Targeting Auditory Hallucinations With Alternating Current Stimulation
Phase: NA
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: University of North Carolina, Chapel Hill

1 
 
TARGETING AUDITORY HALLUCINATIONS WITH 
ALTERNATING CURRENT STIMULATION 
IRB # 14-3285 
 
Funding Mechanism: National Institute of Mental Health 
Grant Number: 1R21MH105574-01 
NCT02360228 
Principal Investigator: Dr. Flavio Frohlich, PhD  
Co-Investigators: Dr. Fred Jarskog, MD, Dr. John Gilmore, MD 
Version Number: 4.0 
29 April 2015 
 
 
 
 

2 
 
 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by 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, and 21 CFR Part 312) 
● 
ICH E6; 62 Federal Register 25691 (May 9, 1997)  
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Participants Protection and HIPAA Training. 

3 
 
 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Signed: 
 
Date: 
 
 
 
 
 
 

4 
 
 
TABLE OF CONTENTS 
 
Page 
Statement of Compliance 
2 
Signature Page 
3 
Table of Contents 
4 
List of Abbreviations 
7 
Protocol Summary 
9 
1 
Key Roles 
12 
2 
Introduction: Background Information and Scientific Rationale 
14 
2.1 
Background Information 
14 
2.2 
Rationale 
14 
2.3 
Potential Risks and Benefits 
15 
2.3.1 Potential Risks 
15 
2.3.2 Known Potential Benefits 
16 
3 
Objectives 
17 
3.1 
Study Objectives 
17 
3.2 
Study Outcome Measures 
17 
3.2.1 Primary Outcome Measures 
17 
3.2.2 Secondary Outcome Measures 
17 
4 
Study Design 
18 
5 
Study Enrollment and Withdrawal 
20 
5.1 
Participant Inclusion Criteria 
20 
5.2 
Participant Exclusion Criteria 
20 
5.3 
Strategies for Recruitment and Retention 
21 
5.4 
Treatment Assignment Procedures 
22 
5.4.1 Randomization Procedures 
22 
5.4.2 Reasons for Withdrawal 
22 
5.4.3 Handling of Withdrawals 
22 
5.4.4 Termination of Study 
23 
6 
Study Intervention/Investigational Product 
24 
6.1 
Study Product Description 
24 
6.1.1 Device Description  
25 
6.1.2 Operation 
25 
6.1.3 Safety Precautions 
26 
6.2 
Preparation and Administration of Study Investigational Product 
27 
6.3 
Assessment of Participant Compliance with Study Investigational Product 
28 

5 
 
7 
Study Schedule 
29 
7.1 
Screening 
29 
7.2 
Enrollment/Baseline 
30 
7.3 
Stimulation Sessions 
32 
7.4 
Follow-up 
33 
7.5 
Final Study Visit 
33 
8 
Study Procedures/Evaluations 
34 
8.1 
Clinical Evaluations 
34 
8.2 
Laboratory Evaluations 
35 
8.2.1 Clinical Laboratory Evaluations 
35 
8.2.2 Special Assays or Procedures 
36 
9 
Assessment of Safety 
37 
9.1 
Specification of Safety Parameters 
37 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
37 
9.2.1 Adverse Events 
37 
9.2.2 Expected Adverse Reactions 
39 
9.2.3 Serious Adverse Events 
39 
9.2.4 Unanticipated Problems 
40 
9.3 
Reporting Procedures 
40 
9.3.1 Reporting of Pregnancy 
41 
9.4 
Type and Duration of Follow-up of Participants after Adverse Events 
41 
9.5 
Halting Rules 
41 
9.6 
Safety Oversight 
42 
10 
Clinical Monitoring 
43 
10.1 
Frohlich Lab Monitoring Plan 
43 
11 
Statistical Considerations 
44 
11.1 
Study Hypotheses 
44 
11.1.1 Primary Objective 
 
 
 
 
 
 
        44 
11.1.2 Secondary Objective 
 
 
 
 
 
 
        44 
11.2 
Sample Size Considerations 
45 
11.3 
Final Analysis Plan 
45 
12 
Source Documents and Access to Source Data/Documents 
46 
13 
Ethics/Protection of Human Participants 
48 
13.1 
Ethical Standard 
48 
13.2 
Institutional Review Board 
48 
13.3 
Informed Consent Process 
49 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
49 
13.5 
Participant Confidentiality 
50 

6 
 
13.6 
Study Discontinuation 
50 
14 
Data Handling and Record Keeping 
51 
14.1 
Data Management Responsibilities 
51 
14.2 
Data Capture Methods 
51 
14.3 
Types of Data 
51 
14.4 
Timing/Reports 
52 
14.5 
Study Records Retention 
52 
14.6 
Protocol Deviations 
53 
15 
Publication Policy 
54 
16 
Literature References 
55 
Supplements/Appendices 
60 
Appendix A: Schedule of Events 
 
 
 
 
 
 
 
 
60 
Appendix B: AE Report Form  
 
61 
Appendix C: AE Log  
 
63 
Appendix D: SAE Report Form 
 
64 
Appendix E: UE/SAE Log. 
 
68 
Appendix F: Consent Amendment Tracking Log 
 
69 
Appendix G: Informed Consent Process Documentation 
 
70 
Appendix H: Informed Consent Process Quiz. 
 
72 
Appendix I:  IRB Amendment Tracking Log  
 
73 
Appendix J: Delegation of Authority 
 
74 
Appendix K: Enrollment Log 
 
75 
Appendix L: Inclusion/Exclusion Criteria Checklist 
 
76 
Appendix M: Note to File  
 
77 
Appendix N: Protocol Deviation 
 
78 
Appendix O: Study Startup Checklist 
 
79 
Appendix P: Participant Off Study Form 
 
80 
Appendix Q: Telephone Log  
 
82 
Appendix R: Training Log 
 
83 
Appendix S: Telephone Recruitment Script 
 
84 
Appendix T:EEG Questionnaire 
 
86 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
ACT 
Assertive Community Treatment 
AE 
Adverse Event 
AHRS 
Auditory Hallucination Rating Scale 
AIMS 
Abnormal Involuntary Movement Scale 
ANOVA 
Analysis of Variance 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BDNF 
Brain Derived Neurotrophic Factor 
CAPA 
Corrective and Preventative Action 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression Severity Scale 
Co-I 
Co-Investigator 
CRF 
Case Report Form 
CRMS 
Clinical Research Management System 
dl-PFC 
Dorso-lateral Prefrontal Cortex 
DMV 
Department of Motor Vehicles  
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders (Version IV) 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EEG 
Electroencephalogram  
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
Hz 
Hertz 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
JAMA 
Journal of the American Medical Association 
LAR 
Legally Authorized Representative  
mA 
Milli-amps 
NCPRC 
North Carolina Psychiatric Research Center 
NIH 
National Institutes of Health 
NRB 
Neurosciences Research Building 
OHRE 
Office of Human Research Ethics 
OHRP 
Office for Human Research Protections 
PANSS 
Positive and Negative Syndrome Scale 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAS 
Simpson Angus Scale 

8 
 
SCID 
Structured Clinical Interview for DSM-IV Axis I Disorders 
SOP 
Standard Operating Procedure 
tACS 
Transcranial Alternating Current Stimulation 
tDCS 
Transcranial Direct Current Stimulation  
TMS 
Transcranial Magnetic Stimulation 
TPJ 
Temporo-parietal Junction 
UDS 
Urine Drug Screen 
UE 
Unexpected Event 
UNC 
University of North Carolina 
UNC-CH 
University of North Carolina at Chapel Hill 
US 
United States 

9 
 
 
PROTOCOL SUMMARY 
 
Title: 
Targeting Auditory Hallucinations with Alternating Current 
Stimulation 
Précis: 
 
The purpose to determine the efficacy of transcranial alternating 
current stimulation, tACS, versus sham stimulation (with tDCS 
versus sham as a positive control for assay sensitivity) for the 
treatment of medication-refractory auditory hallucinations in 
patients with schizophrenia. We will recruit 48 males and 
females diagnosed with schizophrenia or schizo-affective 
disorder.  Eligible participants will have 5, twice-daily (one 
week Monday through Friday), 20 minute stimulation sessions.  
Stimulations will be at least 3 hours apart. Participants will be 
randomly assigned to one of three groups; sham stimulation, 10 
Hz (alpha) tACS or 2 mA tDCS. Participation will involve 1 to 8 
visits. At the initial session, informed consent will be obtained 
and subjects will be screened for eligibility. Eligible participants 
will then be scheduled for their, twice-daily stimulation sessions 
which will include daily assessment of stimulation side-effects. 
Clinical assessments will be performed at baseline, 1, 2 and 4 
weeks using the Auditory Hallucinations Rating Scale 
(Attachment 3). Neurophysiological (EEG) and cognitive assays 
will be performed before and after stimulation. Please see 
Appendix A for a detailed schematic describing all visits and 
assessments. 
 
Objectives: 
 
Our primary objective is to demonstrate the value of 
synchronization and information flow measures derived from 
EEG data as novel biomarkers in the treatment of medication 
refractory auditory hallucinations in schizophrenia with 
transcranial current stimulation. To reach this objective, we will 
test the working hypothesis that (1) baseline impairment in EEG 
synchronization and information flow predicts treatment success 
and (2) changes in these markers correlate with improvement of 
clinical symptom presentation as determined by the AHRS, 
PANSS, and BACS (Attachment 12). We will test our working 
hypothesis by measuring whole-head EEG data from all patients 
in our feasibility study (48 patients from Aim 1) before and 

10 
 
immediately after the five day course of stimulation and at both 
follow-up visits. 
 
 
Population: 
We will recruit 48 males and non-pregnant females ages 18-70 
with a diagnosis of schizophrenia or schizoaffective disorder, 
who have at least 3 auditory hallucinations per week, with no 
change in medication dosing for at least 4 weeks and have been 
clinically stable for at least 12 weeks, with no change in their 
level of care during that period.  Participants will be recruited 
from the Chapel Hill, Durham and Raleigh areas. 
Phase: 
Pilot Study 
Number of Sites: 
This is a single site study performed at University of North 
Carolina- Chapel Hill. 
Study Duration: 
This study will take 2 years to complete 
Participant Participation 
Duration: 
Eligible participants who complete this clinical trial will have a 
total of 8 visits; an initial session, 5 days of twice-daily 
stimulation, a one week and a one month follow up visit  (Follow 
up sessions are measured from last day of stimulation).  The 
initial screening session will take approximately 3 hours, each 
follow up screening session will last approximately 2 hours, the 
first day of stimulation will take approximately 6 hours. Days 2 
through 4 of stimulation will take 4.5 hours each day. Day 5 of 
stimulation will last about 9 hours. The one week follow up will 
take approximately 2.5 hours and the one month follow up will 
take approximately 5 hours.  We estimate that total participation 
to be approximately 40 hours. 
Description of Agent or 
Intervention: 
We will be using an active sham, 10 Hz tACS and 2mA tDCS. 
Active sham treatment will include 10 seconds of ramp in to 1 
minute of 10 Hz tACS with a ramp out of 10 seconds for a total 
of 80 seconds of stimulation. The choice of an active sham is 
motivated to enhance success of patient blinding by mimicking 
skin sensations associated with tACS. Both 10 Hz tACS and 
tDCS will also have a 10 second ramp in and ramp out with 20 
minutes of stimulation for a total of 1180 seconds. Stimulation 
waveforms are sine-waves with a peak-to-peak amplitude of 2 
mA.   
Estimated Time to 
Complete Enrollment: 
We estimate that it will take 2 years to complete enrollment of 
participants. 

11 
 
 
*Schematic of Study Design: 
Table 1. The 48 participants will be randomized into one of three of the following arms 
ARM 1 
16 participants 
Sham 
ARM 2 
16 participants 
10 Hz tACS 
ARM 3 
16 participants 
tDCS 
 
 
 
 
 
 
 
 
 
* Weeks are based on time from last stimulation session 
 
 
 

12 
 
1 
KEY ROLES 
Individuals: 
Principal Investigator:  Flavio Frohlich, Ph.D. 
 
Co-Investigator: Fred Jarskog M.D., John Gilmore, M.D 
Medical Monitor: Asa Cordle, M.D. 
 
