Reducing Breast Cancer-related Fatigue and Improving Cognition With Non-Invasive Brain Stimulation
Phase: NA
Conditions: Breast Cancer, Cognitive Dysfunction, Fatigue
Sponsor: Johns Hopkins University

 
 
Reducing Breast Cancer-related Fatigue and Improving Cognition with 
Transcranial Direct Current Stimulation (tDCS) 
NCT03143894 
 
 
Protocol Chair 
Tracy D. Vannorsdall, Ph.D. 
Johns Hopkins Hospital 
600 N. Wolfe Street, Meyer 218 
Baltimore, MD 21287 
Office:  410-955-3268 
Fax:  410-955-0504 
Email:  tvannor1@jhmi.edu 
 
Protocol Co-Chair 
Karen Smith, M.D., M.P.H. 
Kimmel Cancer Center at Sibley Memorial Hospital 
Building B, 1st Floor 
5255 Loughboro Rd NW 
Washington, DC 20016 
Office:  202-660-6500 
Fax:  202-660-6501 
Email:  ksmith60@jhmi.edu 
 
Co-Investigator 
Antonio Wolff, M.D. 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
 
Statistician 
Chiung-Yu Huang, PhD 
Division of Oncology Biostatistics & Bioinformatics 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
 
Supporters 
The Under Armour Women’s Health and Innovation Breast Cancer 
Grant, Johns Hopkins University Catalyst Award 
 
 
 
Protocol Version: 
February 27, 2019

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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Reducing Breast Cancer-related Fatigue and Improving Cognition with 
Transcranial Direct Current Stimulation (tDCS) 
 
 
Original Protocol: 
October 17, 2016 (Original) 
 
 
Protocol Revision Record:   November 4, 2016 (Revised) 
November 17, 2016 (Revised) 
January 30, 2018 (Revised) 
February 27, 2019 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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Table of Contents 
1. SUMMARY ........................................................................................................................................................... 5 
2. SCHEMA ............................................................................................................................................................... 6 
3. OBJECTIVES ....................................................................................................................................................... 7 
3.1 
PRIMARY ................................................................................................................................................................. 7 
3.2 
EXPLORATORY ..................................................................................................................................................... 7 
4. HYPOTHESES ........................................................................................................................................................ 8 
4.1 
PRIMARY ................................................................................................................................................................. 8 
4.2 
SECONDARY ......................................................................................................................................................... 8 
4.3 
EXPLORATORY ..................................................................................................................................................... 8 
5. BACKGROUND AND RATIONALE ................................................................................................................ 9 
5.1 
CANCER-RELATED FATIGUE AND COGNITIVE DYSFUNCTION ............................................................................. 9 
5.2 
TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) ................................................................................. 9 
6. PARTICIPANT SELECTION .......................................................................................................................... 12 
6.1 
INCLUSION CRITERIA ......................................................................................................................................... 12 
6.2 
EXCLUSION CRITERIA ........................................................................................................................................ 12 
6.3 
INCLUSION OF WOMEN AND MINORITIES .......................................................................................................... 13 
7. STUDY DESIGN AND TREATMENT PLAN .................................................................................................. 14 
7.1 
SUMMARY .......................................................................................................................................................... 14 
7.2 
RECRUITMENT ................................................................................................................................................... 14 
7.3 
DETERMINATION OF ELIGIBILITY ...................................................................................................................... 15 
7.4 
RANDOMIZATION AND BLINDING ...................................................................................................................... 15 
7.5 
METHODS AND INTERVENTION .......................................................................................................................... 15 
7.6 
STUDY ASSESSMENTS ........................................................................................................................................ 17 
7.7 
CONCOMITANT AND SUPPORTIVE THERAPY ...................................................................................................... 25 
7.8 
DISCONTINUATION AND WITHDRAWAL OF SUBJECTS ....................................................................................... 25 
7.9 
ADDITIONAL INFORMATION ............................................................................................................................... 26 
8. STUDY CALENDAR ......................................................................................................................................... 27 
9. ADVERSE EVENTS .......................................................................................................................................... 28 
9.1 
GENERAL ........................................................................................................................................................... 28 
9.2 
DEFINITIONS ...................................................................................................................................................... 29 
10. DATA AND SAFETY MONITORING .......................................................................................................... 31 
10.1 
DATA MANAGEMENT ...................................................................................................................................... 31 
10.2 
MEETINGS ........................................................................................................................................................ 31 
10.3 
MONITORING ................................................................................................................................................... 31 
11. ADMINISTRATIVE PROCEDURES ............................................................................................................ 32 
11.1 
PROTOCOL AMENDMENTS ............................................................................................................................... 32 
11.2 
INFORMED CONSENT ....................................................................................................................................... 32 
11.3 
ETHICS AND GOOD CLINICAL PRACTICE ......................................................................................................... 32 
12. STATISTICAL CONSIDERATIONS ............................................................................................................ 33 
12.1 
OVERALL ......................................................................................................................................................... 33 
12.2 
SAMPLE SIZE AND ACCRUAL ........................................................................................................................... 33 
12.3 
ANALYSIS PLAN ............................................................................................................................................... 33 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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12.4 
REPORTING AND EXCLUSIONS ......................................................................................................................... 34 
APPENDICES ............................................................................................................................................................. 35 
APPENDIX A: MEDICATIONS AND SUPPLEMENTS .................................................................................................... 36 
APPENDIX B: HOSPITAL ANXIETY AND DEPRESSION SCALE ................................................................................... 37 
APPENDIX C: MINI MENTAL STATE EXAM .............................................................................................................. 39 
APPENDIX D: QUANTIFIED FATIGUE ASSESSMENT .................................................................................................. 41 
APPENDIX E: PACED AUDITORY SERIAL ATTENTION TEST ................................................................................... 42 
APPENDIX F: FUNCTIONAL ASSESSMENT OF CANCER THERAPY COGNITIVE SCALE ............................................... 44 
APPENDIX G: MULTI-DIMENSIONAL FATIGUE SYMPTOM INVENTORY ................................................................... 47 
APPENDIX H: HOPKINS VERBAL LEARNING TEST- REVISED ................................................................................... 48 
APPENDIX I: BRIEF VISUOSPATIAL MEMORY TEST- REVISED ................................................................................. 52 
APPENDIX J: TRAIL MAKING TESTS PART A & B .................................................................................................. 59 
APPENDIX K: CALIBRATED IDEATIONAL FLUENCY ASSESSMENT ........................................................................... 63 
APPENDIX L: WAIS-IV DIGIT SPAN SUBTEST ........................................................................................................ 66 
APPENDIX M: GROOVED PEGBOARD TESTS .......................................................................................................... 68 
APPENDIX N: PITTSBURGH SLEEP QUALITY INDEX ................................................................................................. 69 
APPENDIX O: EORTC QUALITY OF LIFE SCALE ..................................................................................................... 71 
APPENDIX P: HISTORY FORM ................................................................................................................................ 73 
APPENDIX Q: HOPKINS ADULT READING TEST ..................................................................................................... 77 
APPENDIX R: EDINBURGH HANDEDNESS INVENTORY ............................................................................................. 78 
APPENDIX S: UCLA LONELINESS SCALE .................................................................................................................. 79 
APPENDIX T: NEO-FIVE FACTOR INVENTORY-3 ..................................................................................................... 80 
APPENDIX U: SIDE EFFECTS QUESTIONNAIRE ......................................................................................................... 83 
APPENDIX V: STIMULATION DETECTION........................................................................................................................................86 
REFERENCES ........................................................................................................................................................... 87 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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1. SUMMARY 
 
Fatigue and cognitive dysfunction are commonly reported symptoms associated with impaired 
quality of life and productivity in breast cancer survivors. Working memory, the brain’s system 
for temporarily storing and manipulating information required to carry out more complex 
cognitive tasks, is particularly affected by cancer and its treatment. 
 
In women who have undergone chemotherapy for breast cancer, neuroimaging studies show 
structural brain changes as well as functional inefficiencies in a region critical for working 
memory, the left dorsolateral prefrontal cortex (DLPFC). Fatigue appears to play a critical role in 
the recruitment of the DLPFC during cognitive tasks. 
 
Transcranial direct current stimulation (tDCS) is a safe, portable, non-invasive form of electrical 
brain stimulation that enhances neuronal transmission beneath the scalp electrodes. Active 
treatment consists of a mild electrical current (2mA) administered via saline-soaked sponge 
electrodes placed along the intact scalp for 30 minutes a day for five days. Used as a control in 
the proposed trial, sham stimulation involves the brief delivery of current in a manner that does 
not result in changes in neuronal firing patterns, but is perceived as active treatment by 
participants. Our group and others have shown that when applied to the left DLPFC, active tDCS 
improves cognition in healthy adults and energy in patients with fatiguing medical conditions. 
 
The proposed investigation consists of a randomized, sham-controlled, double-blind, cross-over 
experiment. Women who have finished treatment of breast cancer and who report persistent 
fatigue (≥ 4 on a scale of 1 to 10) will complete measures of fatigue and cognition before and 
after five consecutive days of active or sham tDCS applied to the left DLPFC. Following a four- 
week washout, participants will return to complete the opposing stimulation condition 
(active/sham) over another five consecutive days.  About one week after each session 
participants will receive/complete a brief study phone call with the study staff, with a total time 
on study of about 47 days (± 5 days). 
 
