Physiological Correlates of Active Music-making and Passive Listening in Music Based Interventions
Phase: NA
Conditions: Autonomic Nervous System Imbalance, Hypothalamic Pituitary Adrenal Axis Suppression
Sponsor: University of North Carolina, Chapel Hill

 
 
PHYSIOLOGICAL CORRELATES OF ACTIVE MUSIC-
MAKING AND PASSIVE LISTENING IN MUSIC BASED 
INTERVENTIONS 
 
 
NCT03362944 
12/14/17 
 
 
 
 
 
 
 
 
 
 
 
 

PHYSIOLOGICAL CORRELATES OF 
ACTIVE MUSIC-MAKING AND 
PASSIVE LISTENING IN MUSIC 
BASED INTERVENTIONS 
  
A pilot, randomized, unblinded study of the effects of active participation in music making on stress hormones and 
heart rate variability with a passive listening control 
 
Funding Mechanism: 
 
Principal Investigator: 
Flavio Frohlich, PhD 
Co-Investigator: 
Dorita Berger, PhD, MT-VC, LCAT  
Protocol Number: 
 
Version Number: 
1.0 
Date: 
12/14/17  
 
 
 
 
 
 
 
 
 
 

Initial version: 
1.1 
TABLE OF CONTENTS 
STUDY SUMMARY ........................................................................................................................... 5 
1 
KEY ROLES ........................................................................................................................... 6 
1.1 
INDIVIDUALS ........................................................................................................................... 6 
1.2 
INSTITUTIONS .......................................................................................................................... 6 
1.3 
OPTIONAL ............................................................................................................................... 6 
1.4 
FUNDING SOURCES .................................................................................................................. 6 
2 
INTRODUCTION .................................................................................................................. 6 
2.1 
BACKGROUND ......................................................................................................................... 6 
2.2 
INVESTIGATIONAL AGENT ....................................................................................................... 7 
2.3 
STUDY AIMS/HYPOTHESES ...................................................................................................... 7 
2.4.1 
PRIMARY OBJECTIVE ....................................................................................................................... 7 
3 
SUBJECT SELECTION AND WITHDRAWAL ................................................................... 7 
3.1 
INCLUSION CRITERIA .............................................................................................................. 7 
3.2 
EXCLUSION CRITERIA ............................................................................................................. 7 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................................. 8 
3.3.1 
RECRUITMENT ................................................................................................................................. 8 
3.3.2 
RETENTION ..................................................................................................................................... 8 
4 
BASIC STUDY DESIGN ........................................................................................................ 8 
4.1 
TREATMENT ASSIGNMENT PROCEDURES ................................................................................ 9 
4.1.1 
RANDOMIZATION PROCEDURES ...................................................................................................... 9 
5 
STUDY SCHEDULE .............................................................................................................. 9 
5.1 
SCREENING .............................................................................................................................. 9 
5.2 
SESSIONS ................................................................................................................................. 9 
6 
STUDY PROCEDURES/EVALUATIONS ............................................................................ 9 
6.1 
SELF-REPORT MEASURES ........................................................................................................ 9 
6.2 
SPECIAL ASSAYS OR PROCEDURES ......................................................................................... 10 
7 
STUDY INVESTIGATIONAL PRODUCT ......................................................................... 10 
7.1 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL PRODUCT .... 10 
8 
POTENTIAL RISKS AND BENIFITSPOTENTIAL RISKS AND BENEFITS .................. 10 

