Treatment of Post-Chemotherapy Cognitive Impairment With Transcranial Magnetic Stimulation (Chemobrain TMS)
Phase: NA
Conditions: Chemo-brain
Sponsor: University of Arizona

 
Title: Treatment of Post-Chemotherapy Cognitive Impairment with Transcranial 
Magnetic Stimulation  
 
 
NCT:  NCT04295720 
 
 
Version Date: 01/03/2020 
 
 

 
Title: Treatment of Post-Chemotherapy Cognitive Impairment with Transcranial 
Magnetic Stimulation  
 
Investigator: Phillip Kuo, MD, PhD, Medical Imaging  
 
Version Date: 01/03/2020 
 
 
1) Background 
"Chemo-brain" or Post-Chemotherapy Cognitive Impairment (PCCI) is defined as cognitive 
changes including impairment of memory, learning, concentration, reasoning, executive 
function, attention and visuovisio-spatial skills that occur during or after chemotherapy 
treatment (Argyriou, Assimakopoulos, Iconomou, Giannakopoulou, & Kalofonos, 2010). 
Additionally, anxiety and depression often co-exist with the cognitive symptoms and may be an 
inseparable component of the disease. The extent and duration of PCCI varies from transient, 
subtle manifestations to sustained, long-term cognitive effects that can have long-lasting 
impact on patient quality of life (Ahles & Saykin, 2007; Ahles et al., 2003; Cimprich et al., 2010; 
Dietrich, Monje, Wefel, & Meyers, 2008; Jacobsen et al., 2004; Vearncombe et al., 2009; Wefel 
et al., 2004). PCCI is also a heavy financial and social burden on our society (Artherholt & Fann, 
2012; Boykoff, Moieni, & Subramanian, 2009; Lucas, 2010; Siegel et al., 2012; Wertheimer, 
2010). Its cost is not only from consumption of resources for treatment of symptoms but also 
indirect costs from loss of productivity. With more patients surviving longer with cancer or 
beating cancer entirely, PCCI will become an ever important issue in cancer survivorship. There 
is no treatment, thus research into the understanding and treatment of PCCI need to keep pace 
with our continuously improving treatment of cancer and the side effects of therapy.  
 
A number of studies have sought to better understand PCCI through imaging. Structural and 
functional imaging studies utilizing MRI and specialized PET imaging have shown alterations in 
brain tissue after systemic anti-cancer therapy. PET scanning with O-15 labeled water was 
acquired during performance of control and memory-related tasks in subjects treated 5-10 
years previously with adjuvant chemotherapy with/without adjuvant Tamoxifen for breast 
cancer. Cerebral blood flow in regions of the frontal cortex and cerebellum was significantly 
altered in chemotherapy-treated subjects versus untreated subjects (Silverman et al., 2007).  A 
study in breast cancer patients post chemotherapy that assessed brain gray matter density 
(GMD), a structural measure, by voxel-based morphometry using MRI in a prospective, 
longitudinal design found decreases in GMD in bilateral frontal, medial temporal and cerebellar 
regions at one month post completion of chemotherapy compared with baseline, with return to 
baseline levels in some but not all regions at one year after completion of chemotherapy. No 
changes were seen by MRI analysis in breast cancer patients not receiving chemotherapy or in 
healthy controls (McDonald, Conroy, Ahles, West, & Saykin, 2010).  A prospective, longitudinal 
study utilizing functional MRI to assess cognitive task-related brain activation in breast cancer 
patients who did and did not receive chemotherapy reported frontal white matter hyper-

activation prior to receiving systemic adjuvant therapy compared to controls. Furthermore, 
chemotherapy-treated patients after completing chemotherapy were unable to maintain this 
hyper-activation, which the authors presumed were related to impairment of brain function 
due to chemotherapy (McDonald, Conroy, Ahles, West, & Saykin, 2012). Additionally, a multi-
center trial in breast cancer found a potential link between elevated levels of cytokines IL-6 and 
IL-1 and PCCI {Cheung:2015kc}. These studies support a causal relationship between systemic 
therapy and PCCI.  
 
