Transcranial Direct Current Stimulation Therapy for Sleepiness Related to Shift Work Disorder (tDCS-SWORD)
Phase: NA
Conditions: Shift-Work Sleep Disorder
Sponsor: Ohio State University

 
 
 
 
ClinicalTrials.gov 
 
 
 
 
 
 
 
 
 
 
Transcranial Direct Current Stimulation Therapy for Sleepiness 
Related to Shift Work Disorder (tDCS SWORD) 
NCT Number: 03879044 
 
 
 
 
 
 
 
 
 
 
 
 
Ulysses J. Magalang, MD 
The Ohio State University 
Professor of Medicine and Neuroscience 
Division of Pulmonary, Critical Care, and Sleep Medicine 
Director Sleep Disorders Center 
241 West 11th Avenue, Suite 5000 
Columbus, OH 43201 
Office: 614-292- 4307/Clinic: 614-293-4925 
 
 
 
 

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Title:  Transcranial Direct Current Stimulation Therapy for Sleepiness Related to Shift 
Work Disorder (tDCS-SWORD) 
 
 
 
Principal Investigator: 
Ulysses J. Magalang M.D. 
Professor of Medicine and Neuroscience 
Director, Sleep Medicine Program 
201 Davis Heart and Lung Research Institute 
473 West 12th Avenue 
Columbus, OH-43210 
Phone: 614-292-6563 
ulysses.magalang@osumc.edu 
 
 
Co-investigators: 
 
Jesse Mindel, MD 
Assistant Professor of Medicine and Neurology 
Department of Neurology 
395 W. 12th Ave 
Columbus, OH 43210 
Phone: 614-293-4969 
Fax: 614-293-6111 
Email: jesse.mindel@osumc.edu 
 
 
David M. Kline, PhD 
Research Scientist 
Center for Biostatistics 
The Ohio State University 
College of Medicine Department of Biomedical Informatics 
320 E Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210 
614-688-9676 Office 
david.kline@osumc.edu 
 
Melanie Lyons, CNP, PhD 
Adjunct Assistant Professor 
201 Davis Heart and Lung Research Institute 
473 West 12th Avenue 
Columbus, OH-43210 
M.Melanie.Lyons@osumc.edu 
 
Key Personnel: 
 
Carson Reider, PhD 
Neurological Institute 
Davis Medical Research Center Room 244 

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376 West 10th Ave 
Columbus, OH 43210 
Phone: 614-293-9274 
E-mail: carson.reider@osumc.edu 
 
Samantha Rojas 
Suite 2600 
2050 Kenny Road 
Columbus, OH 43221 
Phone: (614) 366-2186 
 
Rachel Smith, MPH 
Bioinformatics Programmer 
Center for Biostatistics 
The Ohio State University 
College of Medicine Department of Biomedical Informatics 
320 Lincoln Tower, 1800 Cannon Drive, Columbus, OH, 43210 
614-293-7119 Office 
rachel.smith@osumc.edu 
 
Additional contacts: 
Angela Emerson 
Neurological Institute 
Davis Medical Research Center Room 244 
376 West 10th Ave 
Columbus, OH 43210 
Phone: 614-293-9274 
E-mail: angela.emerson@osumc.edu 
 
Christiane Eggers 
Clinical Trials Management Office 
College of Medicine 
The Ohio State University 
Christiane.eggers@osumc.edu 
 
Brooke McDaniel 
Clinical Trials Management Office 
College of Medicine 
The Ohio State University 
Brooke.madaniel@osumc.edu 
 
Amy Long 
Clinical Trials Management Office 
College of Medicine 
The Ohio State University 
Amy.long@osumc.edu 

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Performance Sites: 
The Ohio State University Wexner Medical Center 
 
IND number:  
 
 
 
Not applicable 
 
IDE: non-significant risk (NSR) investigational device that meets the abbreviated Investigational 
Device Exemptions (IDE) requirements at 21 CFR 812.2(b) 
 