 
Flavio Frohlich Ph.D. – Principal Investigator   
 
 
UNC - Chapel Hill Department of Psychiatry 
Email: flavio_frohlich@med.unc.edu 
Office: 4109 Neuroscience Research Building 
Phone: (919) 966-4584 
 
Fred Jarskog M.D- Co-Investigator  
UNC - Chapel Hill Department of Psychiatry 
Email: lars_jarskog@med.unc.edu 
Office: Medical School Wing D, Rm 254 
Phone: (919) 843-7683 
 
John Gilmore M.D- Co-Investigator  
UNC - Chapel Hill Department of Psychiatry 
Email: lars_jarskog@med.unc.edu 
Office: 304 MacNider Hall 
Phone: (919) 445-0209 
 
Robert M. Hamer Ph.D.-Data Management 
UNC - Chapel Hill Department of Psychiatry 
Email: hamer@unc.edu 
Office: 336 Medical School Wing B 
Phone: (919) 843-5508 
 
Juliann Mellin B.A. – Project Manager/Study Coordinator 
UNC - Chapel Hill Department of Psychiatry 
E-mail: juliann_mellin@med.unc.edu  
 
 
 
Office: Medical School Wing C-233 
Phone: (919) 966-9929 
 
Courtney Lugo MPH. – Study Coordinator 
UNC - Chapel Hill Department of Psychiatry 
E-mail: courtney_lugo@med.unc.edu 

13 
 
Office: Medical School Wing C-233 
Phone: (919) 962-5271 
 
Michael Boyle B.S. – Graduate Research Assistant  
 
UNC - Chapel Hill Department of Biomedical Engineering 
Email: mrboyle@live.unc.edu 
 
 
 
Office: 4129 Neuroscience Research Building 
 
Phone: (919)-966- 2682  
 
 
 
Asa Cordle M.D. – Medical Monitor  
 
 
 
UNC - Chapel Hill Department of Psychiatry 
 
 
Email: cordle@email.unc.edu 
 
 
 
Office: UNC Hospitals CB# 7160 
 
 
 
Phone: (919) 966-5217 
 
Institutions: 
University of North Carolina- Chapel Hill 
 
Other: 
IRB 
University of North Carolina-Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-311 
National Institute of Mental Health 
Sponsored Programs Office, SOM 
1140-C Bioinformatics Bldg., CB9525 
Chapel Hill, NC 27599-9525 
 
 
 
 
 

14 
 
2      INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
2.1 
Background Information 
 
About, 30% of patients with schizophrenia have auditory hallucinations that are refractory to 
antipsychotic medication and cause a significant decrease in quality of life (Shergill, Murray et 
al. 1998). All effective antipsychotics introduced over the past 60 years have been premised on 
dopamine D2 receptor antagonism, but clearly this mechanistic approach does not help all 
patients. For this reason, novel treatment approaches are required and transcranial current 
stimulation represents once such promising approach. Thus far, attempts at using transcranial 
current stimulation for treating medication refractory auditory hallucinations in patients with 
schizophrenia have been limited to the use of tDCS (Brunelin, Mondino et al. 2012). However, 
tDCS does not specifically target the known deficits in neuronal synchronization (alpha 
frequency band coherence) between the cortical areas that may play a causal role in auditory 
hallucinations (Winterer, Coppola et al. 2003). 
 
Patients with schizophrenia exhibit disorganized neuronal network dynamics such as 
hypoactivity in the dorso-lateral prefrontal cortex (dl-PFC) and hyperactivity in the temporo-
parietal junction (TPJ) (Silbersweig, Stern et al. 1995; Lawrie, Buechel et al. 2002). A recent 
provocative study has suggested that these abnormalities can be targeted by transcranial direct 
current stimulation (tDCS) (Brunelin, Mondino et al. 2012) resulting in a significant decrease in 
auditory hallucinations that outlasts stimulation for at least three months. However, the relative 
importance of the choices of stimulation parameters (stimulation waveform, number of 
treatments, treatment schedule) remains unknown. In particular, tDCS does not target the known 
deficits in the temporal structure of cortical network activity in patients with schizophrenia.  
 
 
2.2 
Rationale 
 
Here, we propose a new innovative approach driven by rational design where we use non-
invasive brain stimulation to directly target the circuit-level pathology of auditory hallucinations. 
Specifically, we will evaluate simultaneous tACS (10 Hz) to enhance synchronization between 
frontal and temporo-parietal areas of the left hemisphere. Such use of tACS to enhance 
synchronization has recently been introduced as a successful modulator of long-range synchrony 
mediating working memory (Polania, Nitsche et al. 2012). Additionally, we will use EEG data to 
develop a novel biomarker to show that decreases in auditory hallucinations are predicted by an 
increase in coherence and information flow between key brain regions. Ultimately, our goal is to 
treat patients based on demonstrable changes in brain activity, rather than on symptoms 

15 
 
themselves. The proposed research is innovative because it employs a new form of non-invasive 
brain stimulation, tACS, which targets underlying functional neuropathology to treat medication 
refractory auditory hallucinations in schizophrenia. Additionally, we are developing novel EEG 
biomarkers as markers for treatment response.  
 
2.3 
Potential Risks and Benefits 
 
2.3.1 
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. 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 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.  
Risk of Embarrassment: Self-reports and some assessments contain questions regarding 
sensitive personal information. This risk is necessary in order to assess experiences such 
as auditory hallucinations and disease state. Participants will be assured upon intake that 
only study personnel will see any clinical ratings, and study raters are trained to inquire 
about potentially distressing symptoms using a sensitive and respectful approach. 
Participants will be given the option not to answer questions that are too distressing.  
Risk of Injury and Discomfort: Transcranial current stimulation has been used without 
any reports of serious side-effects for more than a decade. This stimulation 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 (Frohlich and McCormick, 2010). In 
particular, tACS has been used without reports of any serious side-effects. Some 
participants report a transient mild tingling, burning, or itching underneath the electrodes 
and headache, but no other side effects have been noted. Importantly, it remains unclear 

16 
 
if these mild side-effects were caused by the transcranial brain stimulation. In order to 
monitor these side-effects, we will be administering an adverse effects stimulation 
questionnaire (Attachments 1 &2) after each stimulation session to determine whether 
these effects were experienced. Research personnel present during these sessions will 
also check in with the participant periodically during the stimulation to see whether they 
are comfortable. If any side-effect occurs (rated by the participant as stronger than 
“moderate”) or the participant is experiencing severe discomfort, the stimulation will be 
immediately stopped.  
While not previously reported with tDCS or tACS in humans, there is a theoretical 
possibility that stimulation of neuronal circuits could lead to epileptic discharges. To 
minimize this occurrence, we screen and exclude patients with personal and family 
history of neurological conditions from the study. If abnormalities or a seizure is 
witnessed during the course of the study, the subject will be referred to a neurology clinic 
for further evaluation and treatment. 
We have no evidence that our treatment paradigms will increase auditory hallucinations if 
not treated (receive the sham treatment), as participants, will be by definition, stable. If an 
enrolled patient shows signs of increase symptoms that were not apparent during 
enrollment, a referral to UNC Psychiatry will be made. Dr. Jarskog, Co-I, will facilitate 
this process. 
2.3.2 
Known Potential Benefits 
Our novel protocol targets the evidence for abnormal neuronal activity displayed in 
schizophrenia, with the intent to decrease auditory hallucinations. tACS has the 
promise to become the next generation stimulation paradigm for non-invasive 
treatment of pathological cortical network dynamics in patients with schizophrenia. A 
significant benefit to society would be the ability to treat medication resistant 
symptoms of schizophrenia. 
 
This study has not been designed to benefit the individual participants. The study has 
been designed to gain knowledge about the potential efficacy of tACS in treating 
auditory hallucinations in people with schizophrenia. In the event that tACS is 
effective, participants in this study who are randomized to the tACS arm could 
experience improvement in auditory hallucinations.  There are no known serious 
risks to the participant from the interventions used in this study. The chance to 
understand and develop a new treatment for persistent hallucinations in schizophrenia 
is an important step in helping the millions of people in the world who suffer from 
this condition.  

17 
 
3 
OBJECTIVES 
3.1 
Study Objectives 
 
Our primary objective is to develop an effective non-invasive brain stimulation paradigm that 
will treat medication refractory auditory hallucinations in patients with schizophrenia. 
 
3.2 
Study Outcome Measures 
 
3.2.1 
Primary Outcome Measures 
 
The Auditory Hallucination Rating Scale (Attachment 3) will be the primary outcome 
measure for this study.  This rating will be administered at baseline, two weeks later at 
the screening visit, the first day of stimulation, last day of stimulation, at the one week 
and the one month follow up visits.  We will compare the AHRS scores immediately 
before the first stimulation session and immediately after the last stimulation session as 
our primary outcome measure. 
 
3.2.2 
Secondary Outcome Measures 
 
We will compare alpha oscillation power from resting state EEG recordings from the 
screening visit and last day of stimulation. We will also collect EEG data at the one week 
and one month follow up visits. We will use these data to analyze alpha frequency 
activity as a pilot study for derivation of EEG biomarkers. 
 
The Positive and Negative Syndrome Scale (PANSS) (Attachment 5) and Brief 
Assessment of Cognition in Schizophrenia (BACS) (Attachment 12) will also be 
secondary outcome measures for this study.  These measurements will be taken at 
baseline, first day of stimulation, and last day of stimulation and at the one month follow 
up visit.  We will compare the PANSS and BACS scores immediately before first 
stimulation session and immediately after last stimulation session as secondary outcome 
measures. 

18 
 
4 
STUDY DESIGN 
The design for this pilot study is a randomized, double blind, sham-controlled, clinical trial 
which will be used to demonstrate feasibility and collect preliminary efficacy data for further 
refinement of a tACS approach. We are recruiting from a clinical population.  For this clinical 
trial we are seeking 48 males and non-pregnant females ages 18-70 with diagnosis of 
schizophrenia or schizoaffective disorder, who have at least 3 auditory hallucinations per week, 
with no change in medication dosing for at least 4 weeks and have been clinically stable for at 
least 12 weeks, meaning no change in their level of care. All women of child-bearing potential 
will have a pregnancy test during the initial session in order to determine eligibility for the study. 
These individuals will be outpatients; most will be referred through psychiatrists in the UNC 
Department of Psychiatry and affiliated ACT clinics, or by mental health practitioners in the 
local community. 
 
This is a single site, clinical trial with 3 arms.  We estimate 2 years to complete study enrollment. 
  
Participants will be randomly assigned to one of three arms; active sham stimulation, 10 Hz 
(alpha) tACS or 2 mA tDCS. Active sham treatment will include 10 seconds of ramp in to 1 
minute of 10 Hz tACS with a ramp out of 10 seconds for a total of 80 seconds of total 
stimulation.  The choice of an active sham is motivated to enhance success of patient blinding by 
mimicking skin sensations associated with tACS.  10 Hz and 2 mA tDCS will have a 10 second 
ramp in and ramp out with 20 minutes of stimulation for a total of 1180 seconds twice daily for 
one week. Stimulation waveform is a sine-wave with a peak-to-peak amplitude of 2 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 to 11 visits; an initial 
screening session, a 2nd screening session, (if needed) 2 more follow up screening sessions, 5 
days of twice daily stimulation sessions, a one week and a one month follow up visit.  The initial 
screening session will take approximately 2 hours, and each follow up screening session will 
take approximately 3 hours each. The first day of stimulation will take approximately 6 hours 
and days 2 through 4 of stimulation will take 4.5 hours each. The last day of stimulation will take 
about 9 hours.  The one week follow up will take approximately 2.5 hours and the one month 
follow up will take approximately 5 hours.  We estimate that total participant participation 
duration will be approximately 41 to 47 hours.  
  
The primary objective is to conduct a pilot clinical trial to establish the feasibility of recruitment 
and implementation of the methodology and to collect preliminary efficacy data for the use of 
tACS by comparing AHRS scores immediately before the first stimulation session and 

19 
 
immediately after the last stimulation session in patients with schizophrenia of schizoaffective 
disorder. As a secondary objective we will assess the differential clinical effects of sham, 10 Hz 
and 2 mA tDCS on EEG measures of alpha oscillations. 
 
In order to ensure symptom stability for each potential participant, there will be up to a 6 week 
period for the participant to achieve a stable AHRS score. The AHRS will be performed at 2 
week intervals during screening. A stable score is defined as having less than or equal to 20% 
change. If the change between the first and second AHRS scores is less than or equal to 20%, 
then the participant will move on to the week of stimulation. If a stable score is not achieved at 
the second screening session, the participant will have two more opportunities at 2 week 
intervals during follow-up screening sessions to achieve a stable score. The participant will be 
paid for each session. If the participant does not achieve a stable score (if there remains a greater 
than 20% change in scores between consecutive AHRS administrations) by the end of the 6 
weeks, the participant will not be eligible to continue participation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

20 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
Participant Inclusion Criteria 
 
In order to be eligible to participate in this study, a participant must meet all of the following 
criteria: 
 
● 
DSM-IV diagnosis of schizophrenia, any subtype, or schizoaffective disorder, with 
refractory auditory hallucinations. Duration of illness >1 year 
● 
18-70 years old 
● 
Clinically stable for at least 12 weeks, i.e. not requiring hospitalization or a change in 
level of care 
● 
On current antipsychotic doses for at least 4 weeks 
● 
Experience at least 3 auditory hallucinations per week. 
● 
Stable auditory hallucinations as demonstrated by having less than or equal to 20% 
change in AHRS scores across a 2 week interval during the screening period. 
● 
Capacity to understand all relevant risks and potential benefits of the study and to provide 
written informed consent, OR has a legal guardian who can provide informed consent on the 
patient’s behalf with the patient providing written assent to participate. 
 