Transcranial magnetic stimulation (TMS) is a painless and safe magnetic brain stimulation 
technique. Since its introduction about 30 years ago, more than 10,000 articles on TMS have 
been published. In clinical practice, a number of TMS devices and protocols have been 
approved by the FDA for the treatment of medication-refractory depression and migraine, as 
well as approved for pre-surgical motor and language mapping. Currently, TMS has been under 
investigation as a treatment tool in diverse disease states including Parkinson’s disease, 
Alzheimer’s disease, schizophrenia, stroke, epilepsy, autism, and tinnitus (for a review, see 
Miocinovic, Somayajula, Chitnis, & Vitek, 2013; Schulz, Gerloff, & Hummel, 2013).  TMS is 
considered safe and well tolerated. It does not involve any form of general anesthesia or 
sedation (Tor and Mok 2016). 
 
TMS was first introduced by Barker et al in 1985 (Barker, Jalinous, & Freeston, 1985).  This 
neurostimulation technique is based on Faraday’s principle of electromagnetic induction. More 
specifically, the TMS coil discharges quick (200-300µs), powerful (0.2-4.0 T) and focal magnetic 
pulses at the surface of the scalp, which creates a secondary electrical current that abruptly 
modulates the excitability of the underlying neurons and, thus, neural activity within specific 
regions of the brain (Tatti, Rossi, Innocenti, Rossi, & Santarnecchi, 2016).  Notably, to provide a 
point of reference, the magnetic field generated by the TMS coil is analogous to those 
employed by conventional MRI scanners (1.5-3.0 T). 
 
TMS has a number of different protocols. The repetitive TMS (rTMS) paradigm is one of the 
commonly used TMS protocols. It utilizes trains of pulses to induce cortical effects that outlast 
the stimulation duration. rTMS allows researchers and clinicians to induce long-lasting changes 
in cortical reactivity and plasticity. In 2008, the FDA approved the use of rTMS for treating 
medically refractory or treatment-resistant depression (FDA approval K061053). This FDA 
approval was finalized after a sham-controlled randomized clinical trial was performed among a 
population of 300 patients who had failed to respond to medication and other forms of 
therapy.  The trial consisted of medication-free patients undergoing rTMS treatment daily for 4-
6 weeks, and this therapeutic intervention showed statistically significant improvements among 
several clinical measures (O'Reardon et al., 2007).  Findings from this study were supported by 
a larger, multi-site study sponsored by the NIH several years later (George et al., 2010).  
Notably, these studies, along with many others, demonstrate that rTMS is a safe practice even 

when performed many times over in therapeutic paradigms. Currently, hundreds of clinics in 
the United States use an FDA-approved TMS system to treat depression. 
 
In addition to improving depression and relieving pain, TMS can also be applied to enhance 
cognitive performance. Cumulative evidence has indicated the effectiveness of high-frequency 
(excitatory) rTMS over the left dorsolateral prefrontal cortex (DLPFC) in improving cognitive 
performance in psychiatric/neurological diseases or healthy volunteers (Guse, Falkai, & 
Wobrock, 2010).  
 
DLPFC is chosen as the rTMS target because it is the most widely used one in the literature. 
DLPFC is a key element of many high-order brain functions including inhibition control, 
attention, working memory, and decision-making. High-frequency rTMS increases brain activity 
of the stimulation site, which may then help improve these complex functions and 
subsequently improve the associated brain disease condition such as PCCI. Moreover, DLPFC is 
both structurally and functionally connected to many cortical and sub-cortical regions. Thus, 
stimulating the DLPFC can also provide a means to assess the remote effects of rTMS through 
either connectivity or network-wise interactions. 
 
PCCI is not surprisingly very difficult to study and is still not well understood including PCCI and 
MRI changes. We hope that this work including the MRI will add to the knowledge on PCCI but 
there is no specific MRI “signature”. Diagnostic criteria for PCCI has been a topic of recent NIH 
RFA but it will likely be years before the publications come out from those grants. 
 
2) Purpose 
 
In this pilot study, we propose to test the efficacy of rTMS for the treatment of PCCI. Efficacy 
measures will include baseline and post-rTMS neuropsychological testing, functional MRI and 
biometry data using body worn sensors. 
 