8.1 
BENEFITS TO SUBJECTS AND SOCIETY .................................................................................. 10 
8.2 
POTENTIAL RISKS ................................................................................................................. 10 
8.2.1 
PSYCHOLOGICAL ........................................................................................................................... 10 
9 
DATA AND SAFETY MONITORING ................................................................................ 11 
9.1 
FROHLICH LAB MONITORING PLAN ...................................................................................... 11 
9.2 
EARLY WITHDRAWAL OF PARTICIPANTS .............................................................................. 11 
9.2.1 
REASONS FOR WITHDRAWAL ........................................................................................................ 11 
10 
SAFETY & REPORTING .................................................................................................... 12 
10.1 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY 
PARAMETERS ..................................................................................................................................... 12 
10.1.1 
UNANTICIPATED PROBLEMS ..................................................................................................... 12 
10.2 
REPORTING PROCEDURES ..................................................................................................... 12 
10.3 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS ............ 13 
11 
STATISTICAL PLAN .......................................................................................................... 13 
11.1 
STATISTICAL ANALYSIS STRATEGIES .................................................................................... 13 
11.2 
SAMPLE SIZE DETERMINATION .............................................................................................. 13 
11.3 
DATA MANAGEMENT ............................................................................................................. 13 
12 
DATA HANDLING AND RECORD KEEPING .................................................................. 14 
12.1 
PHI AND HIPAA ................................................................................................................... 14 
12.2 
CONFIDENTIALITY ................................................................................................................ 14 
12.2.1 
ACCESS TO SOURCE DOCUMENTS ............................................................................................. 14 
12.2.2 
SENSITIVE INFORMATION .......................................................................................................... 14 
12.2.3 
OTHER ....................................................................................................................................... 14 
12.3 
SOURCE DOCUMENTS ............................................................................................................ 15 
12.4 
DATA MANAGEMENT RESPONSIBILITIES ............................................................................... 15 
12.6 
PROTOCOL DEVIATIONS ........................................................................................................ 16 
12.7 
RECORD RETENTION ............................................................................................................. 16 
13 
ETHICAL CONSIDERATIONS .......................................................................................... 16 
13.1 
ETHICAL STANDARD ............................................................................................................. 16 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) ................................................................................. 16 
13.3 
INFORMED CONSENT PROCESS .............................................................................................. 17 
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) ................. 17 
13.5 
PARTICIPANT CONFIDENTIALITY .......................................................................................... 17 
13.6 
STUDY DISCONTINUATION ..................................................................................................... 17 
APPENDIX: AE REPORT FORM ................................................................................................... 18 

 
 
STUDY SUMMARY 
Title 
Physiological correlates of active music making and passive listening in music based 
interventions 
Short Title 
Correlates of active music making 
Protocol Number 
 
Phase 
Pilot study 
Methodology 
Within participants 
Study Duration 
2 sessions per participant, 1 hour 
Study Center(s) 
This is a single-site study performed at The University of North Carolina at Chapel 
Hill. 
Objectives (Purpose) 
Understand how active music making influences correlates of the HPA axis and ANS 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
18-34, non musician, healthy controls  
Description of 
Intervention 
(Procedures/methods) 
Participants will recive a 40 minute music based intervention or will receive a 
listening control.  Physiological measure  will be taken before and after the 
intervention/control 
Related IRB 
Applications 
 
 
 
 

1 
KEY ROLES 
1.1 
INDIVIDUALS 
Principal Investigator 
Flavio Frohlich, PhD 
Co-Investigator 
Dori Berger, PhD, MT-BC, LCAT 
 
 
1.2 
INSTITUTIONS 
The University of North Carolina at Chapel Hill 
1.3 
OPTIONAL 
IRB 
The University of North Carolina – Chapel Hill 
Medical School Building 52 
Mason Farm Road 
CB #7097 
Chapel Hill, NC 27599-7097 
(919) 966-3113 
 
1.4 
FUNDING SOURCES 
Please list below the funding sources for this project 
Sponsor Name 
UNC Ramses 
Number 
Sponsor Type 
Prime Sponsor 
Name 
Prime Sponsor 
Type 
Sponsor/Grant 
Number 
 
 
 
 
 
 
External Funding: This project is externally funded but UNC-CH is not the direct recipient of federal funds. 
UNC-CH Funding: This project is not funded through UNC-CH. 
Classified: This project is not classified. 
 
2 
INTRODUCTION 
This document is a protocol for a human research study. This study is to be conducted according to U.S. and 
international standards of Good Clinical Practice (FDA Title 21 Part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. 
2.1 
BACKGROUND 
 

Major depressive disorder (MDD) is the leading cause of disability for U.S. citizens aged 15-44, and 
affects more than 16 million Americans each year. Existing interventions struggle to combat this societal 
burden and fail to reach the large number of treatment resistant patients, creating an urgent need for the 
development of new treatment paradigms. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) 
axis and dysregulation of the autonomic nervous system (ANS) have been implicated in MDD. Listening 
to music alters stress hormone levels and heart rate variability (HRV), physiological correlates of the 
HPA axis and ANS respectively. Active music-making’s effects on these correlates has yet to be studied. 
Since active musical engagement involves multiple sensory inputs—proprioceptive and motor in addition 
to auditory—it has the potential to heighten physiological changes associated with listening to music 
alone. By contrasting a structured participation MT intervention with a listening control, we will target 
the effects active participation in music-making as a potential treatment for MDD. 
2.2 
INVESTIGATIONAL AGENT 
Our investigational agent is music.  In intervention sessions, participants will be working one on one with a music 
therapist, participating in musical activities.  In control sessions participants will be listening to musical excerpts. 
2.3 
STUDY AIMS/HYPOTHESES 
2.4.1 
PRIMARY OBJECTIVE 
We hypothesize that both conditions will produce a decrease in stress hormone levels and LF/HF, and an 
increase in HF. We also expect these changes to be greater in the active MT intervention than the passive 
listening condition. This would demonstrate the interventions ability to uniquely target the HPA axis and 
ANS, relaxing the participant. 
 