5.2 
Participant Exclusion Criteria 
 
A potential participant who meets any of the following criteria will be excluded from 
participation in this study: 
 
● 
DSM-IV 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 
● 
Medical or neurological illness (unstable cardiac disease, AIDS, malignancy, liver or 
renal impairment) or treatment for a medical disorder that could interfere with study 
participation 
● 
History of traumatic brain injury that required subsequent cognitive rehabilitation, or 
caused cognitive sequelae 
● 
A difference of greater than 20% in AHRS scores between Consent Visit and Screening 
Visit. 
● 
Prior brain surgery 
● 
Any brain devices/implants, including cochlear implants and aneurysm clips 

21 
 
● 
Co-morbid neurological condition (e.g. seizure disorder, brain tumor) 
● 
Non English speakers 
● 
Female participants who are pregnant, nursing, or unwilling to use an adequate method of 
contraception during study participation for those of childbearing potential. 
● 
Anything that, in the opinion of the investigator, would place the participant at increased 
risk or preclude the participant’s likelihood of completing all components of the study 
 
5.3 
Strategies for Recruitment and Retention 
 
We intend to recruit 48 patients with schizophrenia and persistent auditory hallucinations, 
despite optimized antipsychotic medication treatment for at least 3 months. We will do this 
through both the UNC Hospital as well as the NCPRC Raleigh outpatient site, in coordination 
with providers at both locations. Additionally, we will also be contacting local ACT teams to 
recruit patients as well as potentially a small number from other community mental health 
providers. We estimate that approximately 10 subjects will be enrolled at the UNC-CH location, 
approximately 24 subjects will be enrolled at the Raleigh site, and approximately 14 subjects will 
be enrolled through ACT teams, for a total of 48 participants. Providers will be informed of the 
inclusion and exclusion criteria and will be asked to discuss the study with their patients at their 
next appointment or home visit in the case of the ACT team. Providers will include the medical 
teams treating patients at either of the two locations as well as the team that goes to see patients 
in the community through the ACT program. Providers will identify patients they believe to be 
appropriate for this study based on the information we will provide them about the study. 
Providers will ask patients whether they are willing to be contacted by the research team 
regarding participation. Providers will be asked to avoid unnecessary medication changes leading 
up to and over the 1 month course of the study.  
 
Our retention strategy includes monetary compensation for the time and effort required to 
participate in the study. The participant will receive a payment at each session of the study. The 
research staff will also give each participant a reminder call for the initial screening session, each 
follow up screening session, 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 
a professional relationship with the participants so they feel comfortable and willing to discuss 

22 
 
what may be sensitive information. Retention will be quantified by participant attendance at each 
scheduled session (the data from each session will be scored and documented the day of the 
session. Participants will no longer be eligible to continue the study if they miss more than two 
non-consecutive sessions. Participants who miss two consecutive sessions will not be eligible to 
continue their participation.  
5.4 
Treatment Assignment Procedures 
 
Participants will be randomized into one of three arms.  This is a double blind study, so neither 
the participant nor the researcher will know which treatment arm the participant has been 
assigned to.   
 
5.4.1 
Randomization Procedures 
 
A Frohlich Lab member will randomize 48 codes which will be used by the study 
coordinator and research assistants.  These codes are directly linked to which treatment 
participants receive (sham, 10Hz tACS or 2 mA tDCS).  This lab member will have no 
other responsibility in the study other than providing these randomized codes.   
 
5.4.2 
Reasons for Withdrawal 
 
A study participant will be discontinued from further participation if: 
 
● The participant has missed more than 2 stimulation sessions. 
●    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. 
 
5.4.3 
Handling of Withdrawals 
 
We will collect safety data on any participant discontinued because of an AE or SAE.  In 
any case, every effort will be made to undertake protocol-specified safety follow-up 
procedures.  If voluntary withdrawal occurs, the participant will be asked to continue 
scheduled evaluations and complete an end-of-study evaluation.  If an AE has been 
reported, researchers will help the participant seek the medical care they need and a 
follow up will be performed by the PI or Co-I.  In the case of an early withdrawal, the 

23 
 
researcher will complete a Participant Off Study form to document the withdrawal reason 
(Appendix Q). 
 
5.4.4 
Termination of Study  
 
This study may be prematurely terminated if, in the opinion of the investigator, there is 
sufficient reasonable cause.  Circumstances that may warrant termination include, but are 
not limited to: 
 
● 
Determination of unexpected, significant, or unacceptable risk to participants. 
● 
Insufficient adherence to protocol requirements. 
● 
Data those are not sufficiently complete and/or evaluable.  
● 
Plans to modify suspend or discontinue the development of the study device. 
 
The IRB will be informed promptly and provided the reason(s) for the termination or 
suspension by the sponsor or by the investigator/institution, as specified by the applicable 
regulatory requirement(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

24 
 
6 
STUDY INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
 
We will be using a transcranial current stimulator designed in the Frohlich Lab for 
investigational research 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 use of transcranial brain stimulation. Previous studies in the Frohlich 
Lab that used comparable devices have always been classified as “non-significant risk” by the 
UNC IRB. 
 
In addition, some participants will be stimulated with the commercial, CE-certified Neuroconn 
Plus stimulator (for purely logistic reasons of device availability). The use of this device in this 
study has previously received a NSR designation on initial review by the full UNC IRB. Both 
devices are electrically equivalent and provide the same stimulation. The NeuroConn device 
description is as follows: 
 
The DC-STIMULATOR is a CE-certified medical device for conducting non-invasive 
transcranial direct-current stimulation (tDCS) in humans. DC stimulation is used in clinical 
practice and in the research of stroke, epilepsy, migraine, tinnitus, depression, multiple sclerosis, 
dementia and chronic headache. The DC-STIMULATOR is a micro-processor-controlled 
constant current source. It meets the highest safety standards thanks to (hardware- and software-
based) multistage monitoring of the current path. By continuously monitoring electrode 
impedance it can detect insufficient contact with the skin and automatically terminate 
stimulation, maximising patient safety. 
The device's alphanumeric display and the 4 touch keys allow various stimulation modes to be 
selected and stimulation parameters such as current strength, duration, fade-in and fade-out to be 
set. 
 
 
DC-STIMULATOR features: 
• 
1 channel (anodal and cathodal stimulation possible) 
• 
Adjustable current up to 5,000 μA * 
• 
Adjustable application time up to 30 minutes * 
• 
2 standard modes - single (continuous stimulation) and - pulse (cyclical stimulation 
activation/deactivation) with fade in and fade out 
• 
Customer-specific programs possible (optional) 
• 
"Study mode" for blind processing of genuine and 'pseudo' stimulation (optional) 
• 
External trigger input (optional) 
 
 
 

25 
 
6.1.1 Device Description 
 
The device consists of the following main components/subsystems: 
 
1. Tablet with user interface application (App) 
2. Microprocessor 
3. Function generator chip 
4. Voltage controlled current source 
5. Safety circuitry 
 
First, the stimulation parameters are specified by the user through the app.  The 
parameters are: 
 
1. tDCS/tACS 
2. Number of channels 
3. Amplitude 
4. Test duration 
5. Frequency (for tACS) 
6. Password. 
 
Next, the parameters are sent via Bluetooth to the microprocessor.  The microprocessor 
interprets these parameters, and programs the function generator chip accordingly.  The 
function generator then creates the programmed waveform, which is ultimately a voltage 
signal.  The voltage signal is applied to a voltage controlled current source, which 
generates the specified amount of current through an arbitrary load resistance. 
 
 
 
6.1.2 Operation 
 
A. The desired current value is scaled to a register value and stored in the function 
generator. 
 
B. The value in the register determines the percent of full scale output current, generated 
by the function generator. 
 
C. The generated current waveform from the function generator is driven through a 
specified resistance.  The resulting voltage drop is amplified by an instrumentation 

26 
 
amplifier.  
 
D. The voltage waveform from the output of the instrumentation amplifier is applied to a 
voltage controlled current source. 
 
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 
generates a voltage.  The voltage across this resistor is sensed and amplified by the 
AD628 difference amplifier.  The gain of the difference amplifier is set to 9.9039.  The 
current sensor voltage is then shifted before it is read by the microprocessor and the 
hardware overcurrent safety feature.   
 
Voltage Sensor Circuit 
The differential voltage across the electrodes is measured so that the impedance can be 
calculated.  The voltage is measured by buffering the positive electrode and negative 
electrode each with a unity gain op-amp circuit.  The voltage sensor output is then shifted 
before it is read by the microprocessor using the same level shifting circuit described in 
the current sensor section.   
 
6.1.3 Safety Precautions 
 
The device is equipped with 4 different stages of safety protection, all of which protect 
the stimulant 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 +/-3mA peak.  If the 
current exceeds these limits, stimulation is stopped, a relay in series with the electrode is 
opened, and the power supply used for stimulation is turned off.  The user is then given 
the option to investigate the issue, and cancel or resume the test.  Since high-side current 
sensing is used (described above), any short circuit of the electrode terminals to ground 
will be detected. 
 
2. Automatic hardware current cutoff.  The output of the current sensor is fed into a pair 
of comparators which detect if the current exceeds +/-4.5mA.  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 

27 
 
microprocessor immediately stops stimulation and the power supply used for stimulation 
is turned off. 
  
Figure 1: Example of successful hardware cutoff function 
 
 
 
 
3. Permanent hardware current cutoff.  A 5mA 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 stimulant 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 blown.  This fuse is sized with a cutoff of 200% of 
steady-state operating current. 
 
6.2 
Preparation and Administration of Study Investigational Product 
 
After participants have completed the daily questionnaires, they will be comfortably seated.  The 
research team will first measure their heads electrode placement using the 10-20 system.  
Participants will then be fitted with the 3 electrodes for stimulation. The participant will be in the 

28 
 
relaxed yet, experimentally controlled state by watching a nature movie. One session of 
stimulation will be performed twice daily, for 20 minutes.  In the 10 Hz tACS and 2mA tDCS 
groups stimulation will have a 10 second ramp in and ramp out with 20 minutes of stimulation 
for a total of 1220 seconds. Stimulation waveforms are sine-waves with a peak-to-peak 
amplitude of 2 mA.  The sham stimulation will include 10 seconds of ramp in to 1 minute of 10 
Hz tACS with a ramp out of 10 seconds for a total of 100 seconds of stimulation. We will be 
using 5x5cm electrodes covered in 10/20 conductive paste and placed between Fp1 and F3 and 
between T3 and P3 with a 5x7cm electrode placed over CZ as a return electrode.  
 
Stimulation devices will be preprogrammed and codes will be randomized to one of the three 
experimental arms. Researchers will enter the participant-specific code into the App that controls 
the stimulation and monitor participants during the 20 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. Please see Appendix S for an example of the training documentation log. To monitor 
side effects of stimulation a daily questionnaire will be administered after each stimulation 
session.  Please see Attachment 1 for an example of the daily stimulation questionnaire, and 
Attachment 2 for an example of the endpoint stimulation questionnaire.  
 
6.3 
Assessment of Participant Compliance with Study Investigational 
Product 
 
Compliance for this study includes making all 10 stimulation sessions allowing 2 non-
consecutive miss which will be made up the following Saturday. Follow up periods will be able 
to take place ±3 days of scheduled visits.  
 
 

29 
 
7 
STUDY SCHEDULE 
Drs. Gilmore, Jarskog, Cordle or other approved clinician will be present during the initial 
session, the 1st day of stimulation, the 5th day of stimulation, and the one month follow up for the 
first 5 participants, after which the approved clinicians will be present for only the initial session, 
the 5th day of stimulation and the one month follow up. The approved clinician will be present to 
administer the SAS (Attachment 9), the AIMS (Attachment 7) for each participant and the CGI-S 
(Attachment 8) for the first 5 participants until research personnel are comfortable and certified 
to do so (will be determined by accompanying clinician). In order to increase data quality, the 
assessments for an individual participant at the initial session, the 1st day of stimulation, the 5th 
day of stimulation, the one week one month follow ups will be administered by the same 
researcher. Protocol for this study will not require the same researcher to be present during days 
2 through 4 of stimulation although the team will strive to schedule the same researcher for every 
session.  
 
7.1 
Screening 
 
Screening Telephone Call 
Individuals who are referred by a mental health care provider will be contacted by a researcher 
for an initial phone screening.  Researchers will keep a Telephone Contact log for each telephone 
conversation with a participant throughout the study. There will be a log for each participant and 
will be filed in the participant binder (Appendix R).  
 