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Table of Contents 
 
I.   Objectives ...................................................................................................................................5 
II.  Background and Rationale .........................................................................................................5 
III. Procedures ..................................................................................................................................6 
     A. Research Design .....................................................................................................................6 
     B. Subject selection .....................................................................................................................6 
            1. Inclusion/Exclusion criteria.......................................………………………………….. 6 
            2. Vulnerable populations.……………………..…………………………………………. 8 
            3. Populations vulnerable to undue influence or coercion……………………………… ...8 
            4. Inclusion of women and minorities……………………………………………………..8 
     C. Study Plan ..............................................................................................................................8 
     D. Detailed 
procedures…………………………………………………................................... .......................11            
IV. Data Analysis ...........................................................................................................................12 
V. Event Reporting ........................................................................................................................14 
VI. Ethical Considerations .............................................................................................................16 
VII. Data Handling and Record Keeping .......................................................................................16 
VIII. Data and Safety Monitoring Plan ........................................................................................177 
IX. References…………………………………………………………………………………....18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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I. 
Objectives  
1) To determine the effects of tDCS on subjective measures of sleepiness in night-shift 
workers with shift work disorder.   
2) To determine the effects of transcranial direct current stimulation (tDCS) on vigilance in 
night-shift workers with shift work disorder.  
 
The objectives of this study are to determine if active tDCS treatment will improve vigilance and 
subjective measures of sleepiness in patients with shift work disorder. This is a preliminary, 
single-arm efficacy study which will serve as the basis of a larger, confirmatory trial if the 
findings are positive.   
 
The risks associated with this study are minimal compared to the potential benefits. Knowledge 
about the effects of tDCS on vigilance and subjective sleepiness would be an important advance in 
the care of patients suffering from shift work disorder. 
 
II. 
Background and Rationale 
Shift Work Disorder (SWD) is a circadian rhythm sleep disorder characterized by complaints of 
insomnia during hours allotted for sleep or excessive daytime sleepiness that occur during work 
hours that are scheduled during the usual sleep period.1,2 SWD has been estimated to affect 10-
23% of the approximately 22 million Americans currently estimated to be shift workers.2-4 
Among night-shift workers, the prevalence of SWD is estimated to be about 14%.3 SWD is 
considered a public health risk, as the impaired functional ability due to excessive sleepiness in 
persons with SWD may result in impaired occupational performance.2 Excessive sleepiness 
associated with SWD has been shown to be associated with impairments in cognition and 
psychomotor performance, which in turn may contribute to increased accidents during work and 
motor vehicle crashes during the morning commute.3 One-third of night workers admit to 
regularly nodding off or falling asleep at least once a week while working and half admit to 
falling asleep while commuting.5 About one third of nurses are estimated to have SWD.6  
 
While there are two medications (modafinil and armodafinil)7,8 approved by the Food and Drug 
Administration (FDA) for sleepiness during the work hours for those with SWD, they are 
associated with adverse events.9 Caffeine plus naps reduces sleepiness during the night shift, but 
the quality of evidence is considered low.9  Therefore, there is a need to develop non-
pharmacologic treatment strategies for sleepiness related to SWD.   
 
Multiple recent studies have used transcranial direct current stimulation (tDCS) as a novel 
therapy for central nervous system disorders including depression, anxiety, Parkinson’s disease, 
and chronic pain.10-13 tDCS is a form of noninvasive, painless, brain stimulation that uses a mild 
direct electrical current passed between electrodes on the scalp to modify neuronal membrane 
resting potential in a polarity dependent manner, elevating or lowering neuron excitability in a 
region.14 It has several advantages over other brain stimulation techniques because it is 
noninvasive, painless and safe. It is also easy to administer and the equipment is easily portable. 
The most common side effect of tDCS is a slight itching or tingling on the scalp.15 Importantly, 
no studies thus far have provided evidence that tDCS produces more than a minimal risk.16 An 
updated review that consolidated evidence on the safety of tDCS found that to date, the use 

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of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) 
has not produced any reports of a Serious Adverse Effect or irreversible injury across over 
33,200 sessions and 1000 subjects with repeated sessions. This review included a wide 
variety of subjects, including persons from potentially vulnerable populations.16 In addition, 
several studies have shown that tDCS can be used safely in the home environment.17-21  
 
Thus, tDCS is a non-significant risk (NSR) investigational device that meets the abbreviated 
Investigational Device Exemptions (IDE) requirements at 21 CFR 812.2(b) addressing labeling, 
IRB approval, informed consent, monitoring, records, reports, and prohibition against promotion 
for an NSR device study. An expert panel has stated that in the US, IRBs overwhelmingly 
designate tDCS trials as non-significant risk.22 
 
Studies using tDCS have demonstrated improvements in vigilance and cognitive function under 
conditions of sleep deprivation and in a case of a patient with organic hypersomnia.14,15,23  These 
studies suggest potential benefit in those with sleepiness related to SWD. Our hypothesis is that 
patients with sleepiness related to SWD will demonstrate improvements in vigilance and self-
reported sleepiness as co-primary outcomes after receiving active stimulation.   
 