The primary endpoint is change in objectively measured working memory performance (Paced 
Auditory Serial Attention Test; PASAT) before and after five consecutive days of active or sham 
tDCS. Secondary endpoints are changes in subjective fatigue (Multidimensional Fatigue 
Symptom Inventory 30-item short form; MFSI-SF) and subjective cognitive functioning 
(Functional Assessment of Cancer Therapy Cognitive Scale; FACT-Cog) before and after five 
consecutive days of active or sham tDCS. Exploratory objectives include assessing the effect of 
tDCS in other objectively assessed cognitive skills as described below, identifying disease-, 
treatment-, and person-related predictors of response to tDCS intervention, and describing side 
effects in this population. With 45 patients and a two-sided type I error rate of 5%, we have at 
least 80% power to detect a medium effect size (Cohen’s d) of 0.43 or greater. 

tDCS for Breast Cancer Fatigue and Cognition 
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2. SCHEMA 
 
 
 
 
 
Breast cancer survivors 
1 month – 5 years post-active treatment 
Fatigue score ≥ 4 (Scale 1-10) 
N = 45 
 
 
 
 
Randomization: 
Group 1:  Active, then Sham tDCS 
or 
Group 2:  Sham, then Active tDCS 
 
 
 
Days 1-5, and 12: 
tDCS Stimulation (active or sham) (Days 1-5) 
Primary Assessments (Days 1 & 5) 
Assessment/Phone Call (Day 12) 
 
 
 
 
Days 6-35: 
Washout 
 
 
 
Days 36-40, and 47: 
tDCS Stimulation (active or sham) (Days 36-40) 
Primary Assessments (Days 36 & 40) 
Assessment/Phone Call (Day 47) 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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3. OBJECTIVES 
 
3.1 
Primary 
 
3.1.1 To determine the efficacy of five consecutive days of tDCS in improving objectively 
assessed working memory in breast cancer survivors with persistent fatigue. 
 
The Paced Auditory Serial Attention Test (PASAT)1,2 will serve as the primary 
measurement tool for the objective assessment of working memory. 
 
3.1.2 Secondary 
 
3.1.2 To determine the efficacy of five consecutive days of tDCS in improving subjective 
cognition in breast cancer survivors with persistent fatigue. 
 
The primary measurement endpoint for subjective cognition will be scores on the 
Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog), a self-report 
measure addressing cognitive functioning, functional interference, quality of life and 
overall cognitive complaints over the past week. 
 
3.1.3 To determine the efficacy of five consecutive days of tDCS for the treatment of 
subjective fatigue in breast cancer survivors with persistent fatigue. 
 
The primary measurement tool for subjective fatigue will be the Multidimensional 
Fatigue Symptom Inventory 30-item short form (MFSI-SF), which assesses participants’ 
subjective ratings of general fatigue, physical fatigue, emotional fatigue, mental fatigue, 
and vigor over the past week. 
 
3.1.4 To determine whether the effects of tDCS on subjective cognition and fatigue persist at 
approximately seven days following the last day of stimulation in breast cancer survivors. 
 
Secondary endpoints will be ratings on the MFSI-SF and FACT-Cog obtained via phone 
seven days after the fifth tDCS session of each study wave. 
 
3.2 
Exploratory 
To assess the effect of five consecutive days of tDCS in improving other objectively 
assessed cognitive skills in breast cancer survivors with persistent fatigue. 
 
Exploratory endpoints will include changes in performance on objective tests of cognitive 
functioning including measures of learning and memory (Hopkins Verbal Learning Test- 
Revised, HVLT-R3 and Brief Visuospatial Memory Test-Revised, BVMT-R4), auditory 
attention (WAIS-IV Digit Span subtest5), psychomotor speed and executive functioning 
(Trail Making Test Parts A and B 6), speeded lexical fluency (Calibrated Ideational 
Fluency Assessment7), and manual speed (Grooved Pegboard8). 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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3.2.1 To evaluate disease-, treatment- and person-related predictors of improvements in 
cognitive function and fatigue in response to the tDCS intervention. 
 
3.2.2 To describe the side effects of tDCS 
 
 
4. HYPOTHESES 
 
4.1 
Primary 
 
4.1.1 Five days of active tDCS will result in greater improvements in objectively assessed 
working memory (PASAT) relative to sham tDCS. 
 
4.2 
Secondary 
 
4.2.1 Five days of active tDCS will result in greater improvements in subjective cognition 
relative to sham tDCS. 
 
4.2.2 Five days of active tDCS will result in greater improvements in subjective fatigue relative 
to sham tDCS. 
 
4.2.3 Five days of active tDCS will result in greater improvements in subjective fatigue and 
cognition one week following active stimulation relative to sham stimulation. 
 
4.3 
Exploratory 
 
4.3.1 Five days of active tDCS will result in greater improvements (relative to sham tDCS) in 
selected cognitive skills (e.g. attention, processing speed) that are also heavily reliant on 
the functioning of the left DLPFC whereas active tDCS will not alter other cognitive 
abilities (e.g. many language skills, visual perception) that are less reliant on the DLPFC. 
 
4.3.2 Patient factors such as baseline fatigue, depression, and anxiety will predict response to 
tDCS. 
 
4.3.3 Participants will report only mild side effects of tDCS intervention such as tingling under 
the electrode. 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
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Version:  February 27, 2019 (Revised) 
 
 
 
5. BACKGROUND AND RATIONALE 
 
5.1 
Cancer-related Fatigue and Cognitive Dysfunction 
The American Society of Clinical Oncology defines cancer-related fatigue as distressing, 
persistent, subjective sense of physical, emotional and/or cognitive tiredness or exhaustion 
related to cancer and/or its treatment such that it is disproportional to recent activity and 
interferes with usual functioning 9. A majority of women with breast cancer (56-95%) report 
persistent fatigue following treatment with adjuvant chemotherapy 10. Cognitive dysfunction is 
also reported at high rates, with approximately one third of women experiencing subjective 
cognitive declines following treatment 11. These subjective cognitive complaints are closely 
linked to objective cognitive impairments on formal neuropsychological testing 12. Cognitive 
deficits most commonly occur in the areas of working memory and vigilance, processing speed, 
memory, and other higher cognitive functions 12,13. Both fatigue and cognitive dysfunction are 
associated with reduced quality of life and productivity 14. There are currently no effective 
treatments for either the enduring fatigue or cognitive dysfunction experienced following 
treatment for breast cancer 10. 
 
The DLPFC region is involved in cognitive skills other than working memory, such as executive 
functioning, attention and processing speed. Other cognitive abilities are generally less reliant on 
DLPFC functioning. For example, many language skills and visual perception are driven by 
more posterior or distributed brain regions. 
 
Among healthy adults, functional neuroimaging studies have documented relatively consistent 
patterns of brain activation during working memory tasks involving the left prefrontal and 
premotor regions 15. When completing tests of higher order cognition, breast cancer survivors 
fail to recruit these left frontal regions at a level seen in their non-affected peers, which may 
account for their poorer performance on cognitive testing 16,17. Functional MRI-derived measures 
of neural activity in networks supporting attention and working memory are strong predictors of 
post-treatment cognition and fatigue in breast cancer survivors 18. Importantly, fatigue has been 
shown to mediate the relationship between DLPFC activation and cognitive performance in 
breast cancer patients 17. 
 
5.2 
Transcranial Direct Current Stimulation (tDCS) 
A rapidly growing body of evidence demonstrates that transcranial direct current stimulation 
(tDCS) can induce changes in physical and cognitive functioning 19, and it may represent an 
effective way of resuscitating higher cognitive functions and reducing fatigue in patient 
populations. The technique involves passing weak direct electrical current through the scalp to 
produce a relatively localized, polarity-dependent alteration of the electrical potential in cortical 
tissue beneath the scalp electrode 20,21, which appears to alter the excitability of underlying 
cortical neurons and to modulate their firing rates, as measured by single-unit recordings in 
animals or evoked potential measures in animals and in humans 22.  The effects of these 
alterations can be excitatory (with anodal stimulation) or inhibitory (with cathodal stimulation). 
 
As it has been previously used, tDCS is administered to the scalp via 25-35 cm2 saline-soaked 
sponges. A weak (1-2 mA) direct current is applied through the electrodes for up to 40 minutes at 
a time. Under these conditions, the technique has been shown repeatedly to be safe in healthy 
 
 
 

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Version:  February 27, 2019 (Revised) 
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individuals from childhood to older adulthood as well as in a variety of patient populations such 
as those with stroke, epilepsy and mental illness23-25. TDCS is also generally unobtrusive. Many 
subjects do not perceive the current being applied. Some subjects report a tingling sensation 
under the electrode during tDCS, although increasing the current can eliminate this perception. 
 
