Feasibility and Efficacy of Transcranial Direct Current Stimulation (tDCS) and Cognitive Training for Executive Dysfunction in Adult Survivors of Childhood Acute Lymphoblastic Leukemia
Phase: NA
Conditions: Acute Lymphoblastic Leukemia
Sponsor: St. Jude Children's Research Hospital

IRB Approval Date: 12/08/2015 
IRB Expiration Date: 11/25/2016 
 
NCT02336282 – MIND 
St. Jude 
ALLSTIM 
Initial Version, dated: 09-26-14, (IRB Approved: 12-16-14) Activation date: 01-12-15 
Revision 0.1, dated: 01-20-15, (IRB Approved: 02-06-15) Activation date: 02-12-15 
Revision 0.2, dated 11-12-15, (IRB Approved: 12-8-15) Activation date: 12-14-15 
 
 
 
 
 
Feasibility and Efficacy of Transcranial Direct Current Stimulation (tDCS) and Cognitive 
Training for Executive Dysfunction in Adult Survivors of Childhood Acute Lymphoblastic 
Leukemia 
 
 
 
Principal Investigator 
Kevin Krull, PhD1 
 
Co-Principal Investigator 
Wei Liu, PhD2 
 
 
 
 
Department of Epidemiology and Cancer Control1 
Department of Biostatistics2 
 
 
 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee 38105-3678 
Telephone: (901) 595-3300 
 
 
Contents of this document may not be extracted without permission from the Principal Investigator. 

IRB Approval Date: 12/08/2015 
IRB Expiration Date: 11/25/2016 
 
 
Protocol ALLSTIM and Title: Feasibility and Efficacy of Transcranial Direct 
Current Stimulation (tDCS) and Cognitive Training for Executive Dysfunction in 
Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
Principal Investigators: Kevin Krull, PhD; Wei Liu, PhD 
IDE Holder: Soterix Medical 
Brief Overview: A common and potentially debilitating late effect of childhood cancer 
treatment is neurocognitive impairment, frequently in the domain of executive dysfunction, 
which can limit educational attainment, employment, and quality of life. Among the 
survivors of childhood acute lymphoblastic leukemia (ALL) in the SJLIFE cohort, the 
rate of executive function impairment has been shown as high as 58.8%, with moderate to 
severe impairment rates as high as 33.5%, and risk for impairment increased with time 
from diagnosis. Given the potential of pervasive impact of neurocognitive impairment 
on daily life, interventions directed at reducing neurocognitive dysfunction among 
childhood cancer survivors with long-term follow-up are needed. Transcranial Direct 
Current Stimulation (tDCS), a form of non-invasive brain stimulation, is a potentially 
useful tool to enhance cognitive function. tDCS involves modulation of cerebral cortex 
excitability by the application of weak direct current through the scalp. 
Researchers at St. Jude Children's Research Hospital want to evaluate the influence of 
tDCS and cognitive training on cognitive performance in long-term survivors of childhood 
ALL. 
Intervention: Transcranial Direct Current Stimulation 
In phase I, the short-term effect of tDCS intervention will be evaluated in the clinical 
setting using a randomized cross-over trial. The survivors will be randomized to receive 
either the tDCS intervention at the current dose level of 1mA or Sham for 15 minutes on 
day 1, with the other treatment given on day 2 (i.e. those who got tDCS intervention on 
day 1 will get sham on day 2 and vice versa). The tDCS intervention will be delivered by 
the Soterix Transcranial Direct Current Stimulator Clinical Trials (1x1-CT). 
Neurocognitive testing using the NIH Toolbox will be conducted within two hours of 
completing stimulation each day. 
In phase II, the feasibility and potential efficacy of self-administration of the tDCS 
intervention paired with cognitive training will be evaluated over 5 weeks. Research 
participants will be taught to use the mobile tDCS device and will be provided one to take 
home. The device will be programmed by the investigators in advance to control the 
intensity and duration of the stimulation. The research participants will use the device 
twice per week as directed, and will be required to obtain a unique access code from the 
investigators prior to each stimulation session. Each stimulation session will be monitored 
using FaceTime on an institutional iPad given to the participants. Within two hours of 
completing each tDCS session participants will complete 20 minutes of cognitive training 
using a mobile app installed on the iPad. Neurocognitive testing will be conducted pre- 
and post- intervention using remote assessment. 
Study Design: Pilot study 
Sample Size: 45 research participants 
Data Management: Data management for this study will be supervised by the 
Neuropsychology Research Team Clinical and Survey Research Center in the 
Department of Epidemiology and Cancer Control.    Statistical analysis will be provided 

IRB Approval Date: 12/08/2015 
IRB Expiration Date: 11/25/2016 
 
 
Protocol ALLSTIM and Title: Feasibility and Efficacy of Transcranial Direct 
Current Stimulation (tDCS) and Cognitive Training for Executive Dysfunction in 
Adult Survivors of Childhood Acute Lymphoblastic Leukemia 
locally by the Biostatistics Department at St. Jude Children’s Research Hospital. 
Human Subjects: There is low risk to participants related to the tDCS. Potential side 
effects include redness and slight tingling at the site of stimulation, and all side effects are 
reversible. Recent meta-analyses show side effects to occur no more frequently than 
placebo conditions. Time commitment could be seen as a burden and some of the questions 
may make the participant uncomfortable. Adverse events will be monitored, reported, 
and treated accordingly. 