III. 
Procedures 
A. Research Design 
This is a single-arm preliminary study involving those with SWD.  
  
Informed consent will be obtained from all participants. If the subject is agreeable, the 
consent form will be sent to them via mail or electronically so that they will have the 
opportunity to read the document ahead of time. 
 
A separate informed consent for the purpose of screening potential candidates will be 
obtained. 
 
B. Subject Selection: 
 
1. Inclusion/Exclusion Criteria 
 
A. Key Inclusion Criteria 
 age 18-65 years  
 works 5 or more night shifts per month (each shift lasting at least 10 hours, with ≥6 
hours worked between 10 pm and 8 am) with plans to maintain this schedule for the 
duration of the 3-week trial  
 meets the criteria for SWD according to the International Classification of Sleep 
Disorders24 and evaluation of a sleep medicine provider (physician or nurse 
practitioner) during a screening evaluation: 
a) affirmative answers to Do you experience excessive sleepiness? (yes/no); “Do 
you experience difficulties with falling asleep during opportunities for sleep? 
(yes/no); “Is the sleep or sleepiness problem related to a work schedule where you 

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have to work when you would normally sleep? (yes/no)”; and “Has this sleep or 
sleepiness problem related to your work schedule persisted for at least three 
months? (yes/no) 
b) based on the evaluation of the sleep medicine provider, the sleep and/or wake 
disturbance are not better explained by another current sleep disorder, medical or 
neurologic disorder, mental disorder, medication use, poor sleep hygiene, or 
substance abuse disorder. 
 Stable medication dosage over previous 4 weeks. 
 Able to understand English and give a written informed consent document. 
 
B. Key Exclusion Criteria 
 Currently taking stimulant medications such as Modafinil, Armodafinil, Methylphenidate, 
or Dextroamphetamnie. 
 History of automobile accident due to falling asleep while driving 
 Inability to understand or read English  
 Self-reported Substance abuse (current) 
 Excessive alcohol consumption defined as: 
 More than 3 glasses of wine a day 
 More than 3 beers a day 
 More than 60 mL of hard liquor a day 
 Presence of cardiac pacemaker or automatic implantable cardioverter-defibrillator 
(AICD).  
 Pregnancy, lactation (will be screened with urine pregnancy test) 
 Non-removable metal or tattoos around head 
 Use of implantable birth control device such as Implanon 
 History of frequent severe headaches 
 Unstable coronary artery disease 
 Uncontrolled Seizure disorder 
 Uncontrolled hypertension 
 Any other clinically significant condition that, in the opinion of the Investigator, might put 
the subject at risk of harm during the study or might adversely affect the interpretation of 
the study data. 
 
b) 
Screening Procedures 
A screening visit will be scheduled to determine eligibility as above.  A separate informed consent 
for the purpose of screening potential candidates will be obtained. Female patients of childbearing 
potential will be required to have a negative pregnancy test result at screening. Those with known 
sleep apnea are eligible for the study provided they are compliant with therapy (defined as > 4 
hours of average nightly use for at least 30 days).  
 
The modified neck circumference (MNC) score will be obtained during the screening visit. The 
MNC is calculated as the neck circumference measured in centimeters and adjusted if the patient 
has hypertension (4 cm is added), is a habitual snorer (3 cm is added), or is reported to choke or 
gasp most nights (3 cm is added). Those with an MNC score >48 cm water which indicates an 
increased risk of having obstructive sleep apnea (OSA) will have home sleep apnea testing (HSAT). 

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Those with an apnea-hypopnea index of >15/hour based on the HSAT will be excluded and referred 
to their primary care physician for treatment discussion.  
3.  Vulnerable Populations  
 Children, fetuses, neonates, or prisoners are not included in this research study.  
 