During the telephone screening, researchers will provide a brief background about Schizophrenia 
and tACS.  Any initial questions will be answered at this point. The timeline of visits will then be 
explained; there will be 1 to 8 sessions, with 1 initial session, 5 consecutive week days of twice 
daily stimulation, with follow ups one week after the last stimulation and one month after last 
stimulation. The participant will be informed that compensation for their participation will be 
received at each session throughout the study. The participant will be asked if they have any 
additional questions.  Once all questions have been answered, the participant will be asked if 
he/she is still interesting in participating in the study.  If yes, the researcher will begin the initial 
phone screening which will determine eligibility for the initial session. The screening questions 
are shown below. If the required answers are given for each question, the initial session will be 
scheduled and a reminder call will be given at least 24 hours before initial session. We will use 
the telephone script provided in Appendix T for all telephone screenings.  
 
o Are you 18 years or older? (Yes) 
o Have you ever, or are you currently being treated for a neurological condition (i.e. 
epilepsy)? (No) 

30 
 
o Have you ever had brain surgery? (No) 
o Do you have any brain devices or implants, including a cochlear implant or 
aneurysm clip? (No) 
o Have you ever been diagnosed with a traumatic brain injury? (No) 
o For females only, is there a chance you may be pregnant? (No) 
 
7.2 
Enrollment/Baseline 
 
Initial Screening Visit (Visit 1, Day 0) 
At the consent visit, participants will sign both a HIPAA authorization form and the consent 
form. Each form will be read to the participant by the researcher, and the participant will be 
given the time to ask any questions about the information discussed. The researcher will verify 
that the participant meets inclusion criteria. If the participant is female, she will be asked to 
provide urine for a pregnancy test. All participants (male and female) will be asked to complete a 
urine drug screening to determine eligibility for the study. Next, the SCID (Attachment 6) will be 
administered in order to confirm diagnosis of schizophrenia or schizoaffective disorder and to 
verify that the participant does not have active alcohol or illicit drug abuse or dependency. Once 
the diagnosis has been confirmed, demographic information will be collected, which will include 
a history of medication, alcohol, and drug use and information about symptom onset and baseline 
vitals will be taken. A short handedness questionnaire and a Belief about Treatments 
questionnaire will also be administered. Each participant will be asked a series of questions 
(Appendix H) to ensure that the consent form is fully understood. After consent has been 
obtained, a baseline Auditory Hallucinations Rating Scale (AHRS) will be administered to 
document hallucinatory severity and frequency. The 2nd screening visit will be scheduled for 
approximately 2 weeks later, and the participant will be paid. 
 
2nd Screening Visit (Visit 2)  
At the beginning of the 2nd screening visit, vitals will be taken and an EEG will then be 
administered. The EEG recording will include resting state data along with two auditory tasks. 
After each EEG, an EEG questionnaire (Appendix U) will be administered to document the 
participant’s auditory experiences during the EEG tasks. The following questionnaires will then 
be administered to further check eligibility; Auditory Hallucination Rating Scale (AHRS) in 
order to document any change in auditory hallucination severity/frequency (Attachment 3). The 
AHRS scores from the initial screening visit and the current visit will be compared. If a change 
in score greater than 20% exists, then a 3rd screening visit will be scheduled for approximately 2 
weeks later. If a change in AHRS score is less than or equal to 20% then the Simpson Angus 
Scale (SAS) (Attachment 9) and the Abnormal Involuntary Movement Scale (AIMS) 
(Attachment 7) will be administered as a baseline assessment of extrapyramidal syndromes or 
tardive dyskinesia due to antipsychotic medication use. In order to ensure proper assessment, 

31 
 
each AIMS administration will initially be recorded to be reviewed and scored by Dr. Jarskog 
until the researcher is deemed to have sufficient experience. At the end of the initial session, and 
once eligibility has been confirmed, a saliva sample will be collected (for testing of BDNF 
allele), the week of stimulation will be scheduled, and the participant will be paid.  
 
3rd Screening Visit (Possible Visit 3) 
At the beginning of the 3rd screening visit, vitals will be taken and an EEG will then be 
administered. The EEG recording will include resting state data along with two auditory tasks. 
After each EEG, an EEG questionnaire (Appendix U) will be administered to document the 
participant’s auditory experiences during the EEG tasks. The following questionnaires will then 
be administered to further check eligibility; Auditory Hallucination Rating Scale (AHRS) in 
order to document any change in auditory hallucination severity/frequency (Attachment 3). The 
AHRS scores from the 2nd screening visit and the current visit will be compared. If a change in 
score greater than 20% exists, then a 4th screening visit will be scheduled for approximately 2 
weeks later. If a change in AHRS score is less than or equal to 20% then the Simpson Angus 
Scale (SAS) (Attachment 9) and the Abnormal Involuntary Movement Scale (AIMS) 
(Attachment 7) will be administered as a baseline assessment of extrapyramidal syndromes or 
tardive dyskinesia due to antipsychotic medication use. In order to ensure proper assessment, 
each AIMS administration will initially be recorded to be reviewed and scored by Dr. Jarskog 
until the researcher is deemed to have sufficient experience. At the end of the initial session, and 
once eligibility has been confirmed, a saliva sample will be collected (for testing of BDNF 
allele), the week of stimulation will be scheduled, and the participant will be paid.  
 
4th Screening Visit (Possible Visit 4) 
At the beginning of the 4th screening visit, vitals will be taken and an EEG will then be 
administered. The EEG recording will include resting state data along with two auditory tasks. 
After each EEG, an EEG questionnaire (Appendix U) will be administered to document the 
participant’s auditory experiences during the EEG tasks. The following questionnaires will then 
be administered to further check eligibility; Auditory Hallucination Rating Scale (AHRS) in 
order to document any change in auditory hallucination severity/frequency (Attachment 3). The 
AHRS scores from the 2nd screening visit and the current visit will be compared. If a change in 
score greater than 20% exists, then the participant is considered not eligible to participate and 
will be paid for completing the session. If a change in AHRS score is less than or equal to 20% 
then the Simpson Angus Scale (SAS) (Attachment 9) and the Abnormal Involuntary Movement 
Scale (AIMS) (Attachment 7) will be administered as a baseline assessment of extrapyramidal 
syndromes or tardive dyskinesia due to antipsychotic medication use. In order to ensure proper 
assessment, each AIMS administration will initially be recorded to be reviewed and scored by 
Dr. Jarskog until the researcher is deemed to have sufficient experience. At the end of the initial 

32 
 
session, and once eligibility has been confirmed, a saliva sample will be collected (for testing of 
BDNF allele), the week of stimulation will be scheduled, and the participant will be paid.  
 
 
7.3 Stimulation Sessions 
 
Day 1 of Stimulation (Visit 5) 
At the first day of stimulation, vitals will be recorded and several questionnaires will be 
administered. First, the AHRS (Attachment 3) will be administered followed by the PANSS 
(Attachment 5) and the Brief Assessment of Cognition in Schizophrenia (BACS) (Attachment 
12). The BACS will be used as a baseline assessment of participant cognition, and will be 
administered again during later sessions to assess for any changes in cognitive function 
associated with treatment. After this, the CGI-S (Attachment 8) will be administered in order to 
document any difference in auditory hallucination or symptom severity from the screening visit.  
 
Once the questionnaires are complete, the participant will be administered either sham, 10 Hz 
tACS or 2 mA tDCS treatment for 20 minutes. Participants will be asked to sit still and not talk 
during these 20 minutes, and will be asked to keep their eyes open and facing straight ahead. 
After the 20 minutes of treatment, the participant will be asked to return 3 hours later on the 
same day for another 20 minutes of either sham, 10 Hz tACS or 2 mA tDCS treatment, where the 
participant will again be asked to sit still, not talk, and with their eyes open. 
 
After each stimulation treatment, to assess any side effects of stimulation, the stimulation 
adverse effects questionnaire will be administered. This questionnaire will be administered at the 
end of each stimulation session as a safety assessment to monitor any potential side effects of the 
stimulation (Attachment 1). Participants will be paid at the conclusion of this session.  
 
Days 2 – 4 of Stimulation (Visit 6 – 8) 
Upon participant arrival, vital signs will be taken and documented at the beginning of the first 
stimulation session of each day. The participant will then receive 20 minutes of sham, 10 Hz 
tACS or 2mA tDCS (as per the initial randomization) while sitting quietly with their eyes open.  
After 3 hours, the participant will return for another 20 minutes of sham, 10 Hz tACS or 2mA 
tDCS. Each stimulation session will be followed by the stimulation adverse effects questionnaire. 
Participants will be paid at the conclusion of each session.   
 
Day 5 of Stimulation (Visit 9) 
Upon participant arrival, vital signs will be taken and documented at the beginning of the first 
stimulation session of the day.  An EEG will then be administered. The EEG recording will 
include resting state data along with two auditory tasks, and the EEG Questionnaire will be 

33 
 
administered. The participant will receive 20 minutes of sham, 10 Hz tACS or 2mA tDCS (as per 
the initial randomization) while sitting quietly with their eyes open.  After 3 hours, the 
participant will return for another 20 minutes of sham, 10 Hz tACS or 2mA tDCS. Each 
stimulation session will be followed by the stimulation adverse effects questionnaire.. The AHRS 
(Attachment 3) will be administered. After this the PANSS (Attachment 5), BACS (Attachment 
12), CGI-S (Attachment 8), and SAS (Attachment 9) and AIMS (Attachment 7) data collection 
assessments will be administered at the end of this session. After the assessments are completed, 
the participant will then be paid at the completion of the session.  
 
7.4 
Follow-up  
 
One week Follow-up Visit (Visit 10, one week after last day of stimulation) 
Upon participant arrival, vital signs will be taken and documented. An EEG will then be 
administered. The EEG recording will include resting state data along with two auditory tasks, 
and the EEG Questionnaire will be administered. The AHRS will then be administered to assess 
severity of auditory hallucinations. Each participant will be asked whether they believe their 
symptoms have improved (Attachment 11). Participants will be paid at the conclusion of this 
study visit. 
 
7.5 
Final Study Visit 
 
One month Follow-up Visit (Visit 11, one month after last day of stimulation) 
Upon participant arrival, vital signs will be taken and documented. An EEG will then be 
administered. The EEG recording will include resting state data along with two auditory tasks, 
and the EEG Questionnaire will be administered. The AHRS will then be administered to assess 
severity of auditory hallucinations, followed by the adverse events questionnaire and a review of 
current medications. The PANSS (Attachment 5), CGI-S (Attachment 8), and SAS (Attachment 
9), AIMS (Attachment 7), and BACS (Attachment 12) data collection assessments will be 
administered at the end of this session for endpoint assessment. Each participant will be asked 
whether they believe their symptoms have changed (better, worse, no change) over the course of 
the study. After the assessments are completed, the participant will then be paid for the 
completion of the final study visit.  
 
 

34 
 
8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
 
During the initial session, researchers will collect demographics. Participant demographics 
include medical history and medication history.  This information is used to confirm inclusion 
criteria and that no current alcohol and drug abuses or disorder exist. 
 
Several clinical evaluations will be used throughout this study. These assessments are listed 
below and can be found in the attached documents. 
 
i. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) is a semi-
structured interview used to diagnosis major Axis I disorders. For this study, the 
SCID-I (First et al. 2004) will be administered at baseline in order to confirm a 
diagnosis of Schizophrenia or Schizoaffective Disorder.  
 
ii. The Auditory Hallucination Rating Scale (AHRS) is a structured interview, designed to 
assess different aspects of patient’s auditory hallucinations. This assessment has 11 
items and is rated on a scale of 0 – 4 based on the responses given by the patient. The 
AHRS will be administered at the baseline visit, the first day of stimulation, the last 
day of stimulation, and at the one week and one month follow up visits.  
 
iii. The Positive and Negative Syndrome Scale (PANSS) is a structured interview used to 
assess the symptom severity of patients diagnosed with schizophrenia. The PANSS 
(Kay et al. 1987) focuses on the positive and negative syndromes and their general 
severity. This scale will be administered the initial session, first day of stimulation, 
the last day of stimulation and at the one month follow up visit.  
  
iv. The Brief Assessment of Cognition in Schizophrenia (BACS) will be administered at 
baseline, day 5 of stimulation and at the week 5 follow-up session in order to monitor 
changes in participant cognition. This validated assessment (Keefe et al. 2004, Keefe 
et al. 2006) contains 6 tests that focus on verbal memory and learning, working 
memory, motor functioning, attention/processing speed, verbal fluency and reasoning 
and problem solving.  
 