The prefrontal cortex, and the DLPFC in particular, is an attractive 
neuroanatomic target to address cognitive dysfunction and fatigue 
via tDCS in breast cancer survivors. See Figure 1. Numerous prior 
investigations have demonstrated that tDCS applied to the left 
DLPFC can improve working memory in both healthy adults and 
patient groups 26,27. Early work by Fregni and colleagues 28 
demonstrated the specificity of anodal stimulation to the left DLPFC 
in improving working memory, as indexed by an n-back task 
performance, in healthy adults. These results were specific to anodal 
Figure 1. 
stimulation of the left DLPFC, as working memory performance remained unchanged in 
response to both cathodal stimulation of the left DLPFC and anodal stimulation of the left 
primary motor cortex. Similar improvements in working memory have been seen after tDCS in 
patients with stroke 29, Parkinson’s disease 30, and major depression 31. In a case study of a single 
breast cancer survivor, tDCS was found to be safe and tolerable while resulting in improvements 
in cognitive functioning for approximately two weeks 32. In multiple sclerosis, tDCS applied to 
the DLFPC has also repeatedly been shown to be safe and tolerable resulting in reduced fatigue 
ratings, with effects lasting up to three weeks following active stimulation33-35. 
 
Studies of tDCS provide evidence to suggest that sustained and repeated stimulation paradigms 
can prove effective in generating prolonged treatment effects. Depending upon the duration of 
stimulation, and the experimental situation, effects of tDCS have been found to persist for 
minutes, hours, or up to a month 36,37. For example, a single 13-minute session of motor cortex 
stimulation has yielded up to 90 minutes of altered cortical excitability 24, and consecutive daily 
sessions of tDCS were associated with a significant behavioral improvement lasting up to two 
weeks post-treatment in individuals experiencing post-stroke motor dysfunction 36. With respect 
to cognitive enhancement, it has been demonstrated that repeated daily anodal tDCS applied to 
the DLPFC results in improvements in working memory that last up to a week or longer in adults 
with major depression 38, and these cognitive enhancements are independent of tDCS-induced 
changes in mood functioning.  In multiple sclerosis, repeated daily stimulation aimed at reducing 
neuropathic pain yielded significantly diminished pain ratings three weeks following the 
termination of stimulation and was not associated with any adverse reactions 37. Similarly, 
improvements in subjective fatigue ratings have been demonstrated to persist for up to three 
weeks following tDCS in multiple sclerosis 33 and two weeks in a participant with breast 
cancer32. 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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5.2.1 Preliminary tDCS Data at Johns Hopkins 
Our lab has demonstrated the ability of a single tDCS session to improve higher cognitive 
functions in adults 39. We have also shown that tDCS alters resting brain network connectivity 
associated with working memory performance 40. Most relevant to the current proposal are our 
pilot data for five patients with multiple 
sclerosis which, like breast cancer, more 
commonly affects women and is associated 
with persistent fatigue and cognitive deficits. 
TDCS was both safe and tolerable in these 
patients. We observed a relative reduction in 
fatigue ratings and improvement in working 
memory test performance (PASAT, N-back) 
over five days of active stimulation as 
compared to increased fatigue and modest 
cognitive practice effects observed in response 
to sham stimulation. See Figure 2. Depression 
scores remained unchanged and were unlikely 
to have contributed to the observed 
improvements in fatigue and cognition 41. 
Despite the evidence documenting the safety and utility of tDCS as a means of enhancing 
working memory and reducing subjective fatigue in patient populations whose deficits are 
characterized by inefficient prefrontal network activity, working memory deficits, and fatigue 
(e.g., multiple sclerosis, depression 27,34,38,41), it has yet to be thoroughly investigated as a means 
of reducing fatigue and enhancing cognitive functioning in breast cancer survivors. 
Demonstrating efficacy in improving cognitive function and fatigue in breast cancer survivors 
with this short-term tDCS intervention is a first step in evaluating this intervention as a possible 
technique for longer-term management of fatigue and cognitive dysfunction in this population. 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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6. PARTICIPANT SELECTION 
 
6.1 
Inclusion Criteria 
6.1.1 Women, 18 years of age or older 
6.1.2 Stage I-III breast cancer 
Treatment Status:  At least 1 month and no more than 5 years after the conclusion of 
active breast cancer therapy, including surgery, radiation therapy and (neo)adjuvant 
chemotherapy, if administered. 
NOTE:  Adjuvant HER2-targeted therapy and endocrine therapy may be ongoing at the 
time of study enrollment. Those who require  endocrine therapy must have been on their 
current endocrine regimen for at least four weeks prior to study enrollment and must not 
have plans to change or initiate endocrine regimens during the study period.    
6.1.3 Fatigue: Reports moderate fatigue on most days within the past week (i.e., at least 4 out 
of the last 7 days), rated as ≥ 4 on a 0 (no fatigue) to 10 (worst fatigue) scale. 
6.1.4 Able and willing to complete study tasks as evidenced by at least the following:  fluent 
English speaker; hearing and language comprehension; and, sufficient literacy to 
complete study forms and questionnaires 
6.1.5 Patient understands the study regimen, its requirements, risks, and discomforts, and is 
able and willing to sign an informed consent form. 
 
6.2 
Exclusion Criteria 
6.2.1 Evidence of recurrent breast cancer at the time of enrollment. 
6.2.2 Dementia as assessed by a MMSE score < 24 on initial screening. 
6.2.3 Known pregnancy or nursing. 
6.2.4 Any of the following: diagnosis of schizophrenia or bipolar disorder made by a physician, 
seizure disorder, pacemaker, hearing aids, any metal implanted in the head, or the 
presence of other known current untreated causes of fatigue such as anemia (defined as 
Hgb < 10 g/dL within 3 months of study enrollment) or untreated hypothyroidism. 
6.2.5 Use of the following medications for seven days prior to and during study participation: 
i. Stimulant medications 
ii. Sleep medications 
iii. Carbamazepine/Tegratol 
i. Cough/cold medicines (e.g. Dextromethorphan, Triaminic, Robitussin, Vics Formula 
44) 
ii. Flunarizine/Sibelium 
iii. Propnolol/Inderal 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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iv. Sulpiride 
v. Pergolide 
vi. Rivastigmine/Exelon 
vii. Carbidopa/levodopa or levodopa 
viii. Ropinirole/Requip 
ix. Nicotine patch 
6.2.6 Use of narcotic pain medication, benzodiazepines, or illicit drugs for seven days prior to 
and during study participation. 
6.2.7 Self-reported consumption of > 14 alcoholic drinks per week or positive screening on the 
CAGE questionnaire in relation to the past year.  NOTE:  A single, standard alcoholic 
drink is defined as 10 grams of alcohol, which is equivalent to 285 mL of beer, 530 mL 
of light beer, 100 mL of wine or 30 mL of liquor. 
6.2.8 Skin conditions involving open sores on the scalp that would prevent proper application 
of the electrodes. 
6.2.9 Hairstyles that obstruct placement of the electrodes including cornrows, dreadlocks, 
braids or other hair accessories that cannot be removed. 
6.2.10 Other medical or other condition(s) that in the opinion of the investigators might 
compromise the objectives of the study 
 
6.3 
Inclusion of Women and Minorities 
Individuals of all races and ethnic groups are eligible for this trial. Breast cancer is 
predominantly a disease of women and we anticipate that the majority of participants will be 
women. 

tDCS for Breast Cancer Fatigue and Cognition 
Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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7. STUDY DESIGN AND TREATMENT PLAN 
 
7.1 
Summary 
We propose a straightforward randomized sham-controlled double-blind crossover trial of active 
tDCS versus sham tDCS. 
 
Participants will complete two five-day study waves separated by a four-week washout period. 
During each wave, participants will complete a brief cognitive battery and study questionnaires 
on the first and last day of the study wave (i.e., Monday and Friday). On all five days of each 
wave, participants will engage in cognitive tasks while receiving stimulation (either active or 
sham) in order to maximize stimulation effects 27. In order to assess for duration of subjective 
effects, participants will complete self-report measures of subjective fatigue, mood, and 
cognition by phone approximately seven days after the final day of the first study wave. After a 
washout period of four weeks, participants will repeat a second study wave wherein they engage 
in the same study procedures while receiving the opposite stimulation condition (active/sham); 
again followed by a phone call for subjective ratings of fatigue, mood, and cognition. 
 
 
Days 1 – 5 
Basic Study Schedule* 
Day 12 
Days 6 – 35 
Days 36 – 40 
 
Day 47 
Wave 1 
Washout 
Wave 2 
Follow-up 
5 consecutive 
15-minute 
No study 
study 
activities 
phone call 
5 consecutive 
15-minute 
daily study visits 
daily study visits 
study 
(Monday-Friday) 
(Monday-Friday) 
phone call 
* See Study Calendar, Section 8, for detailed schedule and scheduling windows/allowances. 
 
7.2 
Recruitment 
Patients will be recruited through referrals from their Oncologists, including, but not limited to 
those at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Additionally, 
interested participants may contact the study team directly through study fliers distributed to 
physician offices and patient support groups. 
 
Potential participants may be identified during chart review in advance of a routine clinic visit or 
during a routine clinic visit with a provider. Individuals will be approached by the provider or 
study team to determine willingness to learn more about a study for which they may be eligible. 
Discussions regarding study participation will take place privately and individuals will be 
provided with the IRB approved consent form. 
 
In addition, potential participants may contact the study team directly. This contact may be in the 
form of telephone, email, etc. Initial discussions regarding study participation may take place by 
phone, email, etc., and individuals may be provided with the IRB approved consent form and 
other IRB reviewed and approved materials (e.g., Patient Handout), as applicable. 
 
In all cases, as much time as is needed to consider study participation will be allowed to possible 
participants; resulting in multiple phone calls, visits, emails, or other communication, as 
necessary. For individuals who choose to take part, informed 
consent will happen as per the consent process. 