IRB Approval Date: 12/08/2015 
IRB Expiration Date: 11/25/2016 
 
 
TABLE OF CONTENTS 
1.0 
OBJECTIVES ..................................................................................................................... 1 
1.1. 
Primary Objective ........................................................................................................... 2 
1.2. 
Secondary Objectives ...................................................................................................... 2 
2.0 
BACKGROUND AND RATIONALE ............................................................................... 2 
2.1. 
Background ..................................................................................................................... 2 
2.2. 
Rationale ......................................................................................................................... 2 
3.0 
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY   
ENROLLMENT .................................................................................................................. 4 
3.1. 
Inclusion Criteria ............................................................................................................. 4 
3.2. 
Exclusion Criteria  (examples listed below).................................................................... 5 
3.3. 
Research Participant Recruitment and Screening ............................................................ 5 
3.4. 
Enrollment on Study at St. Jude ...................................................................................... 6 
4.0 
DESIGN AND METHODS ................................................................................................ 6 
4.1. 
Design and Study Overview ............................................................................................ 6 
4.2. 
Study Procedures / Intervention / Observations: ............................................................. 7 
5.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS .................................... 9 
5.1. 
Pre-Study Evaluations ..................................................................................................... 9 
5.2. 
Evaluations During Therapy ......................................................................................... 10 
6.0 
CRITERIA FOR REMOVAL FROM PROTOCOL ........................................................ 12 
6.1. 
Off Study Criteria .......................................................................................................... 12 
7.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS .......................... 13 
7.1. 
Reporting Adverse Experiences and Deaths to St. Jude IRB ........................................ 13 
7.2. 
Reporting to the Sponsor and/or Federal Agencies ...................................................... 13. 
8.0 
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY ............ 16 
8.1. 
Data Collection .............................................................................................................. 15 
8.4. 
Study Monitoring .......................................................................................................... 15 
8.5. 
Confidentiality ............................................................................................................... 15 
9.0 
STATISTICAL CONSIDERATIONS .............................................................................. 17 
9.1. 
Anticipated Completion Dates ...................................................................................... 19 
10.0 
OBTAINING INFORMED CONSENT ........................................................................... 19 
11.0 
REFERENCES.................................................................................................................. 20 
APPENDIX I: EXAMPLE OF A SCHEDULE OF EVALUATIONS ......................................... 22 

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1.0 
OBJECTIVES 
 
1.1 Primary Objectives: 
 
 
1.1.1 To evaluate the feasibility of a home-based intervention using tDCS 
and cognitive stimulation in adult survivors of childhood ALL 
participating in the SJLIFE study. 
 
Hypothesis 1: A home-based tDCS and cognitive training intervention 
will be a feasible intervention strategy to improve executive function  
in long-term survivors of childhood ALL. 
 
1.2 Secondary Objectives 
 
 
1.2.1 To estimate the efficacy of a tDCS intervention paired with cognitive 
stimulation. 
 
Hypothesis 2: The home-based tDCS and cognitive training 
intervention will result in improved executive function in adult 
survivors of childhood after a five week intervention. 
 
1.2.2 To explore the short-term effect of tDCS on measures of executive 
function among adult survivors of childhood ALL participating in the 
SJLIFE study. 

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IRB Expiration Date: 11/25/2016 
 
 
 
 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 Background 
 
With recent advances in treatment the survival rate of childhood cancer exceeds 
80%,1 such that 1 in 640 young adults in the United States is estimated to be a 
pediatric cancer survivor. A common and potentially debilitating late effect 
of childhood cancer treatment is neurocognitive impairment, particularly 
executive dysfunction, which can limit educational attainment and 
employment.2 
 
Prevalence estimates of neurocognitive dysfunction range from 20% to 80% 
of the population of cancer survivors, depending on the diagnoses, treatment, 
cognitive assessment procedure, and definition of impairment.3-6 Treatments 
such as cranial radiation, antimetabolite chemotherapy (i.e. methotrexate) and 
corticosteroids increase the risk of neurocognitive impairment.3,7-9 A recent 
study2 among the survivors of childhood acute lymphoblastic leukemia (ALL) 
in the SJLIFE cohort showed that the rate of neurocognitive impairment to be 
as high as 58.8% for executive functions, the most common domain of 
impairment, with moderate to severe impairment rates as high as 33.5%. 
Furthermore, risk of impairment increased with time from diagnosis. Across 
individual skills, moderate to severe impairment (defined as a score <7th 
percentile compared to the normal population) rates of 25%, 18%, and 3.5% 
were seen for cognitive flexibility, cognitive fluency and working memory, 
respectively.2 Neurocognitive impairment impacts multiple areas of adult 
functioning, 
including 
educational 
attainment3, 
employment,3 
health 
behaviors,10 quality of life11 and social functioning.3,12 Given the potential of 
pervasive impact of neurocognitive impairment on daily life, interventions 
directed at reducing neurocognitive dysfunction among long-term survivors of 
childhood cancer are needed. Even though many studies have characterized 
neurocognitive impairment in long-term survivors of childhood cancer, 
limited research has focused on developing interventions to improve these 
well-established late effects.13-15 Thus there is a strong need for intervention 
studies that will improve the neurocognitive impairment among these 
survivors. 
2.2 Rationale: 
 
Cognitive training has been used in an attempt to improve neurocognitive 
impairment in cancer survivors. We recently completed a pilot study of a 
cognitive stimulation trial to improve function in adult survivors of childhood 
cancer. Twenty-one survivors completed six months of regular cognitive 
exercises, with pre- and post-neurocognitive testing. Compared to an equated 

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IRB Expiration Date: 11/25/2016 
 
 
 
reference group tested at a similar interval, those who completed training 
exercises demonstrated significant improvement in cognitive flexibility and 
processing speed. However, the effect sizes were relatively small and, given 
the long-standing nature of the impairment, extended training, more intensive 
training, or an additional intervention to support the training may be necessary 
to enhance effects. 
 
A potentially useful tool to enhance cognitive intervention is transcranial 
Direct Current Stimulation (tDCS). tDCS involves modulation of cerebral 
cortex excitability by the application of weak direct current to the scalp16. 
tDCS is a technique that applies safe, low level direct current through large 
pads on the scalp to stimulate the underlying brain region, with current level < 
0.10 C/cm2 (as a reference, tissue damage occurs at levels of ~ 200 C/cm2 or 
higher).16 The schematic below demonstrates the manner in which the tDCS 
intervention is delivered to the participants. 
 
