume either an electronic or paper form. Reporting of AEs and SAEs is described within Section 8.3. 
 
The PI and Co-Is (apart from Dr. Schwippel who will act as clinical rater) will have read-only access to the 
REDCap database. This allows the PI and Co-Is 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. 
  
11.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The Carolina Center for Neurostimulation will conduct internal quality management of study conduct, 
data collection, documentation, and completion. Following written Standard Operating Procedures 
(SOPs), research personnel 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)). 
 
11.1.9​ DATA HANDLING AND RECORD KEEPING  
 
11.1.9.1​
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Trained research personnel will be responsible for the informed consent process, review for eligibility, 
questionnaire administration, data entry, device administration, and CRF entries. Research personnel 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. 
 
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Clinical data (including AEs, concomitant medications, and expected adverse reactions data) will be 
entered into a data capture system provided by NCTraCS Clinical Research Data Management Service 
(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. Trained research personnel will have complete access to 
the REDCap system, while the PI and Co-I will have read-only ability. This will enable the researchers to 
enter the data and the PI and Co-I to review. 
 
As discussed in Section 10.1.3, data entered into REDCap is stored on servers that are maintained by 
TraCS. The data is encrypted during transmission. The servers are located in a secure campus area with 
all appropriate physical security measures in place. The web and database servers are monitored by the 
TraCS IT staff, patched frequently, and scanned by a third-party vendor to ensure that they are protected 
against known vulnerabilities. The scanning application is the standard service for the entire campus.  
 
11.1.9.2​
STUDY RECORDS RETENTION  
  
According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services 
schedule for General Records Retention and Disposition Schedule 6.10, records will be kept for 5 years 
after the completion of the study or end of funding, whichever is later. 
 
11.1.10​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. The site PI/study staff will be responsible for knowing and adhering to their IRB 
requirements. 
 
11.1.11​PUBLICATION AND DATA SHARING POLICY 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to 
ClinicalTrials.gov. In addition, every attempt will be made to publish results in a peer-reviewed journal. 
 
11.1.12​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. 
 
11.2​
ABBREVIATIONS 
 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
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CRF 
Case Report Form 
DSM-5 
Diagnostic and Statistical Manual, 5th Edition 
eCRF 
Electronic Case Report Forms 
EEG 
Electroencephalogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDRS 
Hamilton Depression Rating Scale 
HIPAA 
Health Insurance Portability and Accountability Act  
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
PI 
Principal Investigator 
Q-LES-Q-SF 
Quality of Life Enjoyment & Satisfaction Questionnaire, Short Form 
SAE 
Serious Adverse Event 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
 
 
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12.​
REFERENCES   
 
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[6]​
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[8]​
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[9]​
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