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Principal Investigator: Tracy D. Vannorsdall, Ph.D. 
Version:  February 27, 2019 (Revised) 
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7.3 
Determination of Eligibility 
Preliminary eligibility for participation will be reviewed by a member of the study staff via a 
telephone screening process (Appendix). For patients who reach the study team without referral 
of their treating provider, a member of the patient’s oncology care team will be consulted to 
confirm that s/he believes that the participant is appropriate for protocol participation. Patients 
who appear to be eligible after the telephone screening will be invited to meet with the study 
team.  At this time, consent will be obtained and eligibility then confirmed including the 
completion of the screening assessments detailed in section 7.6.1. 
 
Upon confirmation of eligibility, patients will be registered into the study, at which time a study- 
specific subject ID/number will be assigned.  Patients who are found not to be eligible will be 
considered screen failures.  PHI will be retained to justify screen failures, and will be stored 
under the same secure conditions as all study-related data for the length of the trial. 
 
Randomization will occur after study registration. 
 
Study intervention cannot begin until the patient has provided consent, is confirmed eligible, and 
is successfully registered and randomized. 
 
7.4 
Randomization and Blinding 
Upon eligibility confirmation and study registration, participants will be randomized to receive 
active or sham tDCS during the first five-day study wave (to be followed by the opposing 
condition in the second five-day study wave). This is a double-blind study. Both the participant 
and study team members will remain blinded to the application of active or sham tDCS 
throughout the course of an individual’s study participation. 
 
The tDCS device (NeuroConn DC Stimulator Plus Model 0021) comes with a list of pre- 
programed five-digit numeric codes that are manually entered into the stimulator by the study 
team member at the time of an individual’s study participation. These codes cause the device to 
deliver either active or “pseudo stimulation” (i.e., sham stimulation). Pairs of two codes (one 
active, one sham) for each participant will be aggregated by a study statistician who will then 
provide these pairs, and their order of administration, to a member of the study team in a way 
that the stimulation condition is not known (i.e., only the numeric codes and administration order 
will be relayed, not the key linking the codes to the stimulation condition). 
 
All participants will be asked whether they thought that they received active or sham stimulation 
during each wave. This will take place at the end of the fifth day of the final study wave as part 
of the side effects questionnaire. 
 
7.5 
Methods and Intervention 
 
7.5.1 tDCS 
TDCS will be administered to relatively localized brain regions using the international 10-20 
classification system to apply electrodes to the head. See Figure 3.Current will be administered 
via 25-100 cm2 saline-soaked sponge electrodes. To affect the left prefrontal region, the active 
electrode will be placed over the left prefrontal region (F3) and adhered via an adjustable 

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rubberized head strap. The indifferent (reference) electrode will 
be placed over the right supraorbital region (F8) and will also be 
affixed via an adjustable rubberized head strap. 
 
7.5.1.1 Active Stimulation 
Under the active stimulation condition, 30 minutes of 2mA 
stimulation will be applied to the left DLPFC (F3) daily over the 
course of five consecutive days (Monday-Friday). The rationale 
for this approach is based on prior studies exploring left DLPFC 
stimulation to enhance cognition 27-30,38 and reduce fatigue 33-35, 
as well as Ohn’s work 26 documenting greater effects of tDCS on working memory following 
longer stimulation periods and Fregni’s work 38 documenting persistence of effects when 
stimulation is administered over multiple occasions. This approach has also proven useful in 
treatment of fatigue in medical patients33-35. 
 
7.5.1.2 Sham Stimulation 
Under the sham stimulation condition, participants will wear the electrodes in the same manner 
as active stimulation (F3, F8) for 30 minutes. 
 
During sham stimulation, a small current pulses every 550 ms (110 µA over 15 ms) rather than 
delivering constant current as is done in the active stimulation condition. This brief period of 
stimulation causes a slight itching or tingling sensation similar to that experienced during the 
initial period of active stimulation. During active stimulation, participants usually habituate to 
the physical sensations within 30-60 seconds42; which is the characteristic that is thought to 
allow sham stimulation to be effective without delivering enough current to modulate neural 
networks. 
 
All other study activities including self-report measures and cognitive training will remain 
identical across active and sham stimulation sessions. 
 
7.5.1.3 Dose and Application 
The dose and duration of stimulation administered under the active and sham conditions will 
remain identical for all participants. Under the active condition, 2mA of current will be delivered 
for 30 minutes. Under the sham condition, only brief pulses will be administered during the 30- 
minute session. 
 
1. On each study day just prior to the application of electrodes, a participant’s head will be 
measured in order to identify their F3 location. 
2. The sponge electrodes will be moistened with saline prior to insertion of the rubber 
electrode and placement on a participant’s head. 
3. Electrodes will be affixed via adjustable rubberized straps. 
4. The numerical condition code will be entered into the NeuroConn DC Stimulator Plus 
device, which will then administer 30 minutes of either active or sham stimulation. 

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7.5.2 NeuroConn DC Stimulator Plus 
tDCS has been established as a valid and reliable tool for at least 
temporarily affecting brain and behavior with minimal risks (for 
review, see 22 and 43). Stimulation will be delivered by a NeuroConn 
DC Stimulator Plus (Model 0021), which is a battery-driven constant 
current stimulator. See Figure 4. The NeuroConn stimulator is 
certified as an active medical device (class IIa) by the European 
Union Notified Body 0118, and has been safely used in scores of 
published tDCS studies around the world. 
 
Figure 4. 
 
The stimulator is not connected to a mainline power source and cannot produce more than 4.5 
mA of current. The current density, as indexed by stimulation strength (A)/electrode size, is a 
relevant parameter for inducing neuronal damage 44. We will be remaining within the 
recommended current density safety guidelines of 40 μC/cm2 *ph 44. We also reviewed the 
safety notes in the operator manuals provided by the manufacturer of the device. The stimulation 
parameters in the planned investigation do not exceed the stimulation limits or violate the safety 
directives specified in the operator manual. 
 
The active constant current and sham current settings both enable an impedance control that 
reliably detects any electrode disconnection. In the event of an electrode disconnection, the 
experimenter is alerted and the device automatically stops delivering current. The 30-minute 
dose delivery session is paused briefly while the electrode is quickly reaffixed to the head, 
reinitiating the electrical circuit. The 30-minute stimulation session is promptly resumed. 
 
We will use non-metallic, conductive rubber electrodes covered by saline-soaked sponges to 
minimize the potential for chemical reactions at the interface of the scalp or skin and the 
electrodes. 
 
Following IRB approval, the NeuroConn DC Stimulator Plus device will undergo evaluation by 
Johns Hopkins Clinical Engineering. Both active and sham tDCS will be administered by a 
trained study team member. 
 
7.5.3 Cognitive tasks during stimulation 
During each stimulation session under both active and sham tDCS conditions, participants will 
engage in a computerized working memory n-back task that continuously adapts to the 
performance of the individual, remaining equally engaging and demanding over the course of 
training and across individuals of varying working memory ability 45,46. 
 
7.6 
Study Assessments 
Participants are expected to spend no longer than two hours completing cognitive testing and 
questionnaires on any given study day. This battery of cognitive tools and questionnaires consists 
of instruments that are routinely used in the clinical setting with medically frail and elderly 
patients. Their completion is not expected to result in increased fatigue in study participants. 
Nonetheless, breaks will be taken as necessary and appropriate in order to facilitate participant 
comfort and engagement. 

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7.6.1 Screening Instruments 
Screening instruments will be administered at study entry and will take approximately 12 
minutes to complete. 
 
7.6.1.1 Mini Mental State Exam (MMSE; 47). Participants will complete the MMSE, a brief 
cognitive screening measure that assesses orientation, attention, learning/memory, 
language functioning, and visuoconstruction skills. Administration requires 
approximately five minutes and will be used to ensure that all participants meet our 
stated inclusion criteria (i.e., non-demented as defined by a MMSE score ≥24). 
 
 
7.6.1.2 CAGE 51. The CAGE questionnaire is a widely used 4-item screening instrument for 
problem drinking. Each item is scored 0 (absent) or 1 (present). Scores ≥ 2 are 
considered clinically significant. Scores on the CAGE along with the patient’s report of 
the number of alcoholic drinks consumed per week will be used to ensure that all 
participants meet our stated inclusion criteria with respect to alcohol consumption. 
Included within Appendix P. 
 
7.6.1.3 Quantitative Fatigue Assessment. Potential participants will be asked to rate their 
fatigue on a 0 (no fatigue) to 10 (worst fatigue imaginable) scale in order to ensure that 
the study enrollment is limited to those with reports of at least moderate fatigue, as 
stated in our inclusion criteria. Consistent with ASCO guidelines for assessment of 
fatigue in cancer 52, scores of ≥ 4 will be considered indicative of at least moderate 
fatigue. 
 
7.6.2 Tools to Assess Primary and Secondary Endpoints 
The primary and secondary endpoints will be assessed at the beginning and end of each 
five-day study wave in-person (i.e., subjective cognition and fatigue), and approximately 
seven days after the last stimulation session by phone (i.e., subjective cognition and 
fatigue). In-person testing will take approximately 20 minutes; whereas, testing via phone 
will take approximately 10 minutes. 
 
7.6.2.1 Paced Auditory Serial Attention Test (PASAT) 1,2. The primary measurement tool for 
assessing objective cognitive functioning will be performance on the PASAT. 
 