35 
 
v. The Simpson Angus Scale (SAS) (Janno et al. 2005) is a 10 item assessment of 
medication related extrapyramidal side effects. The SAS will be administered at the 
first day of stimulation to obtain a baseline assessment, and again at day 5 of 
stimulation and the week 5 follow-up session to monitor symptom severity or 
development for each participant.  
 
vi. The Abnormal Involuntary Movement Scale (AIMS) will be administered at the initial 
session to obtain a baseline assessment, and again at day 5 of stimulation and the 
week 5 follow-up session to monitor symptom severity or development for each 
participant. The AIMS is a 12 item assessment used to record the occurrence of 
tardive dyskinesia.  
 
vii. The Clinical Global Impression Severity Scale (CGI-S) measures the symptom severity 
for patients diagnosed with mental disorders based on the clinician’s total experience 
with that specific population. The CGI-S (Berk et al. 2008) will be administered by a 
clinician or trained research assistant at the initial session, the first day of stimulation, 
the last day of stimulation, and the week 5 follow up visit.   
 
We will be monitoring the safety of our participants throughout the study with the following 
assessments. These assessments can also be found in attachments. 
 
i. 
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. A similar questionnaire was used in IRB 13-2995 to 
determine ability to successfully blind using transcranial current stimulation.  
(Attachment 1 and Attachment 2) 
 
8.2 
Laboratory Evaluations 
 
8.2.1 
Clinical Laboratory Evaluations 
During the initial session, all participants will be asked to participate in a urine drug 
screen in order to help screen out any individuals who have a drug use problem. A urine 
pregnancy test will also be performed for any female participant who is unable to confirm 
pregnancy status. This information will be recorded on the inclusion/exclusion criteria 
checklist (Appendix M) to be completed by the researcher. Participants will also be asked 
to complete a drug urine test during the initial session to verify drug use status.  
 

36 
 
8.2.2 
Special Assays or Procedures 
 
The Brief Assessment of Cognition in Schizophrenia (BACS) (Attachment 12) will be 
administered during the 1st day of stimulation, the 5th day of stimulation and at the one 
month follow-up. This assay was specifically designed to assess cognition in patients 
diagnosed with schizophrenia and will be used to obtain a baseline assessment of 
cognition in each participant. We will also be using this assay as a safety monitor and 
data collection tool throughout the study to assess any changes in cognition that may be 
seen as a result of the treatment.  
There will be two procedures used throughout this study. Each participant will attend 5 
consecutive weekdays of stimulation for this study. Each participant will be randomly 
assigned to one of three treatment arms for this study (sham, 10HZ tACS or 2mA tDCS). 
Electrodes with a measurement of 5x5cm will be placed between Fp1 and F3 and 
between T3 and P3, and a return electrode, 5x7cm, will be placed over Cz. In order to 
detect any change(s) at the neurophysiological level, an EEG will be performed during 
the 1st day of stimulation, the 5th day of stimulation, and at the one month follow up 
session. This measurement will contribute to the design of novel network-level 
biomarkers of schizophrenia and of treatment response.   
In addition to the above procedures, we will be collecting a saliva sample at the initial 
visit.  This sample will be used to test for a single nucleotide polymorphism in the BDNF 
gene whose presence may have an influence on efficacy of brain stimulation.  Within the 
central nervous system, BDNF regulates survival, proliferation, and synaptic growth as 
well as directly influences synaptic plasticity in the adult human brain (Antal et al. 
2010).  Egan et al. (2003) demonstrated that Val66Met, a single nucleotide 
polymorphism in the BDNF gene, has functional consequences in healthy humans 
including decreased episodic memory and hippocampal inducing a reduction in recall 
capacity. This polymorphism is common in over one third of the Caucasian population 
(65% Val66Val to 35% Val66MET) (Pezawas et al. 2004; Hariri and Weinberger 2003).  
Kleim et al. (2006) found that individuals with the Val/Val polymorphism respond to 
tDCS and transcranial magnetic stimulation treatments (TMS) with expected changes 
whereas individuals expressing the Val/MET allele do not.  These authors indicate the 
difference to be caused by the impairment in synaptic plasticity caused by the Val/MET 
allele. These findings suggest that individual of treatments using brain stimulation may 
be partially genetically predetermined and should be taken into account when preforming 
such procedures. Accordingly, we will conduct genotyping of all participants in this study 
in order to assess BDNF status.  We will perform exploratory analyses in which we group 
participants by BDNF status. 
 

37 
 
9 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
 
There will be three different assessments used to ensure participant safety. First, vitals will be 
recorded at the beginning of each session.  This assessment is used to monitor any physiological 
changes. 
 
A Positive and Negative Syndrome Scale will be administered before the first stimulation session 
and on the last day of stimulation as well as at the one month follow up.  This tool is used to 
assess any changes in symptoms associated with this disorder.  We do not expect any changes in 
these symptoms; additionally we did not find any changes in a related clinical trial (IRB# 13-
2995).  Should there be a significant change in PANSS rating scores, (>25% increase) we will 
direct the participant to Dr. Cordle or Dr. Jarskog for further follow up and file a AE report. 
 
After each stimulation session, a stimulation adverse effects questionnaire (Attachment 1and 
Attachment 2) will be administered.  This tool is used to document any side effects experienced 
during stimulation. The researcher will also check with the participant throughout the 20 minute 
stimulation sessions to make certain no discomfort is felt.  The stimulation session will be 
terminated if the participant reports having unmanageable discomfort or pain (more than 
“moderate”).  Additionally, this information will be reported on an AE report form (Appendix B) 
and an AE log (Appendix C). 
 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
 
9.2.1 
Adverse Events 
 
Adverse Event:  An AE, as defined by the NIH, is any unfavorable changes in health, 
including /abnormal laboratory findings that occur in trial participants during the clinical 
trial or within a specified period following the trial.  
 
All AEs including local and systemic reactions not meeting the criteria for “serious 
adverse events” will be captured on the appropriate CRF.  In addition, the AE Report 
Form will be completed by the study coordinator (Appendix B).  The AE report form 
includes the follow; what is known about the therapy and previous reported side effects, 
if the AE occurred in temporal relation to the therapy, whether or not the AE improves or 
disappears when treatment is stopped, whether the AE is a worsening of baseline 

38 
 
symptoms or related to a concurrent medical condition or medication use. Once complete, 
this form will be given to the PI and the Co-I who will review, comment and sign this 
form.  Completed forms will be placed in the participant’s folder.  
 
The study coordinator will document any AE occurrence on the AE log (Appendix C) 
which includes information such as the date of the AE, severity, relationship to the 
treatment (assessed by the PI), actions taken, and outcome(s). The log will be reviewed 
and initialed by the PI 72 hours after being completed. All AEs occurring during the 
clinical trial will be documented appropriately regardless of relationship to tACS. All 
AEs will be followed to adequate resolution and will be graded for severity and 
relationship to the study treatment.  Any medical condition noted at the initial session 
will be considered as baseline and not reported as an AE. 
 
 
 
All AEs will be graded for severity using the following guidelines. 
 
● Asymptomatic: the participant is exhibiting no symptoms due to the event; no 
treatment needed.  
● Mild Adverse Event– Event results in mild or transient discomfort, not requiring 
intervention or treatment; does not limit or interfere with daily activities (e.g., 
insomnia, mild headache). 
● Moderate Adverse Event – Event is sufficiently discomforting so as to limit or 
interfere with daily activities; may require interventional treatment (e.g., fever 
requiring antipyretic medication).  In the case of a moderate adverse event the medical 
advisor may recommend an over the counter medication. 
● Severe and undesirable Adverse Event – Event results in significant symptoms that 
prevents normal daily activities; may require hospitalization or invasive intervention 
(e.g., anemia resulting in blood transfusion). 
 
Changes in the severity of an AE will be documented with the Note to File document 
(Appendix N) and will be filed in the participant’s folder.  
 
Relationship to Study Products:  The PI and Co-I will together determine whether an 
AE is associated with the study treatment. The event will be labeled associated if the 
event is temporally related to the administration of the therapy and no other factors can 
explain the event. The event will be labeled as not associated if the event is temporally 
independent of the study treatment and can be explained by external factors such as major 
life events. 
 

39 
 
9.2.2 
Expected Adverse Reactions 
 
Transcranial current stimulation has been used without reports of any serious side-effects. 
Some subjects report a transient mild tingling, burning, or itching underneath the 
electrodes and headache, but no other side effects have been noted. Importantly, it 
remains unclear if these mild side effects were caused by the transcranial brain 
stimulation. During the stimulation, the researcher will ask the participant about their 
comfort.  Stimulation will immediately be stopped if any discomfort (more than 
“moderate”) is reported. In theory, there is a possibility that application of weak 
stimulation current could induce a seizure.  
 
These adverse reactions will be monitored with the stimulation adverse effects 
questionnaire (Attachment 1 and Attachment 2). The following scale reflects the scoring 
of severity for any possible side effects.  
 
1 = Absence of the indicated symptom 
2 = Mild (awareness of a symptom but the symptom is easily tolerated) 
3 = Moderate (discomfort enough to cause the researcher to be informed) 
4 = Severe (incapacitating; the stimulation is terminated due to extreme discomfort) 
 
All expected adverse reactions questionnaires are a daily source document that will be 
placed in each individual’s folder.  Should the DSMB ask to see a complete report of this 
information a report can be regenerated for their viewing.   
 
9.2.3 
Serious Adverse Events 
 
Serious Adverse Event (SAE): An SAE, as defined by the NIH, consists of adverse 
events that result in death, require either inpatient hospitalization or the prolongation of 
hospitalization, are life-threatening, result in a persistent or significant 
disability/incapacity or result in congenital anomaly/birth defect. Other important medical 
events, based upon appropriate medical judgment, may also be considered Serious 
Adverse Events if a trial participant’s health is at risk and intervention is required to 
prevent an outcome mentioned.  
 
All SAEs will be recorded on the Serious Adverse Events Form (Appendix D), 
documented in the UE/SAE log and reported to the IRB. The SAE Form will be 
completed by the study coordinator, and includes information relating to the onset and 
nature of the SAE, relationship to the study treatment, seriousness of the SAE, treatment 
required as a response to the SAE, and outcome. This form will be filed in the 

40 
 
participant’s binder at the resolution of the event. The study coordinator will complete the 
UE/SAE log (Appendix E) which includes information such as the date of the event, time 
at which the study team was informed of the event, details, when the IRB has been 
notified, and the date that the SAE Form was completed.  
 
9.2.4 
Unanticipated Problems. 
 
Unexpected Events (UE) will be recorded on the UE/SAE log (Appendix E) and will 
include information such as the date of the event, when the study team was informed of 
this event, details of the event, when the IRB was notified, and whether the SAE Form 
was completed. The IRB will be notified of each UE that may occur during the study.  
 
The Office for Human Research Protections 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. 
 
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. Please see Appendix F for an example of 
the Consent Amendment Tracking log. 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.  
 
9.3 
Reporting Procedures 
 
We will be adopting the follow table for reporting procedures:  
 

41 
 
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 10 working days of 
investigator first learning 
of effect 
Investigator 
● 
Local/internal 
IRBs 
 
Unanticipated Problem 
that is not an SAE 
Within 7 days of the 
investigator becoming 
aware of the problem 
Investigator 
● 
Local/internal 
IRBs/Institutional 
Officials, 
 
All Unanticipated 
Problems 
Within 30 days of the 
IRB’s receipt of the report 
of the UP from the 
investigator. 
IRB 
● 
OHRP 
Investigator3 
● 
External IRBs 
 
9.3.1 
Reporting of Pregnancy 
 
Pregnancy tests will be administered at the initial session 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 and medical monitor.   
 
9.4 
Type and Duration of Follow-up of Participants after Adverse Events 
 
Medical monitors and Co-I will follow up with participants with in one week of an AE. 
 
9.5 
Halting Rules 
 
If a seizure occurs at the time of a study visit, a temporary hold will be placed over the study and 
further investigation will ensue. This could lead to stopping the study prematurely or continuing 
on with further safety measures in place. If two seizures are witnessed during the study visits, the 
entire study will be stopped prematurely. These individuals would be referred for further medical 
attention. It is very unlikely that a seizure will occur, given that previous studies using tDCS in 

42 
 
patients with depression and schizophrenia have had no seizures occur (Berlin et al., 2013, 
Brunelin et al., 2012). The study will also be stopped if other studies provide evidence that 
transcranial current stimulation has been associated with other, previously unrecognized, 
potentially harmful effects, either short-term or long-term. 
 
9.6 
Safety Oversight 
 
Safety oversight will be under the direction of a DSMB composed of Dr. Ross Simpson, an 
epidemiologist, a biostatistician and one or more clinical researchers. The DSMB will review 
AEs every 6 months whereas the medical monitor will review AEs in real time and make 
decisions as to each participant’s continuation in the trial. The PI will review AEs weekly with 
research team and may request additional review by Co-I on a case-by-case basis. The medical 
monitor will also be present at weekly meetings in order to discuss/explain any event(s) that may 
occur. 
 