4. Populations vulnerable to undue influence or coercion 
Should an OSU employee or student (or their surrogate) be approached for enrollment, they 
will be given the opportunity and time to consider participation and will be reassured that 
declining to participate will not jeopardize or hinder their standard of care at the OSU 
Wexner Medical Center, nor will it have any bearing on either their student status or 
employment. 
 
e) Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this study.   
 
C. Study Plan 
This is a preliminary single-arm study. The study will last up to 6 weeks including the screening 
period. Subjects will receive active tDCS for 30 minutes before their scheduled work hours at 
least 3x/week for two consecutive weeks.  
  
Outcome measures will include: psychomotor vigilance test (PVT) and the Karolinska Sleepiness 
Scale (KSS)25,26 which will be obtained during the shift work.  
 
Visit Schedule 
A) Screening visit  
During this visit, the following will be obtained for all subjects:  
a. Screening Informed consent (if not obtained on a prior separate visit) 
b. Evaluation for SWD by investigator 
c. Pregnancy test, if applicable 
d. Height and weight 
e. Blood pressure and pulse rate 
f. Medication list 
g. Cognitive Tasks results 
h. Epworth sleepiness scale (ESS) 
i. CPAP compliance for those who are known to have sleep apnea 
j. MNC score 
k. HSAT, if applicable as explained above 
l. Expected visit length: 60 minutes 
The following are the reasons why subjects may not proceed with the study after screening: 
a) If they are determined to have significant sleep apnea, this will end their participation in 
this research study. The home sleep study results will be provided to research participants 
or their health care provider for referral for appropriate treatment.    
b) The investigators determine that the subject does not have shift work sleep disorder.  
 

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Those who remain eligible will then sign a separate informed consent for the remainder 
of the study. They will be requested to complete a baseline PVT and KSS during their 
shift work prior to the tDCS stimulation sessions. The PVT is a test that measures the 
speed with which subjects respond to a visual stimulus. It is a simple task where the 
subject presses a button as soon as the light appears. The light will turn on randomly 
every few seconds for 3 minutes. The KSS is a subjective measure of sleepiness. They 
will be provided with a mini-IPAD that contains the PVT and KSS apps. The PVT and 
KSS will only take 4 minutes and will be collected around 6 pm, 12 midnight and 4 am.  
 
B) Visit 1  (stimulation #1) 
During this visit, the following will be obtained for all subjects:  
a. Study Informed consent (if not already obtained) 
b. Resting blood pressure and pulse rate 
c. Changes to Medication 
 
They will then receive active tDCS for 30 mins. PVT during the active tDCS 
 
d. Side effects questionnaire after the active tDCS 
e. Actigraphy equipment will be provided to be worn throughout the duration of the 
study. Instructions on how to wear an actigraph device around their wrist that 
measures both the rest-activity cycle will be provided.  
f. Expected visit length: 60 minutes 
 
C)  Visit 2  (stimulation #2) 
During this visit, the following will be obtained for all subjects:  
a. Resting blood pressure and pulse rate 
b. Changes to Medication 
 
They will then receive active tDCS for 30 mins. PVT during the active tDCS 
 
a. Side effects questionnaire after the  active tDCS 
b. Expected visit length: 60 minutes 
 
D)  Visit 3 (stimulation #3) 
During this visit, the following will be obtained for all subjects:  
a. Resting blood pressure and pulse rate 
b. Changes to Medication 
 
They will then receive active tDCS for 30 mins. PVT during the active tDCS. 
 
c. Side effects questionnaire after the active tDCS 
c. PVT and KSS (6 pm, 12MN, and 4 am) 
g. Expected visit length: 60 minutes 
 

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Visits 1-3 will occur during a one week period. Subjects will then be asked to obtain the 
KSS score and PVT during their shift work at 6 pm, 12 MN, and 4 am at the end of Visit 
3.  
 
E) Visits 4, 5, 6 represent the second week of tCDS active stimulation and will be similar to 
Visits 1-3 with an expected visit length of 60 minutes per visit and will occur over a one-week 
period.  
 