The PASAT is working memory task that has been well-validated medical populations 
including breast cancer53. Test administration involves the aural presentation of single 
digits via computer in order to ensure a standardized rate of stimulus presentation. 
Stimuli are presented every three seconds (trial 1) or every two seconds (trial 2). 
Participants add each new digit to the one immediately prior as the test continues to 

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present stimuli. The test score reflects the total number of correct sums given (out of 60 
possible) in each trial. 
 
Two equivalent, alternative PASAT forms will be used to minimize practice effects. 
The test takes approximately 10 minutes to complete. It will be completed prior to and 
following both five-day active anodal and sham stimulation conditions (i.e. on four 
occasions).  Available data indicates that prior to adjuvant treatment, breast cancer 
patients with stage I-III disease score an average of 46.6 ± 11.2 on the PASAT trial 1 (3 
second administration) and an average of 34.3 ± 10.1 on trial 2 (2 second 
administration)54. 
7.6.2.2 Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog version 3)55. 
The measurement endpoint for subjective cognition will be scores on the FACT-Cog, a 
37-item self-report measure addressing cognitive difficulties and their effect on patient 
quality of life. The measure addresses six cognitive domains (memory, concentration, 
mental acuity, verbal fluency, functional interference, and multitasking). The 
questionnaire is easy to use and appropriate for individuals with a history of cancer of 
varying age groups and backgrounds. 
 
Responses are provided on 5-point Likert scales addressing the frequency with which 
each type of cognitive difficulty occurred from 0, “never” to 4, “several times a day” 
over the prior seven days. Two additional subscales address “noticeability” or 
comments from others regarding cognition and “effect of perceived cognitive 
impairment on quality of life.” These are rated on 5-point Likert scales ranging from 0, 
“not at all” to 4, “very much.” The total FACT-Cog score is obtained by summing the 
individual subscale scores and ranges from 0 to 148. Breast cancer patients produce a 
mean FACT-Cog total score of 119.0 ± 23.3.56 
 
The FACT-Cog takes approximately 5 minutes to complete. It will be completed prior 
to and following both five-day active anodal and sham stimulation conditions (i.e. on 
four occasions). It will also be completed by phone (taking approximately 5 minutes) 
seven days (± three days) after the final (fifth) stimulation session of each study wave in 
order to assess for persistence of stimulation effects. 
 
7.6.2.3 Multidimensional Fatigue Symptom Inventory 30-item short form (MFSI-SF)57. The 
primary measurement tool for subjective fatigue will be the MFSI-SF, which assesses 
participants’ subjective ratings across five empirically derived subscales (general 
fatigue, physical fatigue, emotional fatigue, mental fatigue, and vigor). Responses are 
provided on 5-point Likert scales addressing the extent to which each symptom was 
experienced during the preceding week (0, not at all to 4, extremely). The five subscale 
scores are obtained by summing scores within each subscale. The MFSI-SF total score 
is obtained by subtracting the vigor subscale score from the sum of the four fatigue 
subscales. Scores range from -36 to 144. 
 
The MFSI-SF is well validated in breast cancer patients58,59. Breast cancer patients with 
fatigue produce an average score of 14.7 ± 15.260. 

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The MSFI-SF takes approximately 5 minutes to complete. It will be completed by all 
study participants prior to and following both five-day active anodal and sham 
stimulation conditions (i.e. in person on four occasions). It will also be completed by 
phone (taking approximately 5 minutes) approximately seven days (± three days) after 
the final (fifth) stimulation session of each study wave in order to assess for persistence 
of stimulation effects. 
 
7.6.3 Tools to Assess Exploratory Endpoints 
 
In order to determine which domains of cognition are improved by five consecutive 
days of tDCS, other objectively assessed cognitive skills will be assessed at the 
beginning and end of each study wave. Testing will take approximately 40 minutes and 
will include the following outcomes: 
 
7.6.3.1 Hopkins Verbal Learning Test- Revised (HVLT-R)3. The HVLT-R is designed to 
evaluate verbal learning and memory. The task takes approximately 8 minutes to 
complete. Participants attempt to memorize a list of 12 items presented aloud over 3 
consecutive learning trials (learning score). After a 20-25 minute delay (during which 
time other cognitive tests are administered) they are asked to recall as many words as 
possible (recall score) and to identify word list items from a list of targets and 
distractors (recognition score). Scores on the learning trial range from 0 – 36, the recall 
trial from 0 to 12, and the recognition trial from -12 to 12. The HVLT-R has six 
alternate forms. Scoring and interpretation are simple and outlined in a professional 
manual. Normative data are available in the form of demographically-adjusted T- 
scores4. 
 
The reliability and validity of the HVLT-R as a measure of new learning and memory 
has been demonstrated in a variety of patient populations and healthy controls 61. 
Clinical trials have repeatedly shown it to be sensitive to the impact of cancer and 
treatment-related neurotoxicities62-65. It was also recommended for inclusion in a core 
set of neurocognitive tests by the International Cognition and Cancer Task Force 
(ICCTF)11. Breast cancer survivors have been shown to produce a mean HVLT-R 
learning z-score of -0.44 ± 1.2363. 
7.6.3.2 Brief Visuospatial memory Test (BVMT-R4). The BVMT-R serves as the nonverbal 
analogue to the HVLT-R. Here, participants are presented with six figures on a page for 
ten seconds. The stimuli are removed and participants are asked to reproduce the figures 
from memory. As with the HVLT-R, there are three learning trials (learning score). 
After a 20-25 minute delay (during which time other cognitive tests are completed) they 
are asked to reproduce the stimuli (recall score) and identify the figures from an array of 
targets and distractors (recognition score). Scores on the learning trial range from 0 – 
36, the recall trial from 0 to 12, and the recognition trial from -6 to 6. The task takes 
approximately 8 minutes to complete. The BVMT-R has six alternate forms. Scoring 
and interpretation are simple and outlined in a professional manual. Normative data are 
available in the form of demographically-adjusted T-scores 4. 
 
7.6.3.3 Trail Making Test (TMT). The Trail Making Test is composed of two parts (A and B). 

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Part A is designed to evaluate visual motor scanning and processing speed, while part B 
is designed to evaluate executive functioning 66. These tests require patients to connect 
circles in numerical (part A) or alternating numerical and alphabetical sequence (part B) 
as quickly as possible. Results are reported as the number of seconds required to 
complete each part, with higher scores reflecting higher degrees of impairment (range 0 
– 300 seconds per trial). Normative data are available in the form of demographically 
adjusted T-scores67,68. The entire task takes approximately five minutes to complete. 
The Trail Making Test23 is a well-established neuropsychological measure with solid 
psychometric properties 69. Clinical trials have repeatedly shown it to be sensitive to the 
impact of cancer and treatment-related neurotoxicities62-65. It was also recommended for 
inclusion in a core set of neurocognitive tests by the ICCTF11. Breast cancer survivors 
have been shown to produce z-scores of 0.56 ± 1.29 on part A and 0.15 ± 1.22 on part 
B.63 
 
7.6.3.4 Calibrated Ideational Fluency Assessment (CIFA)7. The CIFA verbal fluency trials are 
designed to evaluate verbal fluency and executive functioning. The task requires 
patients to name as many words as possible beginning with two different letters (letter 
fluency) and that belong to two different categories (category fluency) over four 
separate one-minute trials. The task takes approximately five minutes to complete. 
Scoring is based on the number of correct words produced over the course of the four 
trials, with greater values reflecting better performance. Normative data are available in 
the form of demographically adjusted T-scores 7. 
Tests of verbal fluency are reliable and well-validated tests of cognitive processing69,70. 
Clinical trials have repeatedly shown verbal fluency performance to be sensitive to the 
impact of cancer and treatment-related neurotoxicities62-65. This type of task was also 
recommended for inclusion in a core set of neurocognitive tests by the ICCTF11. 
 
7.6.3.5 Wechsler Adult Intelligence Scale-Fourth edition (WAIS-IV) Digit Span subtest5 . The 
Digit Span subtest assesses simple attention and working memory. Participants are read 
aloud increasingly lengthy strings of digits and are asked to repeat these strings in 
forward and backward sequences. The number of digit strings correctly completed 
forward, backward, and overall serve as outcome measures. The test takes 
approximately five minutes to complete. Normative data in the form of demographically 
adjusted scaled scores are available in a professional manual 71. 
 
The Digit Span subtest of the Wechsler scales has excellent psychometric properties and 
is an extremely well-validated measure of simple attention and working memory71. It 
has repeatedly been shown to be sensitive to cancer and treatment-related 
neurotoxicity72-74. Normative data are available in the form of demographically adjusted 
scaled scores. Breast cancer survivors have been shown to produce scaled scores of 
10.04 ± 2.67 on the Digit Span test.63 
 
7.6.3.6 Grooved Pegboard Test8. The grooved pegboard test is a well-validated test of manual 
speed and dexterity that has been shown to be sensitive to treatment-related 
neurotoxicity in breast cancer patients75. The test involves placing grooved pegs into 

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variously oriented holds in a small board as quickly as possible. Participants complete 
the task with the dominant hand followed by the non-dominant hand. The test takes 
approximately five minutes to complete. The test is scored according to the number of 
seconds required to complete the board using each hand (range 0 – 300 seconds per 
hand). Published normative data are available in the form of demographically-adjusted 
T-scores.68 
 
7.6.4 Patient Reported Outcomes to be assessed at the Beginning and End of each five-day 
Study Wave 
Symptoms of anxiety, depression, sleep quality, and quality of life will be administered 
prior to and following each five-day study wave (i.e. on four occasions). Testing will take 
approximately 15 minutes. 
 