3 
SUBJECT SELECTION AND WITHDRAWAL 
A total of 20 participants will be recruited for this study and all data will be collected at UNC-CH. No specific plans 
have been made to enroll participants from vulnerable populations.  
3.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, a participant must meet all of the following criteria: 
• 
18-34 year olds. 
• 
Capacity to understand all relevant risks and potential benefits of the study (informed consent) 
• 
Willing to comply with all study procedures and be available for the duration of the study 
• 
Speak and understand English 
3.2 
EXCLUSION CRITERIA 
A potential participant who meets any of the following criteria will be excluded from participation in the study  
• 
Formal musical training—more than three years of musical training before the age of 12 and any after this 
age. 
• 
Outside age range 
• 
Non-English speaker 
• 
Cardiovascular disease/medications 
• 
Neurological disease/medications 

• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or preclude 
the participant’s full compliance with or completion of the study 
Justifications for any exclusions based on race, gender, or ethnicity: Non-English speaking individuals are 
excluded because the ability to accurately and completely communicate study information, answer questions about 
the study, and obtain consent are necessary. 
Justification for exclusions based on formal musical training: Musical training would predispose individuals to 
interact with an isochronous auditory stimulus in a different way than non-musicians.  Their ability to entrain and 
coordinate with the pulse will likely be better as they have spent significant amounts of time entraining to rhythms 
through musical performance and instruction.   
Justification for exclusions based on cardiovascular disease: Cardiovascular disease would likely influence the 
ANS measures we would be recording in the study (HR, HVR) making our results not representative of healthy 
individuals.  This pilot study is not meant to assess clinical outcomes of the entrainment task. 
Justification for exclusions based on neurological diseases and CNS disorder medication: Neurological 
diseases would likely influence the behavior and cognitive processes of the participants, affecting their entrainment 
ability, making our results not representative of healthy individuals. This pilot study is not meant to assess clinical 
outcomes of the entrainment task. 
 
3.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
3.3.1 
RECRUITMENT 
Fliers will be designed to recruit participants that meet our inclusion criteria, and will be posted around 
campus in locations where undergraduates are likely to see them.  Campus emailing-lists will also be used 
to distribute study information and inclusion criteria to recruit individuals.  Individuals will self-identify 
and email us, at which point we will call them for a telephone screening. 
3.3.2 
RETENTION 
Subjects will receive the full $10.00 immediately at the conclusion of both the first and second visit. If a 
subject withdraws from participation in the middle of their visit after the fitting of EKG electrodes, full 
compensation will still be awarded. 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.  The study team will work hard at forming a professional relationship with each participant so 
that they feel comfortable and willing to discuss what may be sensitive information.  
4 
BASIC STUDY DESIGN 
Figure 1. 
 
 
A within participants design will be used, where each participant receives the active intervention and the 
Phone Screening
Initial Session (control 
or intervention)
Second session (control 
or intervention)

passive control separately. 
 
In the active intervention, participants will undergo a 40 minute structured MT intervention that includes 
standardized breathing, rhythmic, and improvisational exercises. In the passive control, participants will 
listen to 40 minutes of clinician selected music, matched in style and structure to the segments of the 
intervention. 
 
Participants will be fitted with EKG electrodes and 5 minute HRV baseline recordings will be taken, 
during which the participants will be given unrelated reading material to keep them alert and control 
behavior. Stress hormones—cortisol and alpha-amylase—will be assessed though saliva samples taken 
from the participant. Attention, handedness, and musical experience questions will be administered to 
collect supplementary data that can account for and justify the exclusion of outliers. 
 