Subjects will be asked to obtain the KSS score and PVT during their shift work at 6 pm, 12 
MN, and 4 am at the end of Visit 6. In addition, at the end of Visit 6, the following will be 
obtained after the active tDCS  
i. Cognitive Tasks results 
ii. Epworth sleepiness scale (ESS) 
 
 
 
Visit Schedule  
 
Procedures 
Visit # 
S 1 2 3 4 5 6    
Screening consent 
x  
 
 
 
 
 
   
Study consent 
 
x  
 
 
 
 
   
Medication list 
x x x x x x x    
Height and weight 
x  
 
 
 
 
 
   
BP and Pulse rate 
x x x x x x x    
MNC 
x  
 
 
 
 
 
   
HSAT, if applicable 
x  
 
 
 
 
 
   
Pregnancy test, if applicable x  
 
 
 
 
 
   
Cognitive tasks 
x  
 
 
 
 
x    
ESS 
x  
 
 
 
 
x    
Actigraphy 
 
x x x x x x    
tDCS 
 
x x x x x x    
Side-effects 
 
x x x x x x    
*PVT 
 
x  
x  
 
x    
*KSS 
 
x  
x  
 
x    
 
 
 
*obtained during the subjects’ shift work at baseline at baseline prior to stimulation and after  
every 3 tdcs stimulation session 
 
 
S= screening visit (requires a separate consent) 
 
 
BP= blood pressure 
 
 
MNC= modified neck circumference 
 
 
HSAT= home sleep apnea test 
 
 
 
 
tDCS= transcranial direct current stimulation 
 
 
PVT= psychomotor vigilance test 
KSS= Karolinska sleepiness scale 
ESS= Epworth Sleepiness Scale 
 
 

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Detailed Procedures 
 
a)      Medication List  
For all subjects we will obtain information about their medications or any changes to their 
medications.  
 
b) 
Height and Weight  
Weight and height measurements (to calculate BMI) will be done without shoes.   
 
c) 
Blood Pressure  
The standard operating procedure for obtaining sitting blood pressure will be followed.27  
 
Medical Alert Procedure. Subjects in these protocols may be identified to have clinical 
abnormalities that require medical attention. Research staff would notify Dr. Magalang or a 
physician co-investigator immediately for Systolic BP >200 mmHg or diastolic BP >120 
mmHg. 
 
d) 
Modified Neck Circumference (MNC) score  
This will be obtained during the screening visit. The MNC is calculated as the neck circumference 
measured in centimeters and adjusted if the patient has hypertension (4 cm is added), is a habitual 
snorer (3 cm is added), or is reported to choke or gasp most nights (3 cm is added). 
 
e) 
Home sleep apnea testing (HSAT) 
This is part of the screening procedure. Subjects with an MNC score >43 cm high, indicating a 
moderate to high probability of having obstructive sleep apnea (OSA), will have home sleep apnea 
testing (HSAT). Those with an apnea-hypopnea index of ≥15/hour based on the HSAT will be 
excluded and referred to their primary care physician or the sleep medicine clinic for treatment 
discussion. Subjects will be given a copy of the HSAT report. Subjects will be given instructions 
on how to use the HSAT equipment which is used routinely in clinical practice for home sleep 
apnea testing by clinical staff of the OSU Lung Center. The device will be preset to turn on 
automatically at home at the desired time. HSAT includes recordings of nasal pressure, thorax and 
abdominal movements, oxyhemoglobin saturation, and pulse rate. Subjects will be provided a 
telephone number to call should they have any questions about the device.  
 
HSAT will be scored according to standard criteria. Briefly, an apnea is scored when all of the 
following criteria are met: a drop in airflow sensor excursion by > 90% of baseline, the duration 
of the event lasts at least 10 sec, and at least 90% of the event’s duration meets the amplitude 
reduction criteria. An apnea is classified as obstructive if it is associated with continued or 
increased respiratory effort throughout the entire period of absent airflow, central if it is associated 
with absent respiratory effort throughout the entire period of absent airflow, and mixed if it is 
associated with absent respiratory effort in the initial portion of the event, followed by resumption 
of respiratory effort in the second portion of the event. A hypopnea is scored if the following 
criteria are met: the airflow signal excursion drops by >30% of baseline, there is a >4% 
desaturation from pre-event baseline, and at least 90% of the event’s duration meets the amplitude 
reduction criteria. 
 