7.6.4.1 Hospital Anxiety and Depression Scale (HADS)48. Depression and anxiety are common 
in breast cancer survivors 49,50 and can negatively affect cognitive functioning including 
working memory and processing speed69 as well as functioning of the DLPFC76. In 
order to determine whether changes in mood or anxiety are contributing to changes in 
the primary outcome variables, participants will complete the HADS48, a brief, well- 
validated77 self-report questionnaire addressing symptoms of anxiety and depression 
experienced over the previous seven days. In addition to being administered prior to 
and following each five-day study wave, it will also be administered at both study 
phone calls (i.e. study days 12 and 47). It takes approximately five minutes to 
complete. 
 
7.6.4.2 Pittsburgh Sleep Quality Index. In order to control for any differences in sleep quality 
that may affect fatigue ratings, participants will complete the Pittsburgh Sleep Quality 
Index prior to and following both five-day active anodal and sham stimulation 
conditions (i.e. on four occasions) 78. This questionnaire assesses sleep quality and 
disturbances over the prior month. It takes approximately 5 minutes to complete. 
 
7.6.4.3 EORTC Quality of Life Questionnaire (QLQ-C30). Quality of life is frequently 
diminished in breast cancer survivors and is associated with greater rates and severity of 
fatigue 79 and depression80. In order to control for any differences in quality of life that 
may affect self-reported fatigue and mood, participants will complete the EORTC 
Quality of Life Questionnaire (QLQ-C30). This self-report measure assesses health- 
related quality of life in cancer patients participating in clinical trials. Via five 
functional scales, three symptom scales, and a global health status measure, the QLQ- 
C30 addresses physical, role, emotional, cognitive and social functioning as well as 
symptoms of fatigue, pain, insomnia and others in a 30-item questionnaire. This 
questionnaire takes approximately 5 minutes to complete. 
 
7.6.5 Additional Assessments 
Prior to receiving the first session of active tDCS stimulation or sham stimulation (i.e., at 
baseline), all participants will spend approximately 30 minutes completing several 
questionnaires and brief cognitive tests to provide the information necessary to describe 
our sample characteristics fully and to adjust for participant characteristics in our 
statistical analyses. 
 

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7.6.5.1 History Form. Other characteristics with known associations with performance on tests 

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of higher-order cognition include illiteracy, English as a second language, educational 
attainment, occupation, history of learning disabilities, substance abuse and health 
behaviors that impact cerebral vasculature, other cerebrovascular risk factors, 
psychiatric and systemic illness and their treatment, traumatic brain injury, family 
history of several of the above-mentioned variables, and use of disease-modifying drugs 
and cognitively enhancing drugs such as psychostimulants or caffeine. Conditions 
associated with fatigue include anemia, thyroid dysfunction and cardiac dysfunction. As 
such, we will ask participants to complete a history form addressing these issues at the 
start of their participation. The questionnaire takes approximately five minutes to 
complete. 
 
7.6.5.2 Hopkins Adult Reading Test (HART)81. Verbal intelligence has been demonstrated to 
hold moderate correlations with various cognitive abilities. Premorbid IQ is also an 
important predictor of baseline cognitive dysfunction in cancer patients 82. To estimate 
verbal intelligence, participants will complete the HART at baseline. This test requires 
participants to read aloud a list of 35 irregularly spelled words. The HART takes 
approximately 2 minutes to complete. Scoring is based on the number of items correctly 
pronounced, which is then converted into a standard score based on published 
normative data68. 
7.6.5.3 Edinburgh Inventory83. A history of left-handedness places one at greater probability of 
being right hemisphere dominant for language or for being of mixed dominance. 
Because this investigation seeks to alter some verbally-mediated cognitive abilities, 
knowledge of one’s probability of being left hemisphere dominant for language will be 
an important consideration. The Edinburgh Inventory specifically assesses handedness 
and takes approximately 3 minutes to complete. 
 
7.6.5.4 UCLA Loneliness Scale84. Loneliness is associated with subjective cognitive difficulties 
in breast cancer survivors85. As such, at the beginning of study participation participants 
will complete the UCLA Loneliness Scale, which addresses one’s perceived social 
isolation and loneliness. This questionnaire takes approximately 5 minutes to complete. 
 
7.6.5.5 NEO Five Factor Inventory- 3rd edition (NEO-FFI 3)86. Personality characteristics are 
related to fatigue and other factors in cancer patients, as well as with a tendency to 
respond to exhibit a placebo effect87. At baseline all participants will complete the 
NEO-FFI 3 in order to assess their standing on the five primary personality factors of 
openness, neuroticism, extroversion, agreeableness and conscientiousness. This 
questionnaire takes approximately 10 minutes to complete. Scores for each of the five 
factors are presented as T-scores. 
 
7.6.5.6 TDCS Side Effects. Participants will also complete a brief questionnaire to assess 
physical sensations and mood experienced prior to and following each stimulation 
session (i.e. twice during all ten sessions) to document the presence and severity of any 
tDCS-related side effects. Participants will be asked to rate the severity of these 
experiences and to report any other sensations they were not asked about directly. At 
the end of the study each participant will also be asked whether they believed they were 
receiving active or sham tDCS during each of the two study waves, and they will rate 

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their degree of confidence with respect to those judgments. This task takes less than five 
minutes to complete. 
 
NOTE:  Please see questionnaires and cognitive tests in Appendices A through U. 
 
7.7 
Concomitant and Supportive Therapy 
Participation in this study will not disrupt any current care of therapy. The concomitant 
medications and therapies deemed necessary for the supportive care and safety of the subject are 
allowed, with the exception of the following: 
 
The use of concurrent medications for fatigue, alertness or sleep will be assessed at the beginning 
of each study wave and will not be allowed as outlined in the exclusion criteria (above, Section 
6.2). 
 
7.8 
Discontinuation and Withdrawal of Subjects 
All patients who initiate protocol intervention will be included in the overall evaluation of 
response (intent-to-treat analysis). All reasons for discontinuation of intervention will be 
documented clearly in the record. 
 
In the event that the intervention is stopped early and unless the subject refuses, follow-up will 
continue for the planned duration of the study to collect data for the study endpoints. 
 
7.8.1 Discontinuation of Intervention 
The reasons for discontinuation of protocol intervention include: 
 
• 
Unacceptable major toxicity or inability to tolerate the tDCS procedures. 
• 
Intercurrent illness or condition that would, in the judgment of the treating investigator, 
affect assessment of clinical status to a significant degree or require discontinuation of 
study intervention. 
• 
Becoming pregnant or starting to nurse. 
• 
Initiating the use of a prohibited medications that may interfere with the efficacy of 
tDCS. 
• 
At subject’s own request. Note: The reason for discontinuation from the study must be 
documented. The patients will be included in the overall evaluation of response (intent- 
to-treat analysis) if any protocol intervention was administered prior to withdrawal. 
• 
Study is closed or cancelled for any reason. 
 
7.8.2 Withdrawal from Study 
The reasons for withdrawal from the study include: 
 
• 
Subject withdraws consent for follow-up. 
• 
Subject is lost to follow-up. 
• 
Study is terminated for any reason. 

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7.9 
Additional Information 
All participants will be reimbursed for their direct participation, including time spent completing 
the consent and screening process and time spent completing study interventions, at the rate of 
$15.00 per hour or any fraction thereof. In addition, vouchers will be provided for parking in the 
event the participant is seen at a clinic where she must pay for parking. Reimbursement will be 
mailed by check at the end of the study (i.e., after both 5 day tDCS/sham sessions; preferred, if 
acceptable to the subject). If a subject chooses to terminate the testing session early or signs the 
consent but is ultimately deemed ineligible, she will still be reimbursed for the number of hours 
she has participated. Reimbursement will not be provided for the time spent during the follow-up 
telephone calls. 
 
Participants will be involved in a study design that involves several test sessions, across a 
number of days. To encourage participants to finish the study, there will be an incentive of $50 at 
the completion of the final test session (by phone). Of course, as noted before, if a subject should 
choose not to complete the whole study, she will be paid for the portion(s) completed. 