 
 
A cross-over study of tDCS on working memory using healthy volunteers 
showed that tDCS modulated working memory performance (measured by 
letter n-back) by altering dorsolateral prefrontal cortex (DLPFC) brain activity 
in a polarity-specific way, in that anodal tDCS enhanced the performance 
related to working memory.17 Another study18 in healthy volunteers found that 
anodal tDCS of DLPFC or the primary motor cortex (M1) increased 
performance on a cognitive or motor task, respectively.18 
 
tDCS is also a safe method for enhancing cortical responsivity. A recent meta- 
analysis19 looked at over 200 studies for adverse events (AE) related to active 

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tDCS and found that 56% of studies reported mild AEs and no studies 
reported more than mild AE’s. The most common AE’s reported were itching, 
tingling, mild headache, and discomfort, however, none of the AE’s differed 
in frequency between the placebo (sham application) and active treatment 
groups. Levels of less than 2 mA of current over 5-20 minutes for 1-10 days 
has been used in various studies without significant adverse events. In 
addition, clinical studies have demonstrated efficacy of tDCS intervention in 
reducing neurocognitive impairments among patients suffering from strokes,20 
depression,21,22 psychosis, and Alzheimer’s disease23. However, the usefulness 
of tDCS has not been evaluated in long-term adult survivors of childhood 
cancer exhibiting neurocognitive impairments. Since these adults have likely 
experienced neurocognitive impairment for many years, we believe the 
application of tDCS will enhance their ability to benefit from cognitive training. 
 
We propose to conduct a pilot study to assess the feasibility and potential 
efficacy of a 5-week tDCS intervention paired with cognitive training to 
improve executive function in long-term adult survivors of childhood ALL. 
Stimulation and training will be conducted at home twice per week for five 
weeks. However, prior to initiating the home trial, we propose to conduct a 
trial in the clinic in order to evaluate the short-term effect of tDCS on measures 
of executive function. This clinic-based trial will also provide participants with 
on-sight experience with tDCS under direct observation prior to beginning the 
home-based intervention under remote observation. 
 
3.0 
RESEARCH 
PARTICIPANT 
ELIGIBILITY CRITERIA 
AND 
STUDY ENROLLMENT 
 
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background. Institutional experience 
confirms broad representation in this regard. 
 
3.1 Inclusion Criteria 
 
3.1.1 Current St. Jude LIFE Participant 
 
3.1.2 Long term survivor of acute lymphoblastic leukemia (ALL) 
 
3.1.3 Currently ≥ 18 years of age 
 
3.1.4 Wi-Fi internet access at home (estimated at >75% of the SJLIFE cohort) 
 
3.1.5 History of executive dysfunction, documented by SJLIFE 
neurocognitive testing, and defined as having an age-adjusted standard 

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score <20th percentile on Trail Making Test Part B, Verbal Fluency, or 
Digit Span Backward. 
 
3.1.6 History of self-reported executive dysfunction in daily life, defined as 
having a standardized score <20th percentile on BRIEF Initiate, Shift, or 
Working Memory domains OR having scored <20th percentile on the 
Childhood Cancer Survivor Study Neurocognitive Questionnaire Task 
Efficiency or Memory domains. 
 
3.1.7 Participant is able to speak and understand the English language. 
3.2 Exclusion Criteria 
 
3.2.1 Any survivor with full scale IQ <80 
 
3.2.2 Currently on stimulants or other medications intended to treat cognitive 
impairment 
 
3.2.3 History of seizures 
 
3.2.4 No implanted medical devices or implanted metal in the head 
3.2.5 Currently pregnant or planning to become pregnant. 
 
3.2.6 Inability or unwillingness of research participant or legal 
guardian/representative to give written informed consent. 
 
 
3.3 Research Participant Recruitment and Screening 
 
We propose to utilize the SJLIFE alumnus dataset to identify evaluable adult 
long-term ALL survivors. Following review of the SJLIFE patient database, 
we have identified 333 participants with documented executive function 
impairment. Participant eligibility will be identified through hospital admission 
records and consultations with the SJLIFE study team prior to the patient’s 
SJLIFE clinic visit. Individuals eligible for this study will be mailed a letter to 
introduce the study and inform him or her that they are eligible for enrollment. 
The letter will state that an interviewer will be contacting them within two 
weeks to discuss the study and inquire about their desire to participate. A 
second letter and a second phone call will be attempted two to four weeks after 
the original letter if no initial response is received. 
 
A requirement of ALLSTIM eligibility is to be a participant in the SJLIFE 
study. Patients will be assessed for the capacity to consent as part of SJLIFE 
recruitment. If a participant is assessed to be competent to consent for SJLIFE, 
they will be competent to consent for ALLSTIM. 

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3.4 Enrollment on Study at St. Jude 
 
A member of the study team will confirm potential participant eligibility as 
defined in Section 3.1-3.2, complete and sign the ‘Participant Eligibility 
Checklist’. The study team will enter the eligibility checklist information into 
the Patient Protocol Manager (PPM) system. Eligibility will be reviewed, and 
a research participant-specific consent form and assent document (where 
applicable) will be generated. The signed consent/assent form must be faxed 
or emailed to the CPDMO at 595-6265 in order to complete the enrollment. 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A 
staff member is on call Saturday, Sunday, and holidays from 8:00 am to 5:00 
pm. Enrollments may be requested during weekends or holidays by calling 
the CPDMO “On Call” cell phone (901-413-8591) or referencing the “On Call 
Schedule” on the intranet). 
 