f) 
Questionnaires  

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The following questionnaires will be completed by the subjects: 
a. Karolinska Sleepiness Scale (KSS). Values will be collected prior to their shift work 
(around 6pm) and during shift work (around 12 midnight and around 4 am). These data 
will be obtained prior to tDCS stimulation, after the third stimulation and after the 6th 
stimulation sessions. They will be asked to rate how sleepy they are according to the 
following scale:  
9. Extremely sleepy, fighting sleep 
8. Sleepy, some effort to keep alert 
7. Sleepy, but no difficulty remaining awake 
6. Some signs of sleepiness 
5. Neither alert nor sleepy 
4. Rather alert 
3. Alert 
2. Very alert 
1. Extremely alert 
 
b. Epworth Sleepiness Scale Score (ESS) at baseline and after the 6th stimulation session. 
c. Side Effects  
 
g) Actigraphy  
This device is the size of a small wristwatch that measures activity and is a non-invasive method 
of monitoring human rest/activity cycle. The instructions for the device use as well as a sleep 
diary will be provided. The data is then downloaded into a computer.  
 
h) Psychomotor Vigilance Test (PVT) 
The PVT is a sustained-attention, reaction-timed task that measures the speed with which 
subjects respond to a visual stimulus. The PVT is a simple task where the subject presses a 
button as soon as the light appears. The light will turn on randomly every few seconds. The 
purpose of the PVT is to measure sustained attention and give a numerical measure of 
sleepiness.28 The purpose of the PVT is to measure sustained attention, and give a numerical 
measure of sleepiness by counting the number of lapses in attention of the tested subject. 
Subjects will be provided with a min-IPAD and the PVT will be done prior to their shift work 
(around 6pm) and during shift work (around 12 midnight and around 4 am). Values will be 
obtained prior to tDCS stimulation, after the third stimulation and after the 6th stimulation 
sessions. 
 
i) 
Cognitive Performance 
In addition, subjects will also be asked to make judgements or decisions on stimuli such as words 
or images presented on a computer screen to track memory and thought process (cognitive 
performance).   
 

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j) 
Transcranial Direct Current Stimulation 
(tDCS) 
The neuroConn DC stimulator (neuroCare Group, 
Munchen, Germany) will be used to provide the tDCS 
stimulation. This battery-powered device will be 
controlled with a microprocessor to ensure constant 
current at up to 2000 µA. For safety, multistage 
monitoring of the output current and electrode/tissue 
impedance will be included. The device automatically 
shuts off if the impedance becomes greater than 50 kΩ 
to prevent electric shocks or burns. This device will be 
investigational only (not FDA approved). As above, 
tDCS is a non-significant risk (NSR) investigational 
device that meets the abbreviated Investigational 
Device Exemptions (IDE) requirements at 21 CFR 
812.2(b) addressing labeling, IRB approval, informed 
consent, monitoring, records, reports, and prohibition 
against promotion for an NSR device study. 
 
We will use a custom set of silver/silver chloride 
electroencephalographic (EEG) electrodes (at location F3 according to the 10-20 system) as 
described in McKinley et al.28 These new electrodes were shown to be more stable over time, 
produce lower sensation levels, and produce fewer skin reactions when compared to standard 
sponge electrodes. Both the anode and cathode consist of a separate array of 5 EEG electrodes as 
pictured in Fig. 1. Each electrode has an inner diameter of 1.6 cm yielding a contact area of 2.01 
cm2 for each electrode. At 2 mA of supplied current, the average current density will be 0.199 
mA/cm2 as calculated by current (2 mA) divided by area (10.05 cm2).  
 
For the active anodal stimulation condition, tDCS will be applied at 2mA for 30 min. The anode 
will be applied to scalp location F3 according to the 10-20 EEG electrode placement system while 
the cathode will be placed over the contralateral (i.e. right) bicep. Electrodes will be secured using 
medical bandages, and connectivity will be ensured using highly conductive gel.14 
 
IV. Data Analysis 
 
Sample size: 
The sample size is selected such that we have power to detect differences in the mean reciprocal 
reaction time (mean 1/RT) and KSS, which are our co-primary endpoints. Differences from 
baseline in the co-primary endpoints will be assessed at Visit 6.   
 