3) Lay Summary (approximately 400 words) 
 
Transcranial magnetic stimulation (TMS) is a safe and non-invasive brain stimulation technique. 
It uses a magnetic coil to stimulate brain tissue painlessly using only a magnet (no electrodes or 
electrical wires) in a procedure that does not involve any surgery or sedation. TMS is currently 
FDA approved to treat depression and migraines. Although this technology is applicable to 
many other brain conditions as well, it has not been systematically examined in individuals with 
"Chemo-brain". Chemo-brain or Post-Chemotherapy Cognitive Impairment (PCCI) is defined as 
cognitive changes including impairment of memory, learning, concentration, reasoning, 
executive function, attention and visuo visio-spatial skills that occur during or after 
chemotherapy treatment. 
 
In this study, we will: 

1) use high-resolution magnetic resonance imaging (MRI) of individuals’ brains to determine 
precisely where to place the TMS magnetic coil in order to stimulate the target brain region 
based off their unique brain structure. 
2) use TMS to stimulate the target region of the brain. 
3) take high-resolution MRI pictures of the brain both baseline and post-TMS to study whether 
the brain activity of the target region changes as a result of the TMS stimulation. 
4) perform neuropsychological tasks baseline and post-TMS to study if performance is 
improved following stimulation of the target brain region. 
5) collect data from completing Frailty assessments, baseline and post-TMS. 
6) study the short-term and long-term treatment effects. 
7) collect subject’s daily activity and sleep/wake patterns from watch style device 
(http://www.actigraphy.com/solutions/actiwatch/actiwatch-plus-specifications.html). 
8) perform behavioral assessments, baseline and post-TMS, to study whether there are 
measurable changes following stimulation of the target brain region. 
 
4) Resources: Describe the resources (personnel, facilities, time, emergency resources, etc.) 
available to recruit, consent, conduct study procedures, and analyze data. 
 
Our clinical collaborators will participate in patient recruitment. MRI scans, TMS treatment,  
neuropsychological assessment, and assessments with body worn devices will be done at the 
Biosciences Research Laboratories (BSRL) at 1230 N Cherry Ave. All persons assisting with the 
study have received appropriate training and are or will be knowledgeable in their study-
related duties and functions. 
 
Ying-hui Chou, Assistant Professor, Cognition and Neural Systems, and her team will be involved 
in the neuropsychological testing as well as the TMS treatments. Her research focuses primarily 
on 1) characterizing the mapping between brain organization and behavior, and 2) studies of 
transcranial magnetic stimulation (TMS) techniques for modulation of human brain function 
and behavior. 
 
5) Study Population 
 
12 participants with PCCI will be recruited to participate in this trial.   
 
Inclusion Criteria: 
• Adult (>=18). 
• PCCI diagnosis (see information below). 
• Right Handed (We will not enroll left-handed dominant people because they tend to have more 
symmetric brain function and thus targeting the left frontal region may not be as effective.) 
• English speaking.  
• Cancer treatment completed and considered curative with the exception of endocrine therapy after 
chemotherapy. 
• Able to attend daily intervention (Monday-Friday) for 2 weeks. 
• Not enrolled in another interventional study within 6 months prior to beginning this study. 
 

Exclusion Criteria: 
• Pregnancy or thinking of becoming pregnant. 
• Undergoing active treatment for cancer. 
• Routine contraindications for MRI (including incompatible medical implants or metal fragments in the 
body at risk for migration or heating with application of the magnetic field) including severe 
claustrophobia. 
• History of brain metastasis or other brain tumor. 
• History of stroke or traumatic brain injury. 
• Frequent or severe headaches. 
• Cognitive or mood disorder prior to chemotherapy (i.e. dementia or depression). 
• History of epilepsy, or other seizure disorders. 
• History mental health disorders, such as substance misuse, bipolar disorder or psychosis. 
• Taking medication for seizures or that could lower seizure threshold if withdrawn. 
• Inability to complete neuropsychological testing. 
• Prior treatment with rTMS. We will enroll subjects without prior experience with rTMS. 
 
PCCI Diagnosis: Given lack of universally accepted criteria, we will initially follow commonly 
used criteria for mild cognitive impairment (MCI). The following revised Mayo clinic criteria for 
MCI will be used: (a) self- or informant-reported cognitive complaint; (b) objective cognitive 
impairment; (c) preserved independence in functional abilities; and (d) absence of dementia. 
The MCI diagnosis will be supported by the measures of general cognitive function using Mini-
Mental State Exam (MMSE) 24-27 points (inclusive); (2) Montreal Cognitive Assessment (MoCA) 
18-26 points (inclusive); and (3) Clinical Dementia Rating Scale score of 0.5. In addition, the 
Jak/Bondi actuarial neuropsychological test method and NACC UDS 3.0 Neuropsychological 
battery will be used identify MCI (i.e., 1 standard deviation below the mean for their age and 
education matched peers on normative data in at least 2 memory tasks). We will not include 
those with unstable medical condition, contraindications to MRI and TMS, clinical evidence of 
stroke, psychiatric disorder, and other neurological disorders or head injury.   
 