4.1 
TREATMENT ASSIGNMENT PROCEDURES 
The treatment order will be randomized and counter balanced.  Participants will be randomly sorted into 
either intervention first or control first conditions. 
4.1.1 
RANDOMIZATION PROCEDURES 
Trials types will be randomly dispersed throughout an experimental block, and block design will be 
automated and randomized in Matlab. 
 
5 
STUDY SCHEDULE 
It is important to note that consent, scales, and experiments will all take place in a private room. Any phone calls 
will take place in a private lab environment as well.  
5.1 
SCREENING 
Telephone screening will take place before the first session to ensure the participant is eligible to participant and to 
schedule a session time. 
5.2 
SESSIONS 
Upon arrival for the first session participants will look over and sign a consent form. They will then 
complete initial attention and handedness questionnaires, followed by a baseline HRV recording and 
collection of initial saliva samples. Then either the intervention or the control will be administered, 
followed by another HRV baseline recording and collection of saliva samples. After this, participants will 
be allowed to leave. Total participation time will be 1 hour and participants will be compensated $10 
upon the completion of each session. In session 2 participants will go through the same procedure, but 
will receive the opposite treatment condition, and will not complete the handedness questionnaire a 
second time. A week will pass before the participant can come back for their second session. Sessions 
will be held in UNC’s Keenan Music Building. We have previously conducted studies here, working 
closely with the music department to secure equipment, storage space, and study locations. 
 
6 
STUDY PROCEDURES/EVALUATIONS 
6.1 
SELF-REPORT MEASURES 

A. Attention questionnaire—assess the arousal and engagement of the participant at the beginning of 
each session 
B. Handedness questionnaire—assess whether the participant is right handed or left handed 
C. Musical experience questionnaire—assess the participant’s past musical experience as well as 
any thoughts or concerns they may have had about the treatments 
6.2 
SPECIAL ASSAYS OR PROCEDURES 
A. 4 HRV recordings—2 per session, recorded though disposable EKG electrodes 
B. 4 saliva samples—2 per session, recorded though oral collection swabs 
7 
STUDY INVESTIGATIONAL PRODUCT 
7.1 
ASSESSMENT OF PARTICIPANT COMPLIANCE WITH STUDY INVESTIGATIONAL 
PRODUCT 
Compliance for this study includes attending the entire experimental sessions and following the instructions given 
by the experimenter. Non-compliant participants will be asked to leave, will not be payed, and the experimental data 
will be discarded. 
8 
POTENTIAL RISKS AND BENIFITSPotential Risks and Benefits 
8.1 
BENEFITS TO SUBJECTS AND SOCIETY 
Music based interventions (MT) are a cost-effective, accessible, and holistic treatment option with social, 
rhythmic, creative, sensorimotor, and respiratory components, giving it the potential to improve the 
quality of life for a diverse array of disorders. Despite this, the literature surrounding MT is controversial 
due to the lack of standardization in clinical and research practice. Interventions range in composition 
from passive listening of participant selected music to clinician lead improvisational sessions. This 
inhibits a mechanistic understanding of how MT functions, and what components produce therapeutic 
effects. Controlled studies that target physiological outcomes are vital for the development of evidence 
based MT treatments. 
8.2 
POTENTIAL RISKS 
8.2.1 
PSYCHOLOGICAL 
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 used 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, and 
the document that links study ID numbers to personal identifying information are kept in locked filing 
cabinets in locked rooms, separate from any source documents containing participating dummy identifiers. 
All data is stored in locked cabinets inside locked offices; electronic data will be stored only on password-
protected computers, and data encryption methods will be used during communication between 
investigators. Only study personnel will have access to these data. All study staff participate in annual 