Every 6 months DSMB will review blinded AE reports.  If there is reason to view unblinded 
information, the DSMB will directly receive the list of participants’ identification numbers from 
a Frohlich Lab member, not otherwise associated with this clinical trial.  Participant 
identification number will be displayed in a table according to the three arms of the study; 
however the specific treatment of that arm will not be disclosed.  This will allow the DSMB to 
compare the three treatment groups. 
 
Reasons for stopping the study and asking for further investigation include; decrease in cognitive 
abilities based on baseline and end of study data (>25% decrease in scores in 2/10 of the first 
participants or 20% of participants overall.).  In addition, as mentioned above, if a seizure occurs 
during a study visit, the clinical trial will be temporarily be placed on hold for further 
investigation.   
 
 
  
 

43 
 
10 
CLINICAL MONITORING 
The Purpose of the monitoring plan is to present the Frohlich Lab’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 Frohlich Lab 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 (Appendix O) will be 
filled out.  All team members will be trained on how and when to use this log.  The most up to 
date IRB application will be on file at the Clinical Trials desk in Rm 4109 of the NRB. 
Deviations will be sent to IRB every 4-6 weeks (if necessary). 
 
At the end of the month clinical trials meeting with the PI, 3 randomly selected informed consent 
forms will be chosen. The PI will verify that (1) these forms have been filled out appropriately, 
and (2) the consent form process described in the SOP was followed and properly documented.  
Should any consent form be in violation, the research team will perform and document a 
complete review of all consent forms. 
 
AE and SAE are clearly defined in the Master Protocol.  Documents of AE and SAE can be 
found in the study binder on file at the Clinical Trials desk in Rm 4109 of the NRB.  It is 
responsibility of the study coordinator to report all events to the PI.  In all weekly meetings with 
the PI, all AE and SAE are discussed.  For our practices we have adapted the decision tree 
provided by UNC-CH IRB to assist with reporting of such events (Attachment 10).  
At all weekly clinical trial team meetings, the study coordinator will chose one CRF and Source 
Document to asses for completion and maintenance. At weekly clinical trials meeting, with the 
PI will assess completeness of data on REDCap (data site). The PI has read-only access.  This 
allows the PI to view reports that provide information on any missing data on an individual 
participant basis, but does not allow them to add, change or input any data.

44 
 
11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
 
11.1.1 Primary Objective 
 
Null hypothesis: There is no difference in AHRS score immediately before first 
stimulation session and immediately after last stimulation session between treatment 
groups. 
Alternative hypothesis: There is a difference in AHRS score immediately before first 
stimulation session and immediately after last stimulation session between treatment 
groups. 
 
11.1.2 Secondary Objectives 
 
1. 
Null hypothesis: There is no difference in changes of alpha frequency power 
between baseline EEG and EEG at completion of stimulation between treatment 
groups. 
Alternative hypothesis: There is a difference in changes of alpha frequency power 
between baseline EEG and EEG at completion of stimulation between treatment 
groups. 
 
2. 
Null hypothesis: There is no difference in PANSS score immediately before first 
stimulation session and immediately after last stimulation session between 
treatment groups. 
Alternative hypothesis: There is a difference in PANSS score immediately before 
first stimulation session and immediately after last stimulation session between 
treatment groups. 
 
3. 
Null hypothesis: There is no difference in BACS score immediately before first 
stimulation session and immediately after last stimulation session between 
treatment groups. 
Alternative hypothesis: There is a difference in BACS score immediately before 
first stimulation session and immediately after last stimulation session between 
treatment groups. 
 
 

45 
 
11.2 Sample Size Considerations 
 
This clinical trial represents a pilot study.  A pilot study is a clinical trial that is conducted to 
decide whether a new treatment should be tested in a large controlled trial therefore we do not 
calculate sample size.  It is difficult to recruit a large number of patients diagnosed with 
schizophrenia with persistent auditory hallucinations to participate in a single site extensive 
study.  However, based on our recent prior experience recruiting for patients with these 
symptoms, we expect that we can successfully recruit 48 subjects and that with 16 participants in 
each group that we have enough power to detect significance if there is a large effect size of 
twice daily tACS or tDCS on auditory hallucinations and/or the underlying biomarkers.   
 
11.3 Final Analysis Plan 
 
We will perform spectral analysis of resting state EEG before and after stimulation treatment and 
use a mixed ANOVA with the within subject factor session (immediately before first stimulation 
session and immediately after last stimulation session) and between subject factor treatment 
(sham, 10Hz tACS or 2 mA tDCS). Spectral analysis will be performed with multi-tapered 
estimation of the frequency spectrum followed by integration over the classical alpha EEG band 
(8-12 Hz).  We will apply the same statistical analysis procedure for our primary outcome of 
AHRS, PANSS and BACS scores. 
 
We will also use post-hoc paired or unpaired Student’s t-test to identify the group or groups that 
differed. We will further control for multiple comparisons by using Bonferroni corrections.  
 

46 
 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Human Research Committee (IRB): 
● 
All IRB Correspondences are on file. 
● 
The study staff is IRB approved prior to performing any study procedures. 
● 
Adverse events and deviations are reported to IRB per current guidelines. 
● 
All versions of the IRB protocols and informed consent forms are on file. 
 
Informed Consent: 
● Ensure that participant identification is on all pages of the ICF 
● There is documentation that the participant is given a copy of the consent form (Appendix G) 
● The participant and study representative signed and dated the consent form for him/herself.  
● The participant initialed and dated all appropriate pages on the informed consent form.  
● Note to file (Appendix N) made for any informed consent deviations.   
● Ensure a valid (current version date) copy of the consent form was used. 
 
Protocol: 
● 
Confirm that the study staff is conducting the study in compliance with the protocol 
approved by IRB  
● 
The protocol deviations (exceptions and violations) are documented in the participant 
chart and reported to IRB as required. 
  
Source Documents: 
● Each participant binder will contain a checklist to ensure that each binder has each source 
document. The checklist will be dated by the researcher for each time an assessment is 
administered. (Appendix J) 
● Review participant charts to ensure the accuracy, completeness and legibility of the data 
● Any correction made to the source documents is dated, initialed, and explained. The original 
entry should not be obscured.  
● The protocol specific source documents are on file.  
● Source documents are completed in ink. 
● Note to files (Appendix N) are made for missing or incomplete data and to explain any 
discrepancies or additional comments.  
 
Electronic Case Report Forms (eCRF)  
● 
Ensure the data reported on the eCRF is consistent with the source documents.  
● 
Discrepancies between the source documents and eCRF are explained in a note to file 
(Appendix J) or captured in a comment in the eCRF.  

47 
 
 
 
DNA  
● Participant names will not be on any of the samples collected at the initial session. DNA 
testing is performed within the University of North Carolina at Chapel Hill and the samples 
are not shared with or processed by any third party outside the university. 
 
The research coordinator, research assistants, and PI will have access to all of the above 
information.  Co-I and medical monitor will have access to files upon request as they will need 
access to the locked rooms and filing cabinets in which these documents are located.  The key 
linking dummy identifiers with subject information will be securely destroyed after completion 
of data acquisition. 
 
 
 

48 
 
13 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
13.1 Ethical Standard 
 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research, as drafted by the US National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 
46 and/or the ICH E6; 62 Federal Regulations 25691 (1997). 
 
13.2 Institutional Review Board 
 
The Office of Human Research Ethics is responsible for ethical and regulatory oversight of 
research at UNC-Chapel Hill that involves human participants. The OHRE administers, supports, 
and guides the work of the Institutional Review Boards and all related activities. Any research 
involving human participants proposed by faculty, staff, or students must be reviewed and 
approved by an IRB before research may begin, and before related grants may be funded. OHRE 
and the IRBs are critical components of the coordinated Human Research Protection Program, 
which serves to protect the rights and welfare of human participants. All components of this 
program must work together to ensure institutional compliance with ethical principles and 
regulatory requirements. The following is a mission statement for the coordinated Human 
Research Protection Program: 
 
The University of North Carolina at Chapel Hill is committed to expanding and disseminating 
knowledge for the benefit of the people of North Carolina and the world. An important part of 
that commitment to knowledge is research of the highest quality on all aspects of the health and 
behavior of people, and such research is only possible through the participation of humans as 
research participants. Human participants are partners in research and a precious resource to the 
university. At UNC-Chapel Hill, human participant research is a privilege, but not a right. 
Consistent with that philosophy, it is the mission of the UNC-Chapel Hill Human Research 
Protection Program to ensure that 
 
1. The rights and welfare of human participants are paramount in the research process; 
2. The highest standards of ethical conduct are employed in all research involving human 
participants; 
3. Research investigators are properly trained in the ethical and regulatory aspects of 
research with human participants; 

49 
 
4. Research investigators deal honestly and fairly with human participants, informing them 
fully of procedures to be followed, and the risks and benefits of participating in research; 
and 
5. Research using human participants at UNC-Chapel Hill conforms to all applicable local, 
state, and federal laws and regulations and the policies of the university. 
 
13.3 Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
risks and possible benefits of tACS will be provided to the participants and their families. 
Consent forms describing, in detail, the study intervention, device, procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to the 
administration of any treatment or assessments used in this study.  Please see Appendix G for an 
example of the Documentation of Informed Consent Process form. All consent forms will be 
IRB-approved and updated with any new information as modifications are made throughout the 
study (Appendix F). 
 
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. 
 
13.4 Exclusion of Women, Minorities, and Children (Special Populations) 
 
Non-English speaking individuals are excluded because the ability to accurately and completely 
communicate study information, answer questions about the study, and obtain consent is 
necessary. Female participants will be asked if there is any reason to believe they might be 
pregnant. Pregnant participants will be excluded despite the fact that theoretical risk to mother or 
fetus is exceedingly small, since no safety data for pregnancy is known to exist for transcranial 

50 
 
current stimulation studies. All women of child-bearing potential will be asked to take a 
pregnancy test during the initial session in order to determine eligibility for the study. 
13.5 Participant Confidentiality 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
and the research team.  This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. 
 
All data will only be referenced by dummy identifier code. Data will be stored on a password 
protected computer. A key connecting names and code numbers will be kept in a locked cabinet, 
accessible only by research personnel. All data will be stored and analyzed on password 
protected computers, also only accessible by research personnel. Participants will not be 
identified in any report or publication about this study. 
 
13.6 Study Discontinuation 
 
In the event that the study is discontinued, participants who have completed or who are still 
enrolled in the study will be notified.  Any new information gained during the course of the study 
that might affect participant’s willingness to continue will be communicated within 2 days of the 
PI learning this information. 
 

51 
 
14 
DATA HANDLING AND RECORD KEEPING 
The study coordinator and research assistants are responsible for the accuracy, completeness, 
legibility, and timeliness of the data reported. During weekly meetings, the data will be reviewed 
by the PI to check for completeness and continued safety of the participants and research staff.  
Any changes made to the data will involve crossing out the original data, documenting the new 
data with the initials and date of the researcher making the change.  
 
14.1 Data Management Responsibilities 
 
The responsibilities designated to each member of the research team are documented on the 
Delegation of Authority SOP (Appendix K).  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. Dr. Asa Cordle will be the medical monitor for the study.        
 
14.2 Data Capture Methods 
 
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. 
 
14.3 Types of Data 
 
Data will be collected to determine eligibility. During the initial session, the SCID, AHRS, 
PANSS, CGI-S, SAS and AIMS will be administered. In order to participate in this study, the 
participant must have a diagnosis of schizophrenia or schizoaffective disorder, experience 
medication refractory auditory hallucinations, and are currently not committed in an inpatient 
hospital and on stable medication.  
 
We will also be collecting data to assess cognitive abilities at the 1st day of stimulation, the 5th 
day of stimulation and end point (one month follow-up). The BACS will be used to assess 
cognition in each participant and will be used as a safety monitor and data collection tool to 

52 
 
monitor any changes throughout the course of the study. 
 
The stimulation adverse effects questionnaire will be administered after each stimulation in order 
to monitor any side effects the participant may experience from the stimulation treatment. After 
the last stimulation and at the one week and one month follow-up, participants will be asked 
whether they believe their symptoms have improved due to treatment.  
 
The AHRS will be our primary outcome for this study. We will administer this questionnaire at 
the initial session, on the 1st day of stimulation, the 5th day of stimulation, and the one week and 
one month follow up. As our primary outcome, the data we collect with the AHRS will be used 
to determine efficacy of treatment.  
 
The PANSS, the CGI-S, the SAS and the AIMS will be used to collect additional data 
throughout the study. This questionnaire will also be administered on the 1st day of stimulation, 
the 5th day of stimulation, and the one week and one month follow up, in addition to during the 
initial session.  
 
An EEG recording will be performed at the 1st day of stimulation, the 5th day of stimulation, and 
at the one week and one month follow-up. The data collected from the EEG recording will 
enable assessment of neurophysiological changes induced by stimulation.  
 