 
6) Recruitment Methods and Consenting Process 
 
Recruitment will begin after IRB approval and other approval requirements are complete. We 
plan to recruit for approximately 2 years or until we have recruited and completed 12 subjects, 
whichever comes first. 
 
Our Banner University Medical Center clinical collaborators will participate in patient 
recruitment. When the physicians are seeing cancer patients as part of their routine standard of 
care, potential subjects will be identified. 
 
Pre-screening in clinic is currently envisioned to be the combination of both the patients’ 
symptoms and physicians’ assessment consistent with “chemobrain.” The patient will then be 
asked by the oncologist or staff if they are interested in a clinical trial for the treatment of 
“chemobrain” or whatever terminology the oncologist feels will best describe the symptoms 
the patient is describing (in other words, the oncologist does not need to use the exact term 

“chemobrain”).  If the patient is interested in participating, contact information will be collected 
on a consent to contact form and provided to the research staff. We hope that signing the 
consent to contact form rather than the full consent will save time and minimize disruption of 
the clinic’s workflow.  
 
The research staff will contact the individuals using the consent form as a script to describe the 
study. During this phone conversation, the inclusion and exclusion criteria will be reviewed with 
the patient to verify eligibility. 
 
The identified individuals will be given ample time to review the consent and time commitment 
before consenting to the project. The patient will then receive a detailed schedule of research 
appointments. The first appointment will include the neuropsychiatric exams and pre-
determined cut-offs (previously described) will be used to select appropriate subjects. The 
selection is based on multiple neuropsychiatric tests. 
 
Any information collected during this phone-screening process will be secured under lock and 
key to ensure confidentiality.  If the participants withdraw from the study, all personal 
information collected will be destroyed in a shredding machine to protect confidentiality of any 
PHI or sensitive data that may have been recorded. 
 
7) Consenting Process 
 
The consent will be obtained in a private setting to preserve confidentiality. All patient 
questions will be answered and no procedures will be completed before consent form is signed. 
No undue pressure will be applied to obtain consent. 
 
This consent process will occur with a trained member of the research staff.  The Consent Form 
will be reviewed by both the participant and the member of the research staff. The participant 
will be encouraged to ask any questions that arise while reviewing the informed consent form.  
Upon completion of the consent form and additional oral explanation provided by the research 
staff, the research participant will be asked to sign the consent form and a copy will be 
provided to them. 
 
Throughout this consent process, the research staff will communicate the participant’s right to 
withdraw from the study at any time without penalty.  No minors or participants unable to 
consent will be included in this trial. 
 
8) Research Procedures Involved in the Human Research 
 
Subjects will undergo testing at baseline prior to TMS treatments and once more at the end of 
the 2-week intervention. All study activities will occur at the Biosciences Research Laboratories 
(BRSL) Building, located at 1230 N. Cherry Ave., Tucson, AZ 85721.   
 
 

Child-bearing females will be required to take a urine pregnancy test and requested that 
adequate birth control be used during the treatment phase of the study. 
 
A) Brain imaging data  
We will acquire diffusion weighted imaging (DWI), resting-state fMRI, and T1 structural MRI. 
The MRI technician will ensure that participants have proper ear protection in the scanner (e.g., 
protective headphones so we can still communicate with them for the duration of the scan).  
The MRI technician will take measures to optimize the comfort of the participant (e.g., warm 
blankets, back support cushion). Foam pads will also be used to reduce head motion. Diffusion 
weighted MRI and resting-state functional MRI will be used to measure structural and 
functional connectivity, respectively. During resting-state fMRI scans, participants will be 
instructed to rest and remain awake with their eyes fixated on the cross hair presented before 
them. Total MRI scan time will require approximately 30 minutes. 
 