human participating training that includes education about responsibilities to minimize the risk of 
confidentiality breach. 
9 
DATA AND SAFETY MONITORING 
9.1 
FROHLICH LAB MONITORING PLAN 
The purpose of this monitoring plan is to present the Frohlich Lab’s approach to monitoring clinical trials. The plan 
facilitates compliance with good clinical practice (GCP): 
a. 
The rights and well-being of human subjects are protected. 
b. The reported trial data are accurate, complete, and verifiable from source documents 
c. 
The conduct of the trial is in compliance with the currently approved protocol/amendment(s) with GCP, 
and with applicable regulatory requirement(s) 
This section identifies key monitoring activities and specifies the data to be reviewed over the course of a clinical 
trial. This is a single site, investigator-initiated, clinical trial, so there will be no site monitoring plan in place. 
The latest version of the approved IRB application for this clinical trial will be followed at all times. This 
responsibility falls into the hands of the study coordinator and research assistants. If at any time there is a deviation 
from protocol, the deviation from protocol log will be filled out. All team members will be trained on how and when 
to use this log. The most up-to-date IRB application will be on file in the Clinical Trials office in Room 233 of the 
Medical School Wing C. Deviations will be sent to the IRB every 4-6 weeks (if necessary). 
Periodically, study staff should review 3 randomly selected inform consent forms to ensure that (1) these forms have 
been filled out appropriately, and (2) the consent form process was followed and properly documented. Should any 
consent form be in violation, the research team will perform and document a complete review of all consent forms.  
9.2 
EARLY WITHDRAWAL OF PARTICIPANTS 
9.2.1 
REASONS FOR WITHDRAWAL 
A study participant will be discontinued from further participation if: 
• 
The participant meets any exclusion criteria (either newly developed or not previously 
recognized). 
• 
Failure to comply with instructions  
• 
No show on study dates  
• 
Request by subject  
• 
Anything that, in the opinion of the investigator, would place the participant at increased risk or 
preclude the participant’s full compliance with or completion of the study. 
Participants are free to withdraw from participation in the study at any time upon request. 
 
 

10 
SAFETY & REPORTING 
It is important to assess safety over the course of this study. This section describes in detail how safety is assessed, 
reporting of Adverse Events, Serious Adverse Events, and Unanticipated Problems. This section is a reference for 
internal use. 
10.1 
METHODS AND TIMING FOR ASSESSING, RECORDING, AND ANALYZING SAFETY 
PARAMETERS 
10.1.1 UNANTICIPATED PROBLEMS 
Unexpected Events (UE) will be recorded on the UE/SAE log (Appendix D) and will include information 
such as the date of the event, when the study team was informed of this event, details of the event, when the 
IRB was notified, and whether the SAE form was completed.  The IRB will be notified of each UE that 
may occur during the study. 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
subjects or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (in the guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
If an UE occurs the IRB will be notified and the study will be adjusted as needed to protect the health and 
safety of the participants.  Depending on the nature of the UE, the research protocol, inclusion/exclusion 
criteria, and informed consent will be changed to reflect the possibility of this event reoccurring. During 
this time, no new participants will be recruited and the research procedures for currently enrolled 
participants will be stopped.  Each UE will be recorded and reported throughout the study.      
10.2 
REPORTING PROCEDURES 
We will be adopting the following table for reporting procedures: 
What Event is Reported 
When is Event Reported 
By Whom the Event is 
Reported 
To Whom the Event is 
Reported 
Fatal or life-threatening 
unexpected, suspected 
serious adverse reactions 
Within 24 hours of initial 
receipt of information 
Investigator 
Local/internal IRBs 

Non-fatal, non-life 
threatening unexpected, 
suspected serious adverse 
reactions 
Within 48 hours of initial 
receipt of information 
Study Coordinator 
Local/internal 
IRBs/Institutional 
Officials,  
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 
Investigator 
External IRBs 
10.3 
TYPES AND DURATION OF FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE 
EVENTS 
Co-I will follow up with participants within one week of an AE. 
11 
STATISTICAL PLAN 
11.1 
STATISTICAL ANALYSIS STRATEGIES 
 HRV recordings will be analyzed for high frequency (HF) and low frequency (LF) components which 
can be used to assess the relative activation of the ANS. The HF component corresponds with 
parasympathetic activation, where as the LF component divided by the HF component corresponds with 
sympathetic activation. Saliva samples will be sent to and tested by Salimetrics to calculate hormone 
levels. 
 
Post treatment HRV components and hormone test results will be compared to pre treatment baselines 
through a treatment group (active intervention, passive control) × time (pre treatment, post treatment) 
repeated measures ANOVA. The results we produce will allow us to estimate the target effect size, 
power, and sample size necessary for a future clinical trial that uses the intervention to treat MDD. 
 