 
4 
DESIGN AND METHODS 
 
4.1 
DESIGN AND STUDY OVERVIEW 
 
The proposed study will be conducted in two phases. In Phase I, the short- 
term effect of tDCS on performance on measures of executive function will be 
evaluated over a two-day period. After assessing the effect in Phase I, and 
providing participants with a directly observed experience with tDCS, the 
feasibility of self-administering tDCS over long-term (5 weeks with two 
sessions per week) using a mobile tDCS device and its potential efficacy will 
be evaluated in Phase II. The 5-week intervention will be paired with cognitive 
stimulation using the Lumosity Brain Games program (www.lumosity.com). 
This program involves cognitive exercises designed to enhance executive 
function and processing speed, to be performed on an institutionally 
provided iPad. Cognitive stimulation activities can be completed in 15-20 
minutes per session. The study schema is displayed in the Figure below: 
 
Figure 1. ALLSTIM Study Schema 

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A cross-over randomized trial will be used in Phase I. The survivors will be 
randomized to receive either the tDCS intervention at the current dose level of 
1mA or Sham for 15 minutes on day 1 and then on day 2 the other treatment 
will be provided (i.e. those who got tDCS intervention of day 1 will get sham 
on day 2 and vice versa). The tDCS intervention will be delivered by the 
Soterix Transcranial Direct Current Stimulator Clinical Trials (1x1-CT). The 
effect of one session to tDCS is expected to last for about two hours thus 
conducting the second session the next day will provide sufficient time for the 
“wash-out” and good justification for using a cross-over design. 
 
In phase II, the feasibility and efficacy of long-term (5 week) self- 
administration of the tDCS intervention will be evaluated in concurrence with 
self-administered cognitive stimulation. In this phase the research participants 
will be taught to use the mobile tDCS device and will be provided with one to 
take home. The device will be programmed by the investigators in advance to 
control the intensity and duration of the stimulation. The research participants 
will use the device twice per week as directed. Before each session, the 
participant will use an institutionally provided iPad for video conferencing 
with the study center to obtain a unique access code to start the tDCS device 
and ensure proper device placement. Each stimulation session for each 
participant will have a unique access code. An AE evaluation will be 
conducted by a trained study team member every week. Research participants 
will complete remote neurocognitive testing via the iPad before and after 
phase II. 
 
4.2 
STUDY PROCEDURES: 
 
4.2.1 Transcranial Direct Current Stimulation – Clinical System 
 
The system used for stimulation is the Transcranial Electrical 
Stimulation 1x1 Clinical Trials Device manufactured by 
Soterix Medical. This system allows for double-blinded 
application of the intervention or sham treatment. The 
intervention consists of a direct current of 1 mA applied for 15 

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minutes. The sham procedure provides the same small current 
during ramp up to imitate the intervention, but the current is 
discontinued after ramp up and no intervention is provided. 
 
Direct current is transferred by a pair of saline-soaked sponges, 
with the anode attached to the left frontal region (F3) and the 
cathode attached over the right eyebrow (Fp2). Participants 
will be randomized to receive the intervention on day 1 and the 
sham on day 2 or vice versa. Within two hour of completing 
the intervention and sham, participants will complete the NIH 
Toolbox Cognitive Battery on both days. 
4.2.2 Transcranial Direct Current Stimulation – Mobile System: 
 
The mobile transcranial direct current stimulation system is 
manufactured by  Soterix Medical  and consists of  a battery 
pack, control unit and a self-positioning headband with 
sponges. Participants will be given the device after completing 
the clinical portion of the study and trained in correct usage. 
Participants will complete two stimulation sessions per week 
for 5  weeks. The sessions will  provide  1  mA  DC for  15 
minutes in the same manner as the clinical system. Participants 
will be supplied iPads for the cognitive stimulation training, 
and the iPad will be used to monitor correct tDCS usage. The 
tDCS unit requires a unique code for each stimulation session. 
Study staff will use video conferencing to confirm correct 
electrode placement, then provide the code to initiate treatment. 
Each session will be monitored for compliance and to assess 
any adverse events. 
4.2.3 Cognitive Training: 
 
Survivors who complete phase I and continue to phase II will 
begin the 5 week cognitive stimulation program. Participants 
will use the supplied iPad to complete online cognitive 
stimulation training within one hour of every at-home tDCS 
session. The cognitive training program was developed by 
Lumosity (see Appendix for description of Lumosity program) 
and involves training of attention, processing speed, working 
memory, and executive function skill using cognitive tasks. 
Participants will be asked to engage in training for 20 minutes 
a day, two days per week. Five cognitive tasks will be 
presented during each training session. Survivors will complete 
5-weeks of stimulation and training. The Lumosity program 
records the day and time of training and performance on the 
training activities for each participant, and these records are 
available to study staff via internet. Adherence to training and 

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change in performance following stimulation sessions will be 
examined. 
 
At the end of the 5-week intervention, participants will mail 
back the iPad and tDCS device in a postage-paid and addressed 
FedEx box provided to them at their study visit. 
 
4.3 Adverse Event Monitoring: 
 
Reports of adverse events will be monitored. Adverse events will 
be surveyed at the beginning of each video conference, with 
symptoms reports for the prior stimulation session. Adverse event 
information will be collected by participant reporting and direct 
questioning using the patient report of incidence of side effects 
(PRISE), frequency and intensity of side effect rating (FISER), 
and global rating of side effects burden (GRSEB). The PRISE 
form assesses the presence of side effects for a variety of 
biological systems. For each of the nine organ/function systems 
(gastrointestinal, 
nervous 
system, 
heart, 
eyes/ears, 
skin, 
genital/urinary, sleep, sexual functioning, and other), the 
participant indicates the presence of a side effect, and if present, 
the tolerability of the side effect (tolerable or distressing). The 
FISER and GRSEB assess three domains of side effect impact: 
frequency, intensity, and burden. Each domain is rated on a 7- 
point Likert scale (i.e. Frequency, ranging from no side effects to 
present all the time; Intensity, ranging from no side effects to 
intolerable; and Burden, ranging from no impairment to unable to 
function due to side effects). Reliability and validity have been 
reported. 
 