B) Neuropsychological data and demographic data (see attached document: NACC UDS 3.0 
Neuropsychological battery.pdf) 
We will use  a selection of MMSE, CDR, and NACC UDS 3.0 Neuropsychological battery. The 
NACC UDS Battery includes MoCA, Craft Story 21 Recall (Immediate), Benson Complex Figure 
Copy (Immediate), Number Span Test (Forward and Backward), Category Fluency, Trail Making 
Test, Craft Story 21 Recall (Delayed), Benson Complex Figure Copy (Delayed), MINT, and Verbal 
Fluency – Phonemic Test, to assess cognitive performance. Additionally, AVLT (Immediate 
Recall, Delay Recall), NAART (North American Adult Reading Test), and Stroop will also be 
applied for measuring cognitive function. Some of these tasks require audio recording for ease 
of scoring. Besides, demographics data, health history, medications, family history, and 
handedness questionnaire, will be collected. Acquiring neuropsychological and demographical 
data will take approximately 2 to 3 hours. 
 
C) Memory tasks (see attached document: Memory tasks 20190318.docx) 
A selection of the following memory tasks, which include Face Name Associative Memory Exam, 
Memory Capacity Test, Short-Term Memory Binding test, Behavioral Pattern Separation-Object 
test, Spatial Pattern Separation task, Discrimination and Transfer task, Dual tasking task, and 
other similar memory tasks (Rentz et al.), will be used to assess memory function. These 
memory tasks contain various shapes, colors, numbers, letters, objects, background (e.g., 
environments in our daily life), names, occupation titles, and ordinary faces. The memory task 
will require approximately 30 minutes. 
 
D) Frailty assessment (see attached document: Frailty Meter device manual BioSensics.pdf) 
Frailty will be assessed by measuring motion of forearm and upper-arm via wearable motion 
sensors attached to the upper extremity (tri-axial wearable gyroscope sensor, BioSensics LLC, 
Cambridge, MA). Participants will perform fully elbow flexion and extension with their 
dominant arm repetitively and as quickly as they can within 20 seconds. Motion score will be 
estimated with the following variables: (a) speed; (b) flexibility; (c) power; (d) rise time; (e) 
moment; (f) speed variability; (g) speed reduction, (h) flexion number, (i) BMI; and (j) Age. The 

whole assessment will take around 10 minutes to complete. This will be done pre and post 
treatment. 
 
E) TMS treatment 
The purpose of the study is to test the acceptability and practicality of rTMS for the treatment 
of PCCI. Efficacy measures will include baseline and post-rTMS neuropsychological testing, 
functional MRI and biometry data using body worn sensors.  All study activities will occur at the 
Biosciences Research Laboratories (BRSL) Building, located at 1230 N. Cherry Ave., Tucson, AZ 
85721.  
 
Theta burst stimulation (TBS) is a safe and patterned repetitive TMS protocol. In this project, we 
will apply the intermittent TBS (iTBS) protocol at the left dorsolateral prefrontal cortex. The 
iTBS paradigm consists of 3 pulses of 50 Hz stimulation repeated at 200-ms interval (i.e., 5 Hz) 
for 2 seconds (30 stimuli for 2 seconds). The 2-second train of stimulation will repeat every 10 
seconds for 190 seconds (600 stimuli in total). A single session of iTBS induces transient effects 
on the targeted brain structures/networks that tend to last approximately 60 minutes following 
a single application. Structural MRI for TMS target localization and baseline functional MRI 
(fMRI) will be performed.   
 
After the conclusion of baseline data acquisition, the research team will analyze each 
participant’s unique structural and functional connectivity patterns to determine stimulation 
site for TMS in future study sessions. 
 
The subjects will receive 10-sessions (1 session per day, M-F over 2 consecutive weeks).  
The treatment itself lasts approximately only 190 seconds but we are conservatively planning 
an hour slot in order to not rush the daily planning/positioning.  
After the last rTMS session, follow-up neuropsychological testing, behavioral assessments, and 
fMRI will be performed.  
At 30, 90 and 120 days post the last rTMS session, a selection of neuropsychological and 
behavioral assessments will be mailed to the patients for the subject to complete and mail 
back.  These assessments may be done alternatively over the phone. 
 