We plan to enroll a total of 45 subjects.  We assume a screen failure rate and a loss to follow up 
rate of 40%. Thus, we anticipate at least 27 evaluable subjects. Once 27 evaluable subjects have 
completed the study, enrollment will stop. We will control the type I error rate at 0.10 for 
assessing the primary endpoints conservatively using a Bonferroni correction.29  With this 
sample size, we have 80% power to detect an improvement of 0.50 standard deviations in mean 
1/RT with an alpha level of 0.05 using a one-sided t-test.  For the KSS, we assume a standard 
Figure 1. tDCS electrode array (anode only 
pictured). All five elements are standard 
silver-silver chloride EEG electrodes placed 
in a plastic cup which is then filled with a 
conductive gel.  

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deviation of 2 9 and have 80% power with this sample size to detect a reduction in KSS of 1 with 
an alpha level of 0.05 using a one-sided t-test. 
 
Statistical Methods: 
The primary analysis will examine the difference in KSS and mean 1/RT at 4 AM at Visit 6 and 
baseline.  To analyze differences in KSS at Visit 6 and baseline, and differences in mean 1/RT at 
Visit 6 and baseline, we will use paired t-tests using the worst values during the shift work.  We 
will use Holm’s Method to account for multiple testing and control the familywise error rate. 
 
Secondary analyses will include the mean inverse response time and additional outcomes from 
the PVT and subjective questionnaires. To analyze differences in the number of lapses at Visit 4, 
we will use a Poisson regression model to compare the lapse rate at Visit 6 to the baseline rate.  
Additional questionnaires (ESS) will be assessed using paired t-tests.  
 
We will also build longitudinal models to fully explore changes in outcomes both across weeks 
and within shifts.  We may also explore joint models of subjective and objective outcomes to 
better characterize correlation between outcomes and their changes over time.  Characteristics of 
participants will be summarized by randomized treatment group using appropriate descriptive 
statistics.  We will also summarize any reported side effects of treatment.  Additional exploratory 
analyses may be conducted at the discretion of the study team. 
 
Interim Analysis: 
An interim analysis will be conducted when 50% of the evaluable patients have reached the 
primary endpoint at Visit 6.  That is, it will be conducted after 14 patients have an evaluable 
primary endpoint.  The analysis will assess both co-primary endpoints using the error spending 
approach described by Lan and Demets.30,31  The study will be stopped early for efficacy if the p-
value is less than 0.006 for both co-primary endpoints.  If only one endpoint reaches the efficacy 
boundary, the trial will not be stopped early and will enroll the full planned number of 
participants. 
 
V.  Event Reporting 
(a) Adverse Events 
The ICH Guideline for Good Clinical Practice E6(R1) defines an adverse event (AE) as: 
 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
 
As this is a study that does not include a pharmaceutical product intervention, this definition 
would include AEs that occur as a result of protocol procedures and protocol treatment. 
 
A serious adverse event (SAE) is any AE that: 
 Results in death 
 Is immediately life-threatening 

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This term refers to an event in which the subject was at risk of death at the time of the event; 
it does not refer to an event that may have led to death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in an outpatient setting. 
 Results in persistent or significant disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 
 
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse. 
 
1. Collecting and reporting adverse events: 
All AEs occurring after subject has signed consent and up to the study completion visit must be 
recorded on specific data collection forms. 
 
2. Collecting and reporting Serious Adverse Events: 
The OSU Event Reporting Form should be used to report untoward events that may affect 
participants in research approved by an OSU IRB.  Events requiring prompt reporting include 
adverse events, protocol deviations, and other unforeseen problems or findings that suggest 
participants, research staff, or others are placed at greater risk by the research than previously 
expected.  These events, classified broadly as unanticipated problems involving risks to 
participants or others, must be reported promptly to the IRB.  Unanticipated problems can occur 
in any type of research and may involve physical, psychological, social, legal, or economic harms. 
 
Events Requiring Prompt Reporting  
Events that may represent unanticipated problems involving risks to participants or others and 
therefore require prompt reporting include the following: 
 
Adverse events or injuries that are serious, unexpected, and related;  
 
Events requiring prompt reporting according to the protocol or sponsor;  
 
Reports, interim analyses, or other oversight committee/monitoring reports altering the 
risk/benefit profile;  
These events should be promptly reported (see below), regardless of whether they occur during 
the study, after study completion, or to a participant who has withdrawn from or completed study 
participation.   
 