11.2 
SAMPLE SIZE DETERMINATION 
This clinical trial represents a pilot study. A pilot study is a clinical trial that is conducted to decide 
whether a new treatment should be tested in a large controlled trial; therefore, we do not calculate sample 
size. This study can be considered a pilot study, as it is the first time this specific treatment will be 
performed on this clinical population. The results from this study will be used to determine sample sizes 
for future, large-scale clinical trials. In addition, we have to restrict the number of included participants to 
a small sample size due to limited funding resources.  
11.3 
DATA MANAGEMENT 

Data will be stored in a password-protected cloud-based data system that does not contain any patient information. 
Individual records are referred to by dummy identifiers that cannot be traced back to the study participants except 
with the master code list that is stored separately in a secured location. 
12 
DATA HANDLING AND RECORD KEEPING 
The study coordinator and research assistants ae responsible for the accuracy, completeness, legibility, and 
timeliness of the data reported. 
12.1 
PHI AND HIPAA 
Information about study participants will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject 
authorization informing the subject of the following: 
• 
What protected health information (PHI) will be collected from the participants in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of participant authorization. For participants that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital 
status (i.e., that the subject is alive) at the end of their scheduled study period. 
12.2 
CONFIDENTIALITY 
To ensure confidentiality, all data will only be referenced by a dummy identifier. Source documents (i.e. paper 
forms) will be kept in a locked file cabinet in a locked office. In addition, all data will be stored on a password-
protected computer using a password-protected data collection tool (REDCap). The key linking dummy identifiers 
with participant information will be securely located separate from all other data collected. 
12.2.1 ACCESS TO SOURCE DOCUMENTS 
The research coordinator, research assistants, and PI will have access to all of the source documents 
collected over the course of the study. The Co-I and medical monitor will have access to files upon request, 
as they will need access to the locked rooms and filing cabinets in which these documents are located.  
Data will stay on a password-protected computer. Subsequently, a copy will be processed on a separate, 
password-protected desktop computer in the Frohlich Lab (Neuroscience Research Building 4129). 
12.2.2 SENSITIVE INFORMATION 
No sensitive information will be collected.  Some potentially sensitive medical questions will be asked for 
screening purposes—such as “Do you suffer from cardiovascular disease?”—but dummy identifiers will be 
used to mask sensitive information. 
12.2.3 OTHER 
Please note that there is no significant risk of deductive disclosure in this study. In addition, none of the 
groupings or subgroupings used in analysis will be small enough to allow individuals to be identified. 

12.3 
SOURCE DOCUMENTS 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. Source 
data include: 
PARTNERS HUMAN RESEARCH COMMITTEE (IRB). 
• 
All IRB correspondences are documented 
• 
The study staff is IRB approved prior to performing any study procedures 
• 
Adverse events and deviations are reported to the IRB per current guidelines and stored appropriately 
• 
All versions of the IRB protocols and informed consent forms are on file 
INFORMED CONSENT. 
• 
Ensure that participant identification is not recorded on the ICF (i.e., no participant ID) 
• 
There is documentation that the participant is given a copy of the consent form 
• 
The participant and study representative signed and dated the consent form for him/herself 
• 
The participant initialed and dated all appropriate pages on the informed consent form 
• 
Note to file (Appendix F) made for any informed consent deviations 
• 
Ensure a valid (current version date) copy of the consent form was used 
PROTOCOL DEVIATIONS. 
• 
Any and all protocol deviations (exceptions and violations) are documented in the participant folder and 
reported to the IRB as required 
OTHER SOURCE DOCUMENTS. 
• 
Each participant folder will contain a checklist to ensure that all source documents are administered and 
collected properly. The checklist will be dated by the researcher for each time an assessment is 
administered 
• 
Review participant folders to ensure the accuracy, completeness, and legibility of the data. 
• 
Any correction made to the source documents is dated, initialed, and explained. The original entry should 
not be obscured. 
• 
The protocol-specific source documents are on file. 
• 
Source documents are completed in ink. 
• 
Note to files (Appendix F) are made for missing or incomplete data and to explain any discrepancies or 
additional comments. 
DNA. 
• 
Participant names will not be on any of the samples collected. DNA is sequenced to check for one 
nucleotide. When testing is performed, only de-identified information is shared with an outside party. This 
information will not be shared with anyone outside of the study personnel, including the participant.  
12.4 
DATA MANAGEMENT RESPONSIBILITIES 
The responsibilities designated to each member of the research team are documented on the Delegation of Authority 
Form. The study coordinator and research assistants will be responsible for the informed consent process, review for 
eligibility, questionnaire administration, data entry, device administration, 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.  