F) Actiwatch 
Data will be collected using Actiwatch spectrum plus (hardware) over a period of up to 2 weeks 
from our subjects. This data will be stored in a computer and processed using Actigraph 
(software licensed from Philips Respironics). The equipment is off the shelf commercial 
products with FDA approvals. 
The subject will wear Actiwatch on their wrist and perform regular activities: sleeping, sitting, 
running, walking, etc.  After finishing data collection, the Actiwatch will be returned to the 
study staff. The study staff will use USB cord to download the data to computer with actigraph 
software. This assessment is optional. 
 
G) Behavioral Assessments 

A selection of the following assessments may be performed, either on paper, electronically or 
over the phone. Assessments include PRO-CTCAE and the PSQI Sleep Questionnaire.  See details 
in file "Behavioral assessments.pdf".  These assessments will require approximately 30-60 
minutes. 
 
9) Cost to Subjects 
 
There is no monetary or financial cost incurred by participants who enroll in this trial.  
Participants will, however, be responsible for their own travel to the research laboratory.  While 
the participants will not be reimbursed for travel, the research team will cover the cost of 
parking. 
Though no other monetary/financial costs are affixed with participation in this trial, there is a 
significant “time cost” associated with completing this trial.  Given the nature of this trial, we 
understand that this may place a burden on the participant’s scheduling and whereabouts. 
 
10) Risks to Subjects 
 
There are no know long-term health risks to the use of magnetic resonance imaging (MRI) when 
operated within FDA guidelines. There are no known long-term health risks to the use of TMS 
when operated within consensus safety guidelines (Rossi et al. 2009).  In 2008, the FDA 
approved the use of high frequency rTMS in the treatment of depression.  In 2013, the FDA 
approved the use of single-pulse TMS in the treatment of migraine.  
Although seizure is a theoretical risk with repetitive TMS, “the occurrence of seizures has been 
extremely rare, with most of the few new cases receiving rTMS protocols exceeding previous 
guidelines, often in patients under treatment with drugs which potentially lowered the seizure 
threshold” (Rossi et al. 2009).  As Rossi et al. delineate, “rare” means that 16 cases (out of tens 
of thousands of rTMS sessions over the last two decades) of seizure related to rTMS have been 
reported (~ 0.1%).  Notably, eight of these adverse events occurred before safety parameters 
were established in 1997 and, of the other eight reports, six occurred either when the safe 
rTMS parameters were exceeded or other safety guidelines ignored, and the actual occurrence 
of a seizure has been questioned in the other two (i.e., convulsive syncope or pseudoseizure 
may have occurred). In a workshop convened by the National Institute for Neurological 
Disorders and Stroke (NINDS) in 1996, researchers in the field agreed upon a set of rTMS 
consensus safety guidelines (Wassermann 1998), including recommended stimulation 
parameters and contra-indications, and these consensus guidelines have been recently updated 
(Rossi et al. 2009). Widespread adherence to the 1996 guidelines has resulted in the virtual 
elimination of inadvertent seizures in rTMS studies (Rossi et al. 2009). The levels of stimulation 
used in this protocol are well within safety guidelines (Wassermann 1998; Rossi et al. 2009).   
 
Actiwatch: There is no known risk involved in this experiment. The Actiwatch and actigraph are 
FDA approved. 
 
11) Potential Benefits to Subjects and Society 
 

We do not expect any direct benefits to the participants. 
 
12) Provisions to Protect the Privacy of Subjects and the Confidentiality of Data 
 
The risks are minimized by using standard clinical safety procedures. Procedures will be 
performed by trained personnel.  
 
MRI checklist will be completed before each MRI to make sure no metal or other 
contraindications exist for the subject. We will not perform the MRI if such risks are identified. 
 
All testing and interviews will be done in a private setting by individuals who have completed 
CITI and HIPAA training. 
 