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8. STUDY CALENDAR 
 
 
 
Procedure 
 
 
Screening 
End of 
Study 
Intervention 
Day(s) 
1 
2-4 
5 
12b 
36 37-39 40 
47b 
Approximate Duration of Participation 
(minutes) 
12 
140 
45 
115 
10 
115 
45 
115 
10 
Consent, Demographics, Medical and 
Cancer History 
X 
 
 
 
 
 
 
 
 
Concomitant Medication and 
Supplement Use 
X 
 
 
 
 
X  
 
 
Mini Mental State Exam 
X 
 
 
 
 
 
 
 
 
CAGE 
X 
 
 
 
 
 
 
 
 
Quantitative Fatigue Assessment 
X 
 
 
 
 
 
 
 
 
Transcranial Direct Current Stimulation 
(active/sham) 
 
X 
X 
X  
X 
X 
X  
Computerized Working Memory Taska  
X 
X 
X  
X 
X 
X  
Paced Auditory Serial Attention Test 
 
X  
X  
X  
X  
Functional Assessment of Cancer 
Therapy Cognitive Scale 
 
X  
X 
X 
X  
X 
X 
Multi-dimensional Fatigue Symptom 
Inventory 
 
X  
X 
X 
X  
X 
X 
Hopkins Verbal Learning Test-Revised  
X  
X  
X  
X  
Brief Visuospatial Memory Test- 
Revised 
 
X  
X  
X  
X  
Trail Making Test Parts A and B 
 
X  
X  
X  
X  
Calibrated Ideational Fluency 
Assessment 
 
X  
X  
X  
X  
WAIS-IV Digit Span Subtest 
 
X  
X  
X  
X  
Grooved Pegboard Test 
 
X  
X  
X  
X  
Hospital Anxiety and Depression Scale  
X  
X 
X 
X  
X 
X 
Pittsburgh Sleep Quality Index 
 
X  
X  
X  
X  
EORTC Quality of Life Questionnaire  
X  
X  
X  
X  
History Form 
 
X  
 
 
 
 
 
 
Hopkins Adult Reading Test 
 
X  
 
 
 
 
 
 
Edinburgh Inventory 
 
X  
 
 
 
 
 
 
UCLA Loneliness Scale 
 
X  
 
 
 
 
 
 
NEO-Five Factor Inventory - 3 
 
X  
 
 
 
 
 
 
Side Effect Questionnairec 
 
X 
X 
X  
X 
X 
X  
 
a. 
Computerized working memory task is administered during transcranial direct current stimulation 
b. 
Day 12 and Day 47 assessments will be performed by phone -1/+3 days of days 12 and 47. 
c. 
The side effect questionnaire will be completed before and after each transcranial direct current stimulation session (a 
total of 20 times). On days 5 and 40, participants will be asked if they believed they were receiving active or sham 
tDCS during the wave they have just completed and to rate their degree of confidence with respect to these judgments. 
 
NOTE: If there is a greater than 21-day period between the screening procedures/determination of eligibility and the initiation of 
the study intervention, participants will be re-screened during an appointment reminder phone call approximately one week prior 
to the study intervention. We will permit a between-wave washout period of five rather than four weeks, in which case the second 

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wave and end of study will be delayed by seven days. The schedule should be followed as closely as is realistically possible; 
however, the schedule may be modified due to problems such as scheduling delays or conflicts (e.g., clinic closure, poor weather 
conditions, vacations, etc.) with the guidance of the Principal Investigator/designee, as appropriate, and will not be reportable as a 
deviation unless the endpoints of the study are affected. 
 
9. ADVERSE EVENTS 
 
In previous studies, a serious adverse event related to tDCS has been defined as that which is 
caused by tDCS and/or aggravated by tDCS and which results in: irreversible damage to brain 
tissue, persistent disability or incapacity, unexpected inpatient hospitalization, death or is life- 
threatening, or medical or surgical intervention to preclude impairment of a bodily function due 
to tDCS 43. Bikson and colleagues recently reviewed the literature on over 33,000 tDCS sessions 
and 1,000 participants who underwent repeated tDCS sessions 43. They found no reports of 
serious adverse effects or irreversible injury. Similarly, in our experience running over 125 
healthy adults and patients through tDCS trials, we have not observed any serious adverse 
events. There have been a handful of patients who reported mild temporary skin irritation. 
Adverse events will be assessed through the tDCS Side Effects Questionnaire, which is 
administered before and after each stimulation session. 
 
It has been demonstrated that tDCS does not:  (1) cause heating under the electrodes; (2) result in 
harmful changes on MRI; or (3) alter levels of serum neuron-specific enolase, a sensitive marker 
of neuronal damage 24,88. Many subjects (up to 71%) perceive a tingling sensation under the 
electrode during tDCS, although “ramping up” the current can eliminate this perception. 
Stimulation will be administered via saline-soaked sponge-covered rubber electrodes in order to 
minimize potentially unpleasant cutaneous sensations during both active and sham stimulation 
(itching, tingling, etc.). During tDCS, the most common partially adverse effects include mild 
tingling (71%), moderate fatigue (35%), and light itching under the electrode (30%). Following 
tDCS, the most common reported adverse effects are headache (12%), nausea (3%), and 
insomnia (<1%).25 Taken together, all available research suggests that prolonged application 
should not pose a risk of brain damage when applied according to safety guidelines. There have 
been rare cases of temporary skin burns related to tDCS; these have all resolved. High electrical 
impedance at the site of electrode contact could theoretically have been the cause of such burns. 
The NeuroConn Stimulator Plus monitors electrical impedance and, as a safety precaution, the 
device terminates current flow if impedance exceeds 55kΩ. The completion of the side effects 
questionnaire will help determine whether participants experience any negative consequences of 
the stimulation and will add to the growing literature on tDCS safety and side effects. 
 
9.1 
General 
In the case that adverse events related to the study intervention are reported, these will be 
recorded per the descriptions and grading scales found in the revised National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for adverse event 
reporting that can be found at http://ctep.cancer.gov/reporting/ctc.html. 
 
Information about all intervention-related adverse events, including those volunteered by the 
subject verbally or reported by the patient on the tCDS side effect questionnaire, discovered by 
investigator/study personnel questioning, or detected through other means, will be collected, 
followed, and reported appropriately. 

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Only adverse events thought to be related to tDCS will be collected, tracked and reported (as per 
section 9.2.4 on attribution).  The adverse events related to any ongoing treatment for the 
patients’ other medical conditions, including breast cancer, will not be collected. 
 
All adverse events experienced by subjects will be collected from the time of first administration 
of tDCS (active or sham), throughout the study and until the final study visit. Subjects continuing 
to experience toxicity believed to be related to tDCS after discontinuation of the study may be 
contacted for additional assessments until the toxicity has resolved or is deemed irreversible. 
 
9.2 
Definitions 
 
9.2.1 Adverse event (AE): An adverse event is any undesirable sign, symptom or medical 
condition occurring after starting study drug (or therapy) even if the event is not considered 
to be related to the study. 
 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in 
the protocol). 
 
Abnormal laboratory values or test results constitute adverse events only if they induce 
clinical signs or symptoms or require therapy. 
 
9.2.2 Serious adverse event (SAE): A serious adverse event is an untoward sign, symptom, or 
medical condition which: 
 
• results in death; 
• is immediately life-threatening; 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly/birth defect; 
• jeopardizes the subject and requires medical or surgical intervention to prevent; or one 
of the outcomes listed above. 
 
The definition of serious adverse event (experience) also includes important medical event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 

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• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not worsen 
• emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• respite care 
 
A hospitalization planned before the start of study participation) and/or for a preexisting 
condition that has not worsened does not constitute a serious adverse event. A 
hospitalization for a social reason in the absence of an adverse event also does not meet the 
criteria for a serious adverse event. 
 
The following events will also require expedited reporting for this protocol, similar to those 
events meeting the definition of SAE above: 
 
• a female subject becomes pregnant while receiving investigational therapy, the 
pregnancy must be reported; follow-up to obtain the outcome of the pregnancy should 
also occur; 
• abortion, whether accidental, therapeutic, or spontaneous, should additionally always 
be classified as serious, and expeditiously reported; 
• exposure of a baby during lactation to study treatment 
 
9.2.3 Expectedness 
 
• Unexpected adverse event: An adverse event is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the current 
adverse event list, the Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk 
 
• Expected (known) adverse event: Expected adverse events are those that have been 
previously identified as resulting from administration of the agent. For the purposes 
of this study, an adverse event is considered expected when it appears in the current 
device manual or is included in the informed consent document as a potential risk. 
 
9.2.4 Attribution 
The relationship of all adverse events and serious adverse events to the study intervention will be 
assessed by an investigator and assigned as follows: 
 
• Definite: The AE is clearly related to the study treatment. An adverse event which has a 
timely relationship to the administration of the investigational intervention, follows a 
known pattern of response, for which no alternative cause is present. 
• Probable: The AE is likely related to the study treatment. An adverse event, which has a 
timely relationship to the administration of the investigational intervention, follows a 
known pattern of response, but for which a potential alternative cause may be present. 
• Possible: The AE may be related to the study treatment An adverse event, which has a 
timely relationship to the administration of the investigational intervention, follows no 

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known pattern of response, but a potential alternative cause does not exist. 
• Unlikely: The AE is doubtfully related to the study treatment. An adverse event which 
does not have a timely relationship to the administration of the investigational intervention, 
follows no known pattern of response, does not reappear or worsen after re-administration 
of the investigational intervention (if applicable), and for which there is evidence that it is 
related to a cause other than the investigational agent. 
• Unrelated: The AE is clearly NOT related to the study treatment. An adverse event, for 
which there is evidence that it is definitely related to a cause other than the investigational 
intervention. In general, there is no timely relationship to the administration of the 
investigational intervention, or if there is a timely relationship, the event does not follow a 
known pattern of response, and there is an alternative cause. 
 
Only adverse events which are definitely, probably or possibly related to tDCS will be tracked, 
recorded and reported for this study. 
 
9.3 
Reporting Procedures 
 
9.3.1 General 
All adverse events will be captured on the appropriate study-specific case report forms (CRFs). 
 
9.3.2 Serious Adverse Events 
All serious adverse events, regardless of causality to study intervention, will be reported to the 
Principal Investigator. 
 