12.6 
PROTOCOL DEVIATIONS 
All deviations from the protocol will be addressed in study participant source documents. The researcher will 
complete a Protocol Deviation Log using the participant code as the identifier. This form will collect information 
such as the date the deviation occurred, details of what the deviation consisted of, any corrective and preventative 
actions that were taken as a result of the deviation, and the date that the PI and IRB were notified. The PI will review 
the information and initial once approved. A completed copy of the Protocol Deviation Form will be maintained in 
the regulatory file, as well as in the participant’s source document. Protocol deviations will be sent to the IRB per 
their guidelines. The site PI/study staff will be responsible for knowing and adhering to their IRB requirements. 
12.7 
RECORD RETENTION 
According to the University of North Carolina at Chapel Hill’s Archives and Record Management Services schedule 
for General Records Retention and Disposition Schedule 6.10, records will be kept for 5 years after the completion 
of the study or grant end date, whichever is later. 
13 
ETHICAL CONSIDERATIONS 
13.1 
ETHICAL STANDARD 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, as drafted by 
the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (April 
18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 (1997). 
13.2 
INSTITUTIONAL REVIEW BOARD (IRB) 
The Office of Human Research Ethics is responsible for ethical and regulatory oversight of research at UNC-Chapel 
Hill that involves human participants. The OHRE administers, supports, and guides the work of the Institutional 
Review Boards and all related activities. Any research involving human participants proposed by faculty, staff, or 
students must be reviewed and approved by an IRB before research may begin, and before related grants may be 
funded. OHRE and the IRBs are critical components of the coordinated Human Research Protection Program, which 
serves to protect the rights and welfare of human participants. All components of this program must work together to 
ensure institutional compliance with ethical principles and regulatory requirements. The following is a mission 
statement for the coordinated Human Research Protection Program: 
The University of North Carolina at Chapel Hill is committed to expanding and disseminating knowledge for the 
benefit of the people of North Carolina and the world. An important part of that commitment to knowledge is 
research of the highest quality on all aspects of the health and behavior of people, and such research is only possible 
through the participation of humans as research participants. Human participants are partners in research and a 
precious resource to the university. At UNC-Chapel Hill, human participant research is a privilege, but not a right. 
Consistent with that philosophy, it is the mission of the UNC-Chapel Hill Human Research Protection Program to 
ensure that: 
a. 
The rights and welfare of human participants are paramount in the research process; 
b. The highest standards of ethical conduct are employed in all research involving human participants; 
c. 
Research investigators are properly trained in the ethical and regulatory aspects of research with human 
participants; 
d. Research investigators deal honestly and fairly with human participants, informing them fully of 
procedures to be followed, and the risks and benefits of participating in research; and 

e. 
Research using human participants at UNC-CH conforms to applicable local, state, and federal laws and 
regulations and the policies of the university. 
13.3 
INFORMED CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study and 
continues throughout the individual’s study participation. Extensive discussion of risks and possible benefits of 
tACS will be provided to the participants and their families. Consent forms describing, in detail, the study 
intervention, device, procedures, and risks are given to the participant and written documentation of informed 
consent is required prior to the administration of any treatment or assessments used in this study. All consent forms 
will be IRB-approved and updated with any new information as modifications are made throughout the study. 
Together, the researcher and potential participants will review the clinical trial in its entirety by reviewing the 
consent form together in a private location. At several intervals during the consent review, the researcher will ask 
the participant questions that will assess the comprehension of the information in the consent. If the participant is 
unsure or does not know, the researcher will return to that section and more carefully explain the information. 
Participants must sign the informed consent document prior to any procedures taking place.  If needed, the 
participants will have the opportunity to discuss the study with their surrogates or think about it prior to agreeing to 
participate.  Participants may withdraw consent at any time throughout the course of the trial.  A copy of the 
informed consent document will be given to the participants for their records.  The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
13.4 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) 
Special populations will not be excluded. 
13.5 
PARTICIPANT CONFIDENTIALITY 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the research team.  
This confidentiality is extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. 
All data will only be referenced by dummy identifier code. Data will be stored on a password protected computer. A 
key connecting names and code numbers will be kept in a locked cabinet, accessible only by research personnel. All 
data will be stored and analyzed on password protected computers, also only accessible by research personnel. 
Participants will not be identified in any report or publication about this study. See 10 Data Handling and Record 
Keeping for more information on source documentation storage and security. 
13.6 
STUDY DISCONTINUATION 
In the event that the study is discontinued, participants who have completed or who are still enrolled in the study 
will be notified.  Any new information gained during the course of the study that might affect participant’s 
willingness to continue will be communicated within 2 days of the PI learning this information. 
 
 
 

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

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