The federal regulations define ‘private information’ as “information about behavior that occurs 
in a context in which an individual can reasonably expect that no observation or recording is 
taking place, and information which has been provided for specific purposes by an individual 
and which the individual can reasonably expect will not be made public (e.g., a medical or 
education record).” In consideration of protecting the privacy of participants, we will follow 
these provisions: 
• Only use the recruitment methods listed above; no cold-calling 
• Have a private, welcoming environment for research practices 
• Only key personnel will be present during research procedures 
• Limit the number of personnel present for certain procedures (e.g., consent process) 
• Obtain informed consent prior to any research practices 
• Data will be de-identified and participants will be given randomized ID code 
 
13) Access to Private Information 
 
In addition to protecting the privacy of the participant, we will also take measures to protect 
the confidentiality of the data and private information that has been collected.  A major 
component in the pursuit of protecting confidentiality involves formulating an agreement 
between the investigator and research participant about 1) how their data will be used, 2) who 
will have access to it, 3) what procedures will be put in place to ensure only authorized 
individuals will have access to the information, and 4) the limitations (if any) to these 
confidentiality procedures.  This “agreement” will be discussed during the informed consent 
process so participants can be properly informed. Protecting confidentiality, then, relies on the 
research team carefully following through on all components of this agreement.   
 
For this study, we have the following provisions in place to protect data confidentiality: 
• Pertaining to information collected prior to informed consent:  
o Those who are eligible and enroll will receive random subject ID number. For 
those who are not eligible or who no longer wish to enroll in the study, we will 
adequately destroy all information recorded (e.g., shredding). 

• All paper information will be kept under double lock and key in the coordinator’s office.  
Only key personnel will have access to this data. 
• Digital records will be stored in password protected files, on university maintained 
servers that undergo regular and secured back-up.  Any sensitive data will be encrypted. 
• All laboratory computers will be protected with a sign-in password. 
• Any data shared will collaborators will be de-identified. 
• No data will be shared with collaborators without the approval of an additional IRB 
amendment. 
• Pursuant of University guidelines, research records will be stored for six years after the 
completion of the research. 
• A key limitation of this agreement would arise in the event of an audit.   
o If the study is randomly chosen to be audited, regulatory officials would have 
access to all study records.  This is the only instance in which non-key personnel 
would have access to data collected in this study. 
 
14) Subject Compensation 
 
Participants will not be compensated for being a part of this feasibility study. 
 
15) Withdrawal of Subjects 
 
Participants can be withdrawn from the study at any time with no penalty.  The participants can 
prompt this withdrawal themselves if they no longer wish to continue with the trial or their 
participation in the study can be terminated by the research investigators for any reason. 
Participants will be informed of this during the consent process.  This arrangement for 
withdrawal without penalty will promote participant safety and the accuracy of the data 
collected by the investigator. 
 
In the event of participant withdrawal: 1) participants will be asked whether they are willing to 
complete the follow-up testing and surveys, and 2) the research team will thoroughly document 
the event.  In cases that abrupt withdrawal is necessary, participant safety will remain our 
ultimate goal and we will follow protocols to ensure participants are not put at increased risk. 
 
16) Sharing of Results with Subjects 
 
Results will not be shared with research participants.  However, exceptions may be made with 
raw MRI image file if research participants specifically request a picture of their brain as study 
memento. 
 
 
17) Clinical Trials.gov Information 
 
Registration pending 

 
18) Statistical Analysis Plan 
 
Repeated measures ANOVA will be employed. The independent variable is rTMS treatment. The 
primary outcome measure is cognitive function, and the secondary outcome measures is brain 
functional connectivity.  Alpha = 0.05 will be used as the significance level for all analyses. 
Results will be corrected for multiple comparisons. 
 
 19) SCHEDULE OF EVENTS 
 
 
Study stage 
Baseline 
Treatment 
Week #1 
Treatment 
Week #2 
Final 
Treatment 
Follow-Up 
Study event 
Day 0 
Day 1 
Day 2-
5 
Day 8-11 
Day 12 
Day 
42 
+/- 7 
Day 
102 
+/- 25 
Day 
132 
+/- 25 
Consent 
X 
 
 
 
 
 
 
 
Neuropsychological 
testing 
X 
 
 
 
X  
X  
X  
X  
Behavioral testing 
X 
 
 
 
X  
X  
X  
X  
Urine Pregnancy 
test 
X 
 
 
 
 
 
 
 
Structural MRI 
X 
 
 
 
 
 
 
 
Functional MRI 
X 
 
 
 
X 
 
 
 
TMS treatment* 
 
X 
X 
X 
X 
 
 
 
Actiwatch1 
 
X 
X 
X 
X 
 
 
 
Frailty task 
 
X 
 
 
X 
 
 
 
*The TMS treatment sessions do not need to start immediately after Baseline. 
1Optional tasks, subjects can opt out this task. 