9.3.3 Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current institutional 
standards. If an adverse event requires modification of the informed consent, these modifications 
will be provided to the IRB with the report of the adverse event. If an adverse event requires 
modification to the study protocol, these modifications will be provided to the IRB as soon as is 
possible. 

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10. DATA AND SAFETY MONITORING 
 
10.1 
Data Management 
All information will be collected on study-specific case report forms by the study staff.  In the 
event that an electronic database is used, the following procedures will apply: 
 
• The database will be password protected; only authorized staff may enter and view study 
data. 
• Passwords and system IDs will not be shared. 
• Physical security of the workstations/files will be maintained. 
• Staff is trained on the data entry system and importance of security procedures. 
• Workstations with the database open will not be left unattended. 
 
All study data will be reviewed for completeness and accuracy by the Principal Investigator. The 
study data may also be periodically reviewed by the Sidney Kimmel Comprehensive Cancer 
Center Clinical Research Office. 
 
10.2 
Meetings 
The study staff will schedule meetings, as needed, depending on the rate of accrual, and will 
include the Protocol Chair, Co-Chair, and the following study team members as appropriate: 
study coordinators, data managers, research nurses, sub-investigators, collaborators (if 
applicable), and statistician. 
 
During these meetings matters related to the following will be discussed:  enrollment rate relative 
to expectation, characteristics of participants, retention of participants, adherence to protocol 
(potential or real protocol violations), validity and integrity of the data, safety data, analysis of 
samples, and progress of data for objectives. 
 
10.3 
Monitoring 
This is a Level I study under the SKCCC Data Safety Monitoring Plan. The principal 
investigator is responsible for internally monitoring the study and establishing additional external 
data and safety monitoring oversight, as required. The principal investigator will also monitor the 
progress of the trial, review safety reports, and confirm that the safety outcomes and response 
assessments favor continuation of the study. 
 
The study involves a device, NeuroConn DC Stimulator Plus Model 0021, that meets the criteria 
for non-significant risk (NSR) for which an IDE from the FDA is not required for the clinical 
trial outlined 89. 
 
This study will be monitored per the SKCCC Data Safety Monitoring Plan. The Clinical 
Research Office QA Group will perform an audit as the specified intervals. All trial monitoring 
and reporting will be reviewed at least annually by the SKCCC Safety Monitoring Committee. 

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11. ADMINISTRATIVE PROCEDURES 
 
11.1 
Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be approved by 
the IRB before implementation. The Principal Investigator (or her designee) is responsible for 
the coordination and development of all protocol amendments, and will disseminate this 
information to the participating centers. 
 
11.2 
Informed Consent 
Those members of the research team (principal investigator, co-investigator, research staff) who 
consent patients have been trained in informed consent procedures, are familiar with the 
protocol, and are listed as a consenter in the application document. Patients are given adequate 
time and privacy to consider the research study. Before the patient signs the consent, the 
consenter must be satisfied that the participant understands the information provided, has had an 
opportunity to discuss the information and ask questions, and is aware that he/she may withdraw 
from the study at any time. 
 
The investigator (or her designee, as appropriate) will explain to each subject the nature of the 
study, its purpose, procedures involved, expected duration, potential risks and benefits. Each 
subject will be informed that participation in the study is voluntary and that she may withdraw 
from the study at any time, and that withdrawal of consent will not affect her subsequent medical 
treatment. This informed consent will be given by means of a standard written statement and will 
be submitted for IRB approval prior to use. No patient will enter the study before her informed 
consent has been obtained. 
 
In accordance with the Health Insurance Portability and Accountability Act (HIPAA), the written 
informed consent document (or a separate document to be given in conjunction with the consent 
document) will include a subject authorization to release medical information to the study 
sponsor and supporting agencies and/or allow these bodies, a regulatory authority, or 
Institutional Review Board access to subjects’ medical information that includes all hospital 
records relevant to the study, including subjects’ medical history. 
 
11.3 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in: 
 
• ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 
• US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations) 
• Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996) 
 
The investigator agrees to adhere to the instructions and procedures described in it and thereby to 
adhere to the principles of Good Clinical Practice. 

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12. STATISTICAL CONSIDERATIONS 
 
12.1 
Overall 
 
12.1.1 The primary outcome measure will be performance on the PASAT. Specifically, our 
primary hypothesis is that anodal tDCS will result in greater offline (i.e. post-versus pre- 
stimulation) improvement in objective cognitive test scores after multiple days than does 
sham stimulation. Our primary outcome variable reflects the difference between pre- and 
post-anodal stimulation compared to pre- and post-sham stimulation, or [(score before 
anodal minus score after anodal)-(score before sham minus score after sham)]. 
 
12.1.2 Our secondary outcome measures will be subjectively rated fatigue and cognitive 
functioning as indexed by scores on the MFSI-SF and FACT-Cog. Specifically, our 
primary hypothesis is that anodal tDCS will result in greater offline (i.e. post-versus pre- 
stimulation) improvement in subjective fatigue and cognition after multiple days than 
does sham stimulation. Our secondary outcome variables reflects the difference between 
pre- and post-anodal stimulation compared to pre- and post-sham stimulation, or [(score 
before anodal minus score after anodal)-(score before sham minus score after sham)]. 
 
12.1.3 Exploratory outcome measures will include scores on other objective cognitive tests; 
disease-, treatment- and person-related predictors of response to tDCS intervention; and 
side effects of active and sham tDCS intervention as outlined above. 
 
12.2 Sample Size and Accrual 
The proposed study is a randomized, sham-controlled, double-blind, cross-over experiment. Each 
participant will receive five consecutive days of active tDCS and five consecutive days of sham 
stimulation in a random order, with a 4 to 5-week washout period in between. The primary 
endpoint is the difference in PASAT score before and after active/sham tDCS. The effect of 
tDCS in working memory performance will be evaluated by comparing the change in PASAT 
score before and after tDCS with that before and after sham stimulation. The null hypothesis is 
that tDCS usage will yield the same mean change in PASAT score as the sham stimulation. 
 
Our accrual goal is to have 45 patients complete the crossover experiments with both active and 
sham tDCS. In the multiple sclerosis literature studies with a similar design have reported an 
attrition rate of approximately 10%33-35. Hence, to achieve the target accrual, we expect to enroll 
50 breast cancer patients, with the expectation that 5 may not complete the crossover 
experiments. This sample size (n=45) will yield at least 80% power to detect a medium effect 
size (Cohen’s d) of 0.43 or greater at a two-sided type I error rate of 5% using paired t-test. 
 
12.3 Analysis Plan 
The comparison between active tDCS and shame stimulation in change in PASAT score will be 
performed using a two-sided paired t-test based on data from participants who complete the 
crossover experiments. We will also use a linear mixed effects model to evaluate the effect of 
tDCS in the change in PASAT score by including data from all participants who complete at 
least one study wave. 

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For secondary and exploratory endpoints, pre- and post-stimulation scores, including scores on 
the PASAT, FACT-Cog, and MFSI-SF, and the corresponding changes in scores (post-pre) after 
five consecutive days of stimulation will be summarized using descriptive statistics and 
displayed graphically for each stimulation condition. Data may be transformed as appropriate to 
reduce skewness and improve symmetry. To account for correlation among multiple 
measurements within the same patient, linear mixed effects models will be used to evaluate the 
effect of tDCS, where the outcome is the change in scores (post-pre stimulation) and the 
covariates will include the indicator of the stimulation condition. Other covariates in the 
exploratory analyses may include but not be limited to the order of the experiments (for 
assessing carryover effects), number of days receiving active/sham stimulations, baseline fatigue, 
depression, anxiety, loneliness, handedness, cancer stage, and cancer treatment. The change in 
MFSI-SF and FACT-Cog score obtained (via phone) seven days after each study wave will be 
analyzed using the same approach.  Exploratory sensitivity analyses will be carried out to 
examine if dropout/missingness is informative. 
 
Data analyses will be performed by the study statistician, Dr. Chiung-Yu Huang. 
 
12.4 Reporting and Exclusions 
Subjects who sign a consent form, but do not initiate protocol intervention for any reason (e.g., 
subjects who are screen failures), will be replaced and will not count towards our accrual goal. 

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APPENDICES 
 
A 
Medications and Supplements 
B 
Hospital Anxiety and Depression Scale 
C 
Mini Mental State Exam 
D 
Quantified Fatigue Assessment 
E 
Paced Auditory Serial Attention Test 
F 
Functional Assessment of Cancer Therapy Cognitive Scale 
G 
Multi-Dimensional Fatigue Symptom Inventory 
H 
Hopkins Verbal Learning Test- Revised 
I 
Brief Visuospatial Memory Test- Revised 
J 
Trail Making Tests Part A and B 
K 
Calibrated Ideational Fluency Assessment 
L 
WAIS-IV Digit Span subtest 
M 
Grooved Pegboard Tests 
N 
Pittsburgh Sleep Quality Index 
O 
EORTC Quality of Life Scale 
P 
History Form 
Q 
Hopkins Adult Reading Test 
R 
Edinburgh Handedness Inventory 
S 
UCLA Loneliness Scale 
T 
NEO-Five Factor Inventory-3 
U 
Side Effects Questionnaire 
  V 
  Stimulation Detection

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