 
5 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
5.1 Pre-Study Evaluations 
 
5.1.1 Baseline Neurocognitive Evaluation 
 
SJLIFE Evaluation: All participants in SJLIFE undergo 
neurocognitive testing as part of the SJLIFE parent protocol. This 
evaluation involves assessment of intelligence, academic skills, 
processing speed, attention, working memory, long-term memory, 
and executive functions. Specific tests include: 
 
 
Wechsler Abbreviated Scale of Intelligence 
 
Woodcock-Johnson-III: Tests of Achievement 
 
Letter-Word Identification 

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 
Calculation 
 
Wechsler 
Adult 
Intelligence 
Scale-Third 
Edition 
 
Digit Symbol-Coding 
 
Symbol Search 
 
Digit Span 
 
Trail Making Test 
 
Conners' Continuous Performance Test-II 
 
California Verbal Learning Test-II 
 
Brief Symptom Inventory 
 
Verbal Fluency Test 
 
Test 
of 
Memory 
and 
Learning 
Visual 
Selective Reminding 
 
We will use this testing, which is already ongoing, to identify 
survivors who are eligible for this study (<10th percentile on Digit 
Span Backward, Trail Making Part B, or Verbal Fluency). 
 
 
5.2 Evaluations During Therapy 
 
5.2.1 NIH Toolbox – Cognitive Battery 
We will use the three tests from the Cognitive Battery of the 
NIH Toolbox24 to evaluate the acute effect of tDCS on 
executive function. These three measures have a computerized 
format and are nationally standardized. Testing will occur post- 
intervention (total 2 times) during phase I. 
 
NIH Toolbox Dimensional Change Card Sort Test (DCCS): 
The DCCS specifically taps cognitive flexibility, with 
performance generally increasing through childhood and then 
declining across the adult age. A total of 40 trials require 4 
minutes. Scoring is based on a combination of accuracy and 
reaction time. This combination score is then converted to a 
scale score with mean of 100 and SD of 15, where higher 
scores indicate higher levels of cognitive flexibility. 
 
NIH Toolbox Flanker Inhibitory Control and Attention Test: 
The Flanker taps inhibitory control and attention, the capacity 
for new learning and information processing in novel situations 
– measure, in which performance reaches a peak in early 
adulthood, and then tends to decline across the life span. A 
total of  40 trials require 4  minutes. Scoring  is  based on  a 
combination of accuracy and reaction time, this combination 
score is then converted to a scale score with mean of 100 and 

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SD of 15, where higher scores indicate higher executive 
function. 
 
NIH Toolbox List Sorting Working Memory Test: List Sorting 
is tapping both information processing and storage, with 
performance tending to peak in early adulthood and then 
declining across the life span. The raw score obtained is 
converted to Age-Adjusted to the national norms. Higher 
scores on each of these indicate higher levels of working 
memory. This task assesses working memory and requires the 
participant to sequence different visually- and orally-presented 
stimuli. The list scoring task takes approximately 7 minutes to 
administer. List Sorting is scored by summing the total number 
of items correctly recalled and sequenced on Lists-1 and -2, 
which can range from 0-26. 
 
5.2.2 Gray Oral Reading Test 
The Gray Oral Reading Test (GORT) will be used to measure 
reading comprehension. The GORT is one of the most widely 
used measures of oral reading fluency and comprehension in 
the United States. Participants will be asked to read a set of 
passages and recall specific details from the stories. Responses 
to the test require literal as well as inferential comprehension, 
the latter of which involves executive function. Two stories 
will be given each day, one day from Form A and one day from 
Form B. Raw scores will be calculated for total accuracy, and 
compared  within  participants.   Total   testing   time   will 
be approximately 5 minutes after each clinical tDCS session. 
 
5.2.3 Woodcock Johnson Understanding Directions 
The Woodcock Johnson Understanding Directions is a measure 
of listening comprehension. The task requires the participant to 
listen to a series of complex instructions and then follow the 
directions by pointing to various objects in a colored picture. 
Directions 
require 
sequential 
and 
logical 
reasoning, 
components of executive function. Four complex instructions 
will be administered each day, from alternate test forms, and 
raw scores will be calculated and compared within participants. 
Total testing time will be approximately 5 minutes after each 
clinical tDCS session. 
 
 
5.2.4 Remote Assessment Procedures 
We have recently completed a pilot study to evaluate the 
accuracy of remote cognitive assessment, using web and phone 
based procedures.25   We will employ these procedures prior to 

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and following the initiation of phase II of the trial. Specifically, 
the following tests will be administered: 
 
Televideo-based assessment: 
Neurocognitive 
testing 
will 
be 
conducted 
via 
video 
conferencing with the iPad. At a scheduled time, an examiner 
will contact the participant. The following clinical measures 
will be administered: 
 
 
Digit Span Test 
 
Verbal Fluency Test 
 
Oral Trail Making Test 
 
CCSS Neurocognitive Questionnaire 
 
6 CRITERIA FOR REMOVAL FROM PROTOCOL 
6.1 
Off Study Criteria: 
 
6.1.1 All protocol interventions are complete 
 
6.1.2 Request of the Participant/Legally Authorized Representative 
 
6.1.3 Death 
 
6.1.4 Lost to follow-up 
6.1.5 Discretion of the Study PI, such as the following: 
 
 The  researcher  decides  that  continuing  in  the  study  would  be 
harmful 
 A treatment is needed that is not allowed on this study 
 The participant misses so many appointments that the data cannot 
be used in the study 
 New information is learned that a better treatment is available, or 
that the study is not in the participant’s best interest 
 
7 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
7.1 
Reporting Adverse Experiences and Deaths to St. Jude IRB 
 
Only “unanticipated problems involving risks to participants or others” 
referred to hereafter as “unanticipated problems” are 
required to be reported to the St. Jude IRB promptly, but  
in no event later than 10 working days after the investigator  
first  learns  of  the  unanticipated  problem. 