Timeframe for Reporting 
All internal events (those occurring in research at OSU or at a site under an OSU IRB’s 
jurisdiction) as described above should be reported within 10 days of the Investigator’s or research 
staff member’s learning of the event. Events resulting in temporary or permanent interruption of 

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study activities by the Investigator or sponsor to avoid potential harm to participants should be 
reported immediately (within 48 hours) whenever possible. 
 
Additional Information 
Related adverse events and other problems involving risk that do not meet the reporting 
requirements and do not represent potential unanticipated problems involving risks to participants 
or others should be reported in summary form at the time of continuing IRB review.  However, 
any problem or adverse event that an investigator believes could influence the safe conduct of the 
research should be reported promptly. 
 
(b) Protocol Deviations 
Protocol deviations are accidental or unintentional changes to the protocol or procedures.  In the 
event that the protocol deviation involves risk to the subject or potential risk to future 
participants, or with the potential to recur or significantly impacts the integrity of the research 
data, the event should be reported to the IRB in a timely manner, in accordance with their 
reporting guidelines.   
 
1. Ethical Considerations 
 
The study will be conducted in accordance with the ICH guidelines on GCP, the GCPs 
applicable to any region where the study is conducted, and the ethical principles set forth in the 
Declaration of Helsinki. Good clinical practice is defined as a standard for the design, conduct, 
performance, recording, analysis, and reporting of clinical studies in a way that provides 
assurance that the data and reported results are credible and accurate, and that the rights, safety, 
and well-being of study participants are protected. 
 
Per GCP, the protocol will be reviewed and approved by the IRB or IEC of each participating 
center prior to study initiation. The investigator will keep the IRB/IEC informed as to the 
progress of the study. 
 
(a) Consent procedures 
The investigator/study personnel will explain the nature of the study, and will be available to 
answer questions regarding procedures, risks and alternatives to participation.  The consenter 
will inform the subject that participation is voluntary and that the subject can withdraw or be 
withdrawn from the study at any time. The principal investigator or his/her entitled designee will 
obtain written informed consent from each subject. Documentation of the informed consent 
process along with the original consent form will be maintained in the subject’s research folder.  
A copy of the signed informed consent will be provided to the subject for their records. 
 
(b) Subject compensation 
Participants who qualify for the study will receive up to $500 compensation for participating in 
the study in the form of a check or by direct deposit (optional for OSU employees who may elect 
to receive payment by check).  They will receive $250 after Visit 3 and $250 after Visit 6. If the 
participant is unable to complete all the visits, compensation will be prorated for the visits that 
are completed. For check payments, it may take up to 6 weeks for subjects to receive payment. 
All subject payments are taxable income. 

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2. Data Handling and Record Keeping 
 
The investigator shall maintain the records of the study e.g.: subject research charts, regulatory 
documents and all other study specific documentation for a minimum of 15 years or in 
accordance with currently OSU-IRB regulations.   
 
1. Confidentiality 
 Confidentiality of all records will be maintained and data will be kept in a locked 
filing cabinet and only research staff and authorized members of the IRB will have 
access. 
 Electronic data is protected by codes to which only research staff and authorized 
members of the IRB and OHR will have access 
 The PHI to be collected; who will use the information within the institution and why; 
who may disclose the information and to whom; the subjects rights to access research 
information and their right to withdraw authorization (approval) for any future use of 
personal health information are all listed in the HIPAA form specific to the research 
 The names of subjects and any other identifying information will be kept in a 
different secure location.   
 Should publications result from this study all PHI will be removed. 
 
 
 
 
 
3. Data Safety Monitoring Plan 
 
The risks involved with tDCS, completion of questionnaires, PVT, HSAT, and actigraphy are 
minimal.     
 
This study will be monitored to ensure participant safety and data integrity.  The monitoring for 
this study will be conducted by the Principal Investigator and the study team.  The information 
that will be evaluated will be the incidence and severity of adverse reactions related to the study 
procedures, enrollment and efficiency of data capturing.  The adverse events will be assessed 
on a case by case basis at the time the study team is aware of the event.   
 
Overall study monitoring will take place on an ongoing basis with study review meetings taking 
place at least every 6 months.  In the event the side effects suggest the risk outweighs the benefit, 
the study will be stopped and the IRB notified in order to evaluate possible solutions to the risk 
problem. 
 
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