14.4 Timing/Reports. 
 
The stimulation adverse effects questionnaire will be administered at the end of each stimulation 
session and at each follow-up session. Any AE will be reported to the PI within 72 hours and to 
the medical monitor within 24 hours.  Reports will be run at the end of each week and any 
unusual activity that could be a cause of concern will be reported to the PI at weekly meetings.  
 
14.5 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 grant end date, whichever is 
later.  
 

53 
 
14.6 Protocol Deviations 
 
All deviations from the protocol will be addressed in study participant source documents. The 
researcher will complete a Protocol Deviation Log (Appendix O) 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. 
 
 

54 
 
15 
PUBLICATION POLICY 
This study will be registered on clinicaltrials.gov once IRB approved. There are no restrictions 
on publications since this is an investigator-initiated study funded by a grant agency (NIMH) that 
has no influence on the publications resulting from this study. The aim is to publish the results of 
this study in a peer-reviewed, highly-ranked psychiatry journal. 
 

55 
 
16 
LITERATURE REFERENCES 
 
Ali, M. M., K. K. Sellers, et al. (2013). "Transcranial alternating current stimulation modulates 
large-scale cortical network activity by network resonance." The Journal of neuroscience : the 
official journal of the Society for Neuroscience 33(27): 11262-11275. 
 
Antal, A., Chaieb, L., Moliadze, V., Monte-Silva, K., Poreisz, C., Thirugnanasambandam, N., & 
Paulus, W. (2010). Brain-derived neurotrophic factor (BDNF) gene polymorphisms shape 
cortical plasticity in humans. Brain Stimulation, 3(4), 230-237. doi:10.1016/j.brs.2009.12.003 
 
Arns, M., C. K. Conners, et al. (2013). "A decade of EEG Theta/Beta Ratio Research in ADHD: 
a meta-analysis." J Atten Disord 17(5): 374-383. 
 
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Brunelin, J., M. Mondino, et al. (2012). "Examining transcranial direct-current stimulation 
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8674(03)00035-7 
 
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307. 
 
 

 
60 
 
SUPPLEMENTS/APPENDICES 
APPENDIX A: SCHEDULE OF EVENTS 
A detailed schematic describing all visits and assessments. 
 
 
STILL 2 Study Outline 
Procedures 
Consent Visit 
Screening Visit 
Day 1 of 
Stimulation 
Days 2 –4 of 
Stimulation 
Day 5 of 
Stimulation 
1 Week  
Follow-up 
1 Month 
Follow-up 
Signed Consent Form 
X 
 
 
 
 
 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
SCID, Med Hx, Phys. Exam 
 
X 
 
 
 
 
 
Incl/Excl Criteria 
 
X 
 
 
 
 
 
Medications 
 
 
 
 
 
 
X 
AHRS 
X 
X 
X 
 
X 
X 
X 
PANSS, CGI-S 
 
 
X 
 
X 
 
X 
SAS, AIMS 
 
X 
 
 
X 
 
X 
BACS 
 
 
X 
 
X 
 
X 
UDS, beta-HCG 
 
X 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
Stimulation 
 
 
X 
X 
X 
 
 
EEG 
 
X 
 
 
X 
X 
X 
EEG Questionnaire 
 
X 
 
 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
 
 
 
 
 
 
 

 
61 
 
 
APPENDIX B: AE REPORT FORM 
 
Adverse Effects Report:  
Reasons for Report (adverse event, time, date and place of occurrence if available):  
1. What do we already know about the therapy? 
a.  
2. What is the temporal relationship of the AE to the study therapy? 
a.  
3. Does the AE improve or disappear when the therapy is stopped? 
a.  
4. Is the AE a worsening of baseline symptom(s)? 
a.  
5. Is the AE a result of an underlying concurrent medical condition(s) or concurrent 
medication(s)? 
a.   
6. Additional Information provided by research team  
a.  
Research team member signature ______________________________________ 
Date____________ 
Co-Investigator :  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________ 
CI signature 
_______________________________________________________Date___________ 
 
PI Comments:  
______________________________________________________________________________
______________________________________________________________________________

 
62 
 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________ 
 
Steps to be taken (if applicable) 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________ 
 
PI signature 
_______________________________________________________Date___________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
63 
 
APPENDIX C: AE LOG 
 
Participant ID 
 
 if AE meets 
definition of 
serious* 
 
GRADE / 
INTENSITY 
1. Asymptomatic 
2. Mild 
3. Moderate 
4. Severe 
 
 
DATE OF 
INCIDENT 
 
Relationship to 
study device 
 
1. Related 
2. Possibly 
3. Not Likely 
4. Not Related 
 
 
Was Action 
Taken? 
 
 
 
 
 
Action(s) Taken: 
 
 
 
Outcome: 
 
1. Recovered 
2. Not Recovered 
3. Recovered w/Sequel 
4. Fatal 
5. Unknown 
 
PI Initials / Date 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 
 
 
 
 
 
Yes  /  No 
 
 
 

 
64 
 
APPENDIX D: SAE REPORT FORM 
Participant ID: _______________ 
 
1. Location of SAE (e.g., clinic, home): __________________________________________ 
 
2.   Age: ______  
 
3.  Gender: Male Female 
 
4. SAE term (provide diagnosis): _____________________________________________________ 
 
4a. If diagnosis is not known, symptoms: ____________________________________________ 
 
5. Date of onset: ________________________ (dd/mm/yyyy) 
 
6. What is the severity grade of the serious adverse event?  
 
Grade: 1: Mild  
Grade 2: Moderate  
Grade 3: Severe  
Grade 4: Life-threatening  
Grade 5: Death 
 
7. Did the participant receive the investigational product or study intervention prior to this SAE? 
   Yes  
 No  
 
N/A 
 
7a. If yes, identify the investigational product or study intervention received prior to the SAE: 
Investigational Product/Study Intervention 
 
Dose_______ 
Units_______ 
Frequency________ 
 
Start Date _____/_____/______(dd/mm/yyyy) 
Stop Date _____/_____/______( (dd/mm/yyyy) 
Check if Ongoing 
      8. Action taken with investigational product/study intervention: 
 
Continued 
Lowered 
Interrupted 
Discontinued 
Increased 
N/A 
 
9. Outcome of SAE: 
 
Ongoing at this time 
Resolved without sequelae 
Resolved with sequelae 
Death 
Present at death, not contributing to death 
 
 

 
65 
 
10. Date of resolution: ________________________ (dd/mm/yyyy) or  
 Ongoing at end of study 
 
11. Seriousness criteria? (Check all that apply) 
 
Life-threatening 
Required hospitalization or 
Prolongation of existing hospitalization 
Congenital anomaly 
Disabling/incapacitating 
Important medical event 
Fatal 
If fatal: 11a. Date of death: ________________________ (dd/mm/yyyy) 
11b. Primary cause of death: _______________________________________________ 
11c. Was an autopsy performed?  
 
Yes  
No 
 
12. Relationship to investigational product/study intervention: 
 
Related (Associated with the use of the study intervention. There is a reasonable 
possibility that the experience may have been caused by the study intervention.) 
Unrelated 
 
13. If SAE is unrelated to investigational product/safety intervention, select all possible etiologies: 
Concurrent illness, disease, or other external factors, specify: 
_____________________________________________________________________________
_____________________________________________________________________________ 
 
Concurrent medication, specify: 
_____________________________________________________________________________ 
 
Secondary study procedure, specify: 
_____________________________________________________________________________ 
 
Accident, trauma, or other external factors, specify: 
_____________________________________________________________________________ 
 
Other, specify: 
_____________________________________________________________________________ 
 
14. Did the participant receive any relevant concomitant medications in response to the SAE?  
Yes 
 No 
 
 
14a. If yes, please specify: Name, Start and Stop date or On going  
 
_____________________________________________________________________________ 
 
 
 
15. Did the participant receive any treatments/procedures in response to the SAE?  
 
Yes  
No  
 

 
66 
 
15a. If yes, please specify 
 
_____________________________________________________________________________ 
 
_____________________________________________________________________________ 
 
16. Did the participant receive relevant laboratory or diagnostic tests in response to the SAE?  
 
Yes  
No  
 
16a. If yes, provide the name of the test and results with normal ranges and/or supplemental 
 
 exams below:  
 
____________________________________________________________________________ 
 
____________________________________________________________________________ 
 
_____________________________________________________________________________ 
 
 
17. Narrative/Comments (provide a description of the serious adverse event including chronological 
clinical presentation and evolution of the serious adverse event and associated signs/symptoms):  
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
____________________________________________________________________________________ 
 
 
18. Completion of form: printed names, signatures and date of signature  
 
Person Completing Form 
(print name)  
           Person Completing Form  
                   (signature)  
Date  
 
 
 
______________________________________________________________________________ 

 
67 
 
 
Investigator (print name)  
Investigator (signature)  
Date 
 
______________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
68 
 
APPENDIX E: UE/SAE LOG 
 
Participant ID 
  
 
 
Date Event 
Occurred 
 
Date Study 
Team Notified 
of Event 
 
 
Event 
 
 
Date Reported 
to IRB 
 
 
Study SAE Form Completed 
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 
 
 
 
 
Yes     
No      
N/A      
 

 
69 
 
APPENDIX F: CONSENT AMENDMENT TRACKING LOG 
 
 
 
Change Initiated 
by: 
              Adjustments made to consent form
Date 
Submitted 
to IRB 
Date of 
IRB 
Answer 
Requires 
Stipulations? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date  
Initials  
Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
70 
 
APPENDIX G: INFORMED CONSENT PROCESS DOCUMENTATION 
Abbreviated Study Title:  
 
 
 
 
 
 
Participant Name:  
 
 
 
 
 
 
Date of Birth:   
 
 
 
Medical Record #: __________________________ 
 
Please INITIAL next to “Yes” or “No” by each line as appropriate (if “No,” an explanation MUST be 
provided in the notes section below). 
 
 
Yes 
 
No 
Participant and/or the participant’s legally authorized representative (LAR) 
was given a copy of the consent document to read. 
 
Yes 
 
No 
Ample time was provided for reading the consent document, and the 
participant (or participant’s LAR) was encouraged to ask questions. 
 
Yes 
 
No 
All questions and concerns were addressed to the satisfaction of the 
participant (or participant’s LAR) prior to signing the consent document. 
 
Yes 
 
No 
The PI or Sub-I was available for questions prior to the subject signing the 
consent.  
 
Yes 
 
No 
The subject (or subject’s LAR) agreed to participate in the study and 
signed/dated the consent document. 
 
Yes 
 
No 
A copy of the signed consent document was provided to the participant (or 
participant’s LAR). 
 
 
 
 
 Verbal consent was obtained (per IRB approved consent process).  
Documentation of the process and the individual(s) witnessing the process is 
described below. 
 
Yes 
 
No 
No procedures specifically related to the study were performed prior to the 
participant signing the consent document. 
 
The details of this research study were discussed with the participant (or participant’s LAR), including an 
explanation of all of the elements of the consent document.  The IRB-approved consent document was 
signed and dated by the participant (or participant’s LAR) and a copy of the signed consent document 
was placed in the participant’s medical record (unless otherwise noted).  No activities specifically related 
to the research were initiated until after the execution of the consent document.  The principal 
investigator was notified of the participant’s consent to be enrolled in the study and agrees with 
enrollment of subject. 
 
The participant (or participant’s LAR) signed consent document version  
 
 
 
 
on    
 
(date) at  
 
(time). 
 

 
71 
 
Notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent 
 
 
Date 
 
 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
72 
 
APPENDIX H: INFORMED CONSENT QUIZ 
 
Name of Research Study:  
 
 
You have been asked to be in a research study. This sheet will help you think 
of questions to ask but you may have other questions.  This is not a test.  We 
want to be sure you understand what it means to be in this research study.  
You should understand the research before you decide whether or not to 
participate. 
 