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Regardless of whether the event is internal or external (for 
example, an IND safety report by the sponsor pursuant to 
21 CFR 312.32), only adverse events that constitute 
unanticipated problems are reportable to the St. Jude IRB. 
As further described in the definition of unanticipated 
problem, this includes any event that in the PI’s opinion 
was: 
 Unexpected (in terms of nature, severity, or frequency) given (1) 
the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document, as well as other relevant information 
available about the research; (2) the observed rate of occurrence 
(compared to a credible baseline for comparison); and (3) the 
characteristics of the subject population being studied; and 
 
 Related or possibly related to participation in the research; and 
 
 Serious; or if not serious suggests that the research places subjects 
or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously 
known or recognized. 
 
Unrelated, expected deaths do not require reporting to the IRB.  Though death 
is “serious”, the event must meet the other two requirements of “related or 
possibly related” and “unexpected/unanticipated” to be considered reportable. 
Deaths meeting reporting requirements are to be reported immediately to the 
St. Jude IRB, but in no event later than 48 hours after the investigator first 
learns of the death. 
 
The  following  definitions  apply  with  respect  to  reporting  adverse 
experiences: 
 
Serious Adverse Event: Any adverse event temporally associated 
with the subject’s participation in research that meets any 
of the following criteria: 
 results in death; 
 is life-threatening (places the subject at immediate risk of 
death from the event as it occurred); 
 requires inpatient hospitalization or prolongation of existing 
hospitalization; 
 results in a persistent or significant disability/incapacity; 

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 results in a congenital anomaly/birth defect; or 
 any other adverse event that, based upon appropriate 
medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one 
of the other outcomes listed in this definition (examples of 
such events include: any substantial disruption of the ability 
to conduct normal life functions, allergic bronchospasm 
requiring intensive treatment in the emergency room or at 
home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse), a congenital anomaly/birth 
defect, secondary or concurrent cancer,  medication overdose, 
or is any medical event which requires treatment to prevent 
any of the medical outcomes previously listed. 
Unexpected Adverse Event: 
 Any adverse event for which the specificity or severity is 
not consistent 
with the protocol-related documents, 
including the applicable investigator 
brochure, 
IRB 
approved consent form, Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) application, or 
other relevant sources of information, such as product 
labeling and package inserts; or if it does appear in such 
documents, an event in which the specificity, severity or 
duration is not consistent with the risk information included 
therein; or 
 The observed rate of occurrence is a clinically significant 
increase in the expected rate (based on a credible baseline 
rate for comparison); or 
 The occurrence is not consistent with the expected natural 
progression of any underlying disease, disorder, or condition 
of the subject(s)  experiencing the  adverse event  and  the 
subject’s predisposing risk factor profile for the adverse 
event. 
 
Internal Events: Events experienced by a research participant 
enrolled at a site under the jurisdiction of St. Jude IRB for 
either multicenter or single-center research projects. 

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External Events: Events experienced by participants enrolled at a 
site external to the jurisdiction of the St. Jude Institutional 
Review Board (IRB) or in a study for which St. Jude is not 
the coordinating center or the IRB of record. 
 
Unanticipated Problem Involving Risks to Subjects or Others: An 
unanticipated problem involving risks to subjects or others 
is an event which was not expected to occur and which 
increases the degree of risk posed to research participants. 
Such events, in general, meet all of the following criteria: 
 unexpected; 
 related or possibly related to participation in the research; 
and 
 suggests that the research places subjects or others at a greater 
risk of harm (including physical, psychological, economic, 
or social harm) than was previously known or recognized. 
An unanticipated problem involving risk to subjects or others 
may exist even when actual harm does not occur to any 
participant. 
 
 
Consistent with FDA and OHRP guidance on reporting unanticipated 
problems and adverse events to IRBs, the St. Jude IRB 
does not require the submission of external events, for 
example IND safety reports, nor is a summary of such 
events/reports required; however, if an event giving rise to 
an IND safety or other external event report constitutes an 
“unanticipated problem involving risks to subjects or 
others” it must be reported in accordance with this policy. 
In general, to be reportable external events need to have 
implications for the conduct of the study (for example, 
requiring a significant and usually safety-related change in 
the protocol and/or informed consent form). 
 
Although some adverse events  will qualify as unanticipated  problems 
involving risks to subjects or others, some will not; and 
there may be other unanticipated problems that go beyond 
the definitions of serious and/or unexpected adverse events. 
Examples of unanticipated problems involving risks to 
subjects or others include: 
 
 Improperly staging a participant’s tumor resulting in the participant 
being assigned to an incorrect arm of the research study; 

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 The theft of a research computer containing confidential subject 
information (breach of confidentiality); and 
 The contamination of a study drug. Unanticipated problems 
generally will warrant consideration of substantive changes in the 
research protocol or informed consent process/document or other 
corrective actions in order to protect the safety, welfare, or rights of 
subjects or others. 
 
All anticipated Grade III or IV adverse events will be reported to the IRB in the 
continuing review report and/or summary. The study teams will monitor accrual 
and toxicities every six months. 
 
 
7.2 
Recording Adverse Events and Serious Adverse Events 
 
All serious adverse events will be recorded in the source, database and/or case 
report form. Adverse events unrelated to the trial will not be recorded unless they 
are grade III or above (CTCAEv4). Adverse events that are related to the trial will 
be captured in the source document, database and/or case report form. Adverse 
events related to the trial will be collected until the time the study completes. 
 
 
 
 
8 
DATA 
COLLECTION, 
STUDY 
MONITORING, 
AND 
CONFIDENTIALITY 
 
8.1 Data Collection 
Data for this study will be managed by the Neuropsychology Research Team in 
the Department of Epidemiology and Cancer Control. Data collected at   
baseline and follow-up assessments will be entered by optical scanning. The 
optical scanning program has the capacity for designer specific error checks, 
flagged at the time the questionnaires are scanned. After data are scanned, they 
are processed and converted into a SAS (Cary, NC) format where a second error 
check is completed. Data from neurocognitive tests are double-entered          
into a separate secure Access database and compared for accuracy. All data 
mismatches will be reviewed by two members of the survey center staff and 
compared to the original documents (when applicable) for resolution. NIH 
Toolbox data will be stored on remote computer servers and will be completely 
de-identified. Data from the tDCS mobile units and the cognitive training 
(Lumosity) will be downloaded and processed by the study team using  
software provided by the product manufacturers. 

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8.2 Study Monitoring 
 
The study team will hold monthly meetings and review case histories or quality 
summaries on participants. The PI and study team will be responsible for 
ensuring protocol compliance.  Continuing reviews by the IRB and CT-SRC 
will occur at least annually. 
 
This study is associated with an Investigational Device Exemption (IDE) and 
will be monitored by the St. Jude Clinical Research Monitors accordingly. The 
monitors will review up to 15% of the study participants semi-annually for 
appropriateness of the informed consent process, eligibility, adverse event 
recording and participant’s status.  Additional information may be monitored at 
the request of the Internal Monitoring Committee (IMC), the IRB, or other 
institutional administration. 
 
Source document verification of eligibility and informed consent for 100% of 
St. Jude participants will be performed by the Eligibility Coordinators within 5 
working days of completion of enrollment. The Clinical Research Monitor will 
review all SAE reports and other applicable essential regulatory documentation. 
The Monitor will generate a formal report which is shared with the Principal 
Investigator (PI), study team, and the Internal Monitoring Committee (IMC). 
 
8.3 
Confidentiality 
Confidentiality will be maintained. Data forms will be kept in locked file 
cabinets, in locked offices, accessed only by study staff on an “as needed” 
hierarchical basis. All electronic files will stored on a password protected 
computer and identifying information will be stored in separate electronic files 
and linked by participant number. Data files downloaded for statistical 
analyses will not contain personal identifiers. 
 
The medical records of study participants may be reviewed by the St. Jude 
IRB, FDA, clinical research monitors, etc. 
 
 
 
9 
STATISTICAL CONSIDERATIONS 
 
The sample size justification will be based on evaluating the primary 
objective, as that objective is the basic design of how the intervention will be 
delivered in a subsequent randomized controlled trial should this pilot study 
prove feasible. We will consider the trial to be feasible if at least 50% of the 
survivors are able to complete 5 sessions (tDCS along with cognitive 
stimulation) successfully out of 10.  Any participant who completes Phase I, 

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but is unwilling to participate in Phase II due to the tDCS procedure will be 
counted towards failure. In the testing of hypothesis framework we would like 
to test the null hypothesis H0:P≤0.5 vs. H1:P1>0.7. Then, using Simon’s two- 
stage Minimax design with type I error rate =0.05 and power (1-)=0.8 we 
have the following stopping rules. As an additional measure of feasibility, the 
consent rate must be >50% among all participants approached to participate. 
Study staff will track study enrollment, and the study statistician will make the 
determination for study continuation. 
 
In the first stage we will recruit 23 survivors and if the number of survivors 
who complete at least 5 sessions is at least 13 then we will proceed to the next 
stage and recruit an additional 14 survivors and if at least 24 survivors out of 
37 complete at least 5 sessions then the tDCS trial would be considered 
feasible. However, since we expect that roughly 20% of the survivors may not 
initiate the trial after leaving the institution (i.e. may not provide any 
information at all for objective 1.1.1) we anticipate replacing these survivors 
and, thus, a total of 45 survivors will be needed for evaluating the Phase II 
objective. Participant accrual will cease when 37 participants agree to 
participate in Phase II. 
 
With 37 survivors recruited for phase I of the study, we will have roughly 
97.7% power for objective 1.2.1 to detect an improvement of 0.65 in 
standardized units, respectively, with type I error =0.05. 
 
Analysis: 
 
Objective 1.1.1:  The feasibility of the 5-week tDCS intervention will be 
evaluated using Simon's two stage Minimax design with stopping rules 
described above. 
 
Objective 1.2.1: The improvement in scores on symbol digit coding, Stroop 
test, shifting attention test, digit span and verbal fluency from baseline to 5- 
week follow up will be done using matched pair one sample t-tests. In addition, 
the improvement in EF measures over the 5 week period will also be evaluated 
using longitudinal methods and implemented using PROC MIXED or PROC 
GEE in SAS 9.3. 
 
Objective 1.2.2: The improvement in the scores on the NIH Toolbox Card 
Sort, Flanker and Working Memory tasks between tDCS and sham, will be 
done using matched pair one sample t-test. 
 
 
It will be important to monitor for AEs in both phases of the study as well. 
Thus, in an “ad hoc” manner using one sided 95% confidence bounds we will 
monitor for all grade 3 or higher adverse events (All types of AE's included) 

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which are related to study interventions. Among the 45 patients enrolled in the 
study, if at any time point at least 5 patients (≥5) have grade 3 or higher 
toxicity, the 95% lower confidence limit would be 0.059 suggesting that the 
true AE rate could be higher than 5% which would be unacceptable, the 
feasibility of the 5 week intervention would be questionable and a 
consideration will be given to stop or amend the trial. 
 