 
1. What is the purpose of the research? 
 
 
2. What are the possible benefits of the research? 
 
 
3. What are the possible risks of the research? 
 
 
4. Will everyone receive the same treatment? 
 
 
5.   How is this research different than the care or treatment I would get if I wasn’t in 
the research study?  
 
 
6.  Does in the research cost me anything extra? 
 
 
7. Can you stop being in the research once you’ve started? 
 
 
8.  Who will view your medical records? 
 
 
9.   Who do you call if I have questions about being a research subject? 
 
 
10.  Any questions?   

 
73 
 
APPENDIX I: IRB AMENDMENT TRACKING LOG 
 
 
 
Change Initiated 
by: 
Description of IRB: Type and Brief 
Summary  
Date 
Submitted 
to IRB 
Date of 
IRB 
Answer 
Requires 
Stipulations? 
(Y/N) 
Requires 
Updated 
Consent 
Form? 
(Y/N) 
Stipulation 
Submission 
Date 
IRB 
Approval 
Date  
Initials  Reference 
ID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
74 
 
APPENDIX J: DELEGATION OF AUTHORITY 
 
 
 
 
 
 
 
Designee (full 
name) 
 Courtney Lugo 
Juliann Mellin 
Dr. Fred Jarskog 
Dr. John Gilmore  Dr. Flavio Frohlich 
Title & Position 
Study Coordinator 
Study Coordinator 
Co-Investigator  
Co-Investigator  
Principal Investigator 
Delegated Activity 
(see codes) 
 
 
 
 
 
Designee 
Signature & Dates 
 
 
 
 
 
Designee Initials 
(signed) 
 
 
 
 
 
 
Activity Codes: 
01:  Informed Consent                                 04:  CRF Entries                           07:  Data Entry 
02:  Initial Session Review for Eligibility   05:  Device Administration           08: Adverse Event Assessment 
03:  Questionnaire Administration              06:  EEG Administration              09: Adverse Event 
Documentation/Reporting 
10: Medical Monitor   
 
Investigator’s Authorization: I hereby delegate the above significant research-related duties to the following persons 
and understand that the overall responsibility for conduct of the research remains with me. 
 
1Investigator’s Signature: 
Date:  

 
75 
 
APPENDIX K: ENROLLMENT LOG 
 
Subject ID 
Date 
Consent 
Signed 
Gender 
Race 
Ethnicity 
Treatment 
Arm / 
Group 
Explanation if subject did not 
complete study / Comment 
1 
 
 
M 
 F 
 
 
 
 
 
2 
 
 
M 
 F 
 
 
 
 
 
3 
 
 
M 
 F 
 
 
 
 
 
4 
 
 
M 
 F 
 
 
 
 
 
5 
 
 
M 
 F 
 
 
 
 
 
6 
 
 
M 
 F 
 
 
 
 
 
7 
 
 
M 
 F 
 
 
 
 
 
8 
 
 
M 
 F 
 
 
 
 
 
9 
 
 
M 
 F 
 
 
 
 
 
10 
 
 
M 
 F 
 
 
 
 
 
11 
 
 
M 
 F 
 
 
 
 
 
12 
 
 
M 
 F 
 
 
 
 
 
13 
 
 
M 
 F 
 
 
 
 
 
14 
 
 
M 
 F 
 
 
 
 
 
15 
 
 
M 
 F 
 
 
 
 
 

 
76 
 
APPENDIX L: INCLUSION/EXCLUSION CRITERIA CHECKLIST 
Inclusion Criteria 
DSM-IV diagnosis of schizophrenia, any subtype, or schizoaffective disorder,  
with refractory auditory hallucinations. Duration of illness >1 year.  
 
 
Yes  
 
No 
18-70 years old. 
 
 
 
 
 
 
 
 
 
Yes  
 
No 
Clinically stable for at least 12 weeks, i.e. not requiring hospitalization  
or a change in level of care 
 
 
 
 
 
 
 
 
Yes  
 
No 
On current antipsychotic doses for approx. 4 weeks or more 
 
 
 
Yes  
 
No 
Capacity to understand all relevant risks and potential benefits of  
the study (informed consent) OR has a legal guardian who can  
 
 
 
Yes  
 
No 
complete consent forms on the patients behalf 
 
 
 
 
 
 
 
 
 
 
 
 
If the responses to all the inclusion criteria are YES and all the exclusion criteria are NO, the 
participant is able to participate in the trial. 
Is the participant eligible to participate in the trial?   
 
YES 
 
NO 
If NO, discontinue subject. 
If YES, I have reviewed the inclusion and exclusion criteria and have determined that the 
participant is eligible for participation in the trial. 
 
Investigator Signature: ____________________________  
 
Date: _____________ 
 
Exclusion Criteria 
Subjects with a DSM-IV diagnosis of alcohol or substance abuse  
(other than nicotine) within the last month or a DSM-IV diagnosis   
 
 
 Yes   
No 
of alcohol or substance dependence (other than nicotine) within the last 6 months  
 
 
History of significant head injury/trauma, as defined by loss of  
consciousness for more than 1 hour, or recurring seizures, or requiring  
 
 
 Yes   
No 
later cognitive rehabilitation or causing cognitive sequellae 
Prior brain surgery 
 
 
 
 
 
 
 
 
 
 Yes   
No 
Any brain devices/implants, including cochlear implants and aneurysm clips 
 
 Yes   
No 
Co-morbid neurological condition (i.e. seizure disorder, brain tumor) 
 
 
 Yes   
No 
Medical or neurological illness (unstable cardiac disease AIDS, malignancy,  
liver or renal impairment) or treatment for a medical disorder that could   
 
 Yes   
No 
interfere with study participation  
Non English speakers  
 
 
 
 
 
 
 
 
 Yes   
No 
Pregnancy, nursing, or if female and fertile, unwilling to use  
 
 
 
 Yes   
No 
appropriate birth control measures during study participation 

 
77 
 
APPENDIX M: NOTE TO FILE 
 
IRB#: 14-3285 
 
 
 
 
 
 
 
PI: Flavio Frohlich 
Study Title: 
____________________________________________________________________ 
Date of Occurrence: ________________ 
Research Name: ____________________________________ 
Participant ID: _________________ 
Reason for Note: 
______________________________________________________________________ 
______________________________________________________________________ 
Note: 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
Corrective action (if applicable);____________________________________________ 
______________________________________________________________________
______________________________________________________________________
______________________________________________________________________ 
 
 
 
Signature: ______________________________  
    Date: _______________ 

 
78 
 
APPENDIX N: PROTOCOL DEVIATION LOG 
Participant 
ID 
Date 
Occurred 
Description 
CAPA* 
Date PI 
Notified 
Date 
IRB 
Notified 
PI  
Initial/Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
79 
 
APPENDIX O: STUDY START UP CHECKLIST 
Study Start Up Checklist 
Study Title: ______________________________________________________    
 
Funding Source: 
___________________________________________________________________ 
 
 
Date Completed 
 
CRMS Recorded Created 
______________________ 
 
IRB Application Submitted  
______________________ 
Approved Date : ____________ 
CVs/Certifications/Medical 
License 
______________________ 
 
IRB Roster 
______________________ 
 
IRB Statement of Compliance 
______________________ 
 
PI Signature of Protocol 
______________________ 
 
                                                                Date Completed 
Study Binders Created 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
______________________ 
 
 
 
 
______________________ 
______________________ 
______________________ 
______________________ 
 
Regulatory Documents Filed 
Protocol Deviation Tracking Log 
Filed 
Completion of Site Training, 
Filed 
Delegation Log Completed 
Develop Recruitment Plan 
Begin Pre-Screening 
Source Documents Created  
Participant Folders Created 
 
 
 
Schedule Study Start Up 
Meeting 
Lab Kits Received 
Participant Supplies Received 
Investigational Device Received 
 
 
 

 
80 
 
APPENDIX P: PARTICIPANT OFF STUDY FORM 
Participant Initials                            ID 
 
 
           Date:             /               / 
                         Month         Day            Year 
 
 
Participant Off Study 
 
Date participant went Off Study:             /               / 
             
 
                         Month         Day            Year 
 
INDICATE OFF STUDY REASON:  
  Study Activities Completed  
  Side effects of study intervention (complete applicable SAE form or AE Tracking Log) 
  Death 
 
  Participant lost to follow-up* (provide comments below) 
 
  Participant refused follow-up* (provide comments below) 
 
  Other* (provide comments below) 
  Participant withdrew (complete Early Withdrawal section below) 
 
Was treatment unblinded? 
1 Yes    
2 No    
3 Not Applicable 
 
Early Withdrawal  
 
Last Visit Completed:  
 
 
 
 
  Early Withdrawal form not completed 
 
  Screening Visit  
  Visit 1 
 
  Visit 3 
  Visit 4                                         
 
 
  Visit 6   
  Visit 2                                         
  Visit 5                                          
  Visit 7   
 
   
Indicate the primary reason the participant has withdrawn from the study (select only one): 
  Participant deemed eligible but declined participation  
  Participant deemed inappropriate for study participation by the PI  
  Participant was determined to be ineligible after enrollment* (provide comments    below) 
  Identification of disease/condition after enrollment that warrants withdrawal* 
 
  Unable to continue due to personal constraints* 
 
  Side effects of study intervention * (complete UWI-02-007 Adverse Event Tracking   
 
Log)  
  Other * 
 
 
 

 
81 
 
*Additional explanation required:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FORM COMPLETED BY:    
 
 
 
 
 
 
 
 
 
 
 

 
82 
 
APPENDIX Q: TELEPHONE LOG 
 
Date/Time 
 
 
Incoming/Outgoing 
 
Message/Conversation 
 
Reason for calling 
 
Comments/Researcher Initials 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 
 
Incoming 
Outgoing 
 
 
Message 
Conversation 
 
 
 

 
83 
 
 
APPENDIX R: TRAINING LOG 
Title of Training:______________________________ 
 
DATE:__________________________ 
(e.g., Protocol; Amendment; IRB [include version #/date]) 
 
By signing below, each staff member verifies they have been trained on the information and understand the 
obligations/responsibilities associated with this training. 
 
Trainer Name (if relevant):_____________________________ 
(Please print) 
 
Trainer Signature (if relevant):___________________________________
Training Date 
(if different than 
above) 
Trainee Name 
(please print) 
Trainee Signature 
Training Format 
(ie Presentation; Self-Study) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
84 
 
APPENDIX S: TELEPHONE RECRUITMENT SCRIPT 
 
Hello, my name is _________. Are you contacting me in regards to the non-invasive brain 
stimulation study?  
 
If ‘No’, redirect them as necessary) 
(If ‘Yes’, proceed) 
Do you have time now to hear about the study, answer a few screening questions, and schedule 
your first visit?  
 
(If ‘No’, ask for a good time to call back) 
(If ‘Yes’, proceed) 
 
Great! This study is looking at how abnormal rhythms of brain activity in schizophrenia respond 
to very weak applied currents. Findings from this study will help the development of treatments 
for the symptoms of schizophrenia, like auditory hallucinations. In the study, a very weak 
current will be applied to your scalp. Some people report a mild tingling because of this 
stimulation, but no other side effects have been found. It is not a shock and should cause no 
pain.  
 
Participation in this study includes one to eight sessions, with one session being an initial 
information session, then five, twice daily stimulation sessions, followed by a one week then 
one month follow up session. The stimulation sessions need to be on consecutive days with the 
second session occurring 3 hours after the completion of the first session. The maximum 
compensation for this study is $340 for completing all of the sessions. Are you still interested in 
participating? 
 
(If ‘No’, thank them for their time) 
(If ‘Yes’, proceed) 
 
Great! In order to make sure you’re eligible for the study, I need to ask you a few questions. 
Please answer yes or no. You do not need to provide any further details.  
(If the answer given is not the same as the answer shown, thank the individual for his or her 
interest and say unfortunately, they do not qualify for the current study) 
 
x 
Are you 18 years old or older?  (Yes) 
x 
Have you ever, or are you currently being treated for a neurological condition (i.e. 
epilepsy)? (No) 
x 
Are you currently taking any benzodiazepines or anticonvulsant medications? (No) 
x 
Have you ever had brain surgery? (No) 
x 
Do you have any brain devices or implants, including a cochlear implant or aneurysm 
clip? (No) 
x 
Have you ever been diagnosed with a traumatic brain injury? (No) 

 
85 
 
x 
(For females only), Is there a chance you may be pregnant? (No) 
 
Follow-up questions: 
 
x 
Do you wear glasses/contact lenses? 
o 
Could you bring your contact lenses for the study visits instead of wearing your 
glasses? 
 
(If answered according to all indicated responses, continue) 
 
Excellent! Due to the study schedule, some sessions will be longer than others. Is it possible for 
you to be available from 8 – 5 on weekdays to be at the UNC Hospital in order to participate in 
this study? If not, can you specify the days/times that do not work for you? 
 
Would you be willing to participate in an 8 hour session for this study? (This includes a 3 hour 
break).  
 
You are eligible for participation in the first session of the study. At the first session we will 
determine your eligibility for the remainder of the sessions.  I’d like to schedule your first 
session now. It will last approximately 3 hours. All testing will be conducted at either UNC 
Hospital or the NCPRC in Raleigh.  (specific location).  
 
(Schedule a time for first session) 
 
I will give you a call to confirm your appointment 24 hours beforehand. If you have any 
questions before then, please don’t hesitate to contact us at this phone number. 
 
Thank you for your time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
86 
 
APPENDIX T: EEG QUESTIONNAIRE 
 
EEG Questionnaire 
Date:____________ 
 
 
 
 
Participant ID:___________ 
 
After Resting State EEG:  
During this EEG task, can you tell me what you heard (if anything)? 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
After Oddball task: 
During this EEG task, can you tell me what you heard (if anything)? 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
After click train task: 
During this EEG task, can you tell me what you heard (if anything)? 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________