9.1 Anticipated Completion Dates 
 
 
 
 
 
10 
OBTAINING INFORMED CONSENT 
Participants will be briefly introduced to the study during the consent process 
for SJLIFE and told there is a possibility they may qualify for this study. 
Eligible participants will be identified after the completion of the 
neurocognitive testing done as part of the SJLIFE protocol. The participant 
will be informed they are eligible to participate in this protocol at that time. A 
member of the study team will explain the study and review the potential risks 
and benefits. The study team will assure that the potential participant 
understands what the research study involves and the potential risks when the 
participant agrees to participate. Upon agreeing to participate, the consent 
form will be signed by the subject and/or guardian and investigator/designee. 
Anticipated Primary Completion Date: December 1, 2016 
Anticipated Study Completion Date: December 1, 2017 

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11 
REFERENCES 
 
1. 
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2. 
Krull KR,  Brinkman TM,  Li  C,  et  al.  Neurocognitive  Outcomes  Decades  After 
Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St. Jude 
Lifetime Cohort Study. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology 2013. 
3. 
Ellenberg L, Liu Q, Gioia G, et al. Neurocognitive status in long-term survivors of 
childhood CNS malignancies: a report from the Childhood Cancer Survivor Study. 
Neuropsychology 2009;23:705-17. 
4. 
Butler RW, Haser JK. Neurocognitive effects of treatment for childhood cancer. Ment 
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5. 
Moore BD, 3rd. Neurocognitive outcomes in survivors of childhood cancer. Journal 
of pediatric psychology 2005;30:51-63. 
6. 
Mulhern RK, Palmer SL. Neurocognitive late effects in pediatric cancer. Curr Probl 
Cancer 2003;27:177-97. 
7. 
Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ. Change in 
neurocognitive functioning after treatment with cranial radiation in childhood. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 
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8. 
Waber DP, Carpentieri SC, Klar N, et al. Cognitive sequelae in children treated for 
acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 
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9. 
Mrakotsky CM, Silverman LB, Dahlberg SE, et al. Neurobehavioral side effects of 
corticosteroids during active treatment for acute lymphoblastic leukemia in children are age- 
dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. Pediatr 
Blood Cancer 2011;57:492-8. 
10. 
Krull KR, Annett RD, Pan Z, et al. Neurocognitive functioning and health-related 
behaviours in adult survivors of childhood cancer: a report from the Childhood Cancer 
Survivor Study. Eur J Cancer 2011;47:1380-8. 
11. 
Ness KK, Gurney JG, Zeltzer  LK,  et al.  The  impact  of limitations in physical, 
executive, and emotional function on health-related quality of life among adult survivors of 
childhood cancer: a report from the Childhood Cancer Survivor Study. Arch Phys Med 
Rehabil 2008;89:128-36. 
12. 
Gurney JG, Krull KR, Kadan-Lottick N, et al. Social outcomes in the Childhood 
Cancer Survivor Study cohort. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2009;27:2390-5. 
13. 
Butler RW, Copeland DR, Fairclough DL, et al. A multicenter, randomized clinical 
trial of a cognitive remediation program for childhood survivors of a pediatric malignancy. 
Journal of consulting and clinical psychology 2008;76:367-78. 
14. 
Hardy KK, Willard VW, Bonner MJ. Computerized cognitive training in survivors of 
childhood cancer: a pilot study. J Pediatr Oncol Nurs 2011;28:27-33. 

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IRB Approval Date: 12/08/2015 
IRB Expiration Date: 11/25/2016 
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15. 
Patel SK, Katz ER, Richardson R, Rimmer M, Kilian S. Cognitive and problem 
solving training in children with cancer: a pilot project. J Pediatr Hematol Oncol 
2009;31:670-7. 
16. 
Stagg CJ, Nitsche MA. Physiological basis of transcranial direct current stimulation. 
Neuroscientist 2011;17:37-53. 
17. 
Zaehle T, Sandmann P, Thorne JD, Jancke L, Herrmann CS. Transcranial direct 
current stimulation of the prefrontal cortex modulates working memory performance: 
combined behavioural and electrophysiological evidence. BMC Neurosci  2011;12:1471- 
2202. 
18. 
Leite J, Carvalho S, Fregni F, Goncalves OF. Task-specific effects of tDCS-induced 
cortical excitability changes on cognitive and motor sequence set shifting performance. PLoS 
One 2011;6:1. 
19. 
Brunoni AR, Amadera J, Berbel B, Volz MS, Rizzerio BG, Fregni F. A systematic 
review on reporting and assessment of adverse effects associated with transcranial direct 
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Gomez Palacio Schjetnan A, Faraji J, Metz GA, Tatsuno M, Luczak A. Transcranial 
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Sampaio LA, Fraguas R, Lotufo PA, Bensenor IM, Brunoni AR. A systematic review 
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Brunoni AR, Nitsche MA, Bolognini N, et al. Clinical research with transcranial 
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Freitas C, Mondragon-Llorca H, Pascual-Leone A. Noninvasive brain stimulation in 
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Gershon RC, Wagster MV, Hendrie HC, Fox NA, Cook KF, Nowinski CJ. NIH 
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Brinkman TM. Remote Computerized Neurocognitive Assessment in Adult Survivors 
of Childhood Cancer. In; 2013. 

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APPENDIX I: SCHEDULE OF EVALUATIONS 
 
 
 
Event 
Screening 
Phase 1 
Mobile Intervention Period 
Day 1 Day 2 
Pre 
Week 
Intervention 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Post 
Intervention 
Informed 
Consent 
X 
Cognitive 
Assessment 
X 
TDCS 
Clinical 
Intervention 
X 
X 
TDCS Mobile 
Intervention 
X 
X 
X 
X 
X 
Cognitive 
Stimulation 
X 
X 
X 
X 
X 
NIH Toolbox 
Cognitive 
Battery 
Remote 
Cognitive 
Assessment 
X 
X 
X 
X