 
Appendix 1: Data and Safety Monitoring Plan: 
 
 
1. 
Identification of the DSMB obligated for oversight responsibilities: 
The University of Arizona Cancer Center Data and Safety Monitoring Board (DSMB) will 
provide ongoing oversight for this trial. This study has been assigned a Medium Risk 
level by the DSMB. 
 
2. 
Identification of the entity obligated for routine monitoring duties: 
Routine monitoring will be provided by the Quality Assurance/Quality Control (QA/QC) 
Program to ensure that the investigation is conducted according to protocol design and 
regulatory requirements.  
 
This trial will also undergo real-time monitoring by the PI and study team, including 
documentation of real-time monitoring of any new or ongoing safety issues.   
 
The trial will have a AE/SAE log that will be reviewed and signed by the PI in a timely 
manner of the knowledge and documentation of the occurrence of an AE/SAE. SAEs will 
be reviewed within 24 hours of notification of event. 
3. 
Monitoring progress and data review process: 
Routine monitoring of subject data will be conducted at least quarterly.  
The first routine monitoring visit will include at a minimum: 
• Informed consent – 100% of cases enrolled;  
• Subject eligibility – 50% of cases, up to two subjects; 
• Data review – 50% of cases, up to two subjects. 
 
All subsequent monitoring visits will consist of randomly selected subject cases based on 
current enrollment and include continuing review of previously selected cases, as 
applicable. 
 
A monitoring visit report and follow-up letter will be completed approximately two 
weeks after the routine monitoring visit; a copy will be maintained in the study file. The 
monitor will request additional source documentation, clarification, information, or 
corrections to the CRF and/or regulatory records from the Clinical Research Coordinator 
(CRC) or other applicable staff responsible for the study and resolution of 
queries/findings.  Documentation of such a request will be maintained with a copy of 
the monitor’s visit report for follow-up at the next monitoring visit. Electronic records 
will be available in the institutional database or provided by the QA/QC Program staff.  
 
The Principal Investigator will ensure the accuracy, completeness, legibility and 
timeliness of the data reported in the Case Report Form (CRF).  Source documentation 

supporting the study data should indicate the subject’s participation in the trial and 
should document the dates and details of study procedures, adverse events, and patient 
status. 
Case report forms will be created to include study data points and the adverse event 
forms and be completed using the institution database or other acceptable data 
formats. All subject forms and study files will be stored in a secure area limited to 
authorized staff. 
 
Note: Routine monitoring of regulatory documents and test article will be conducted at 
least annually.  
 
4. 
Process to implement study closure when significant risks or benefits are 
 
identified: 
We do not anticipate any additional significant risks or benefits associated with the 
research. If there is a reason to close the study before the planned study end, there are 
no additional risks to the subjects for sudden withdrawal.  
This research is not part of the subject’s standard of care so if the study ends early, 
there would be no continuing interaction with the subject in the event we closed the 
study due to any newly identified significant information. 
 
5. 
Description of adverse events and reporting procedures: 
 
ADVERSE EVENTS  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.  
 
Any and all adverse events will be recorded on the UACC adverse events record form 
and reviewed by the Principal Investigator. 
 
All adverse events will be classified using either the MedDRA term or NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and will address: 
• Grade 
• Relationship to study drug (not related, unlikely, possible, probable, definitely)  
• Causality other than study drug (disease related, concomitant medication related, 
intercurrent illness, other)   
• Date of onset, date of resolution 
• Frequency of event (single, intermittent, continuous) 
• Event outcome (resolved, ongoing, death) 
• Action taken (none, held, dose reduced, discontinued, medication given) 
 

 
SERIOUS ADVERSE EVENTS 
 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
 
1) Results in death;  
 
2) Is life-threatening; 
3) Requires in-patient hospitalization or prolongation of an existing hospital stay;  
 
4) Results in disability persistent or significant disability/incapacity, or: 
 
5) Is a congenital anomaly/birth defect.  
 
Note: A SAE may also be an important medical event, in the view of the investigator that 
requires medical or surgical intervention to prevent one of the outcomes listed above.  
 
All serious adverse events, regardless of attribution, and any deaths will be reported 
within 24 hours of notification of the event to the sponsor and, if applicable, any 
collaborating entity. All serious adverse events and any deaths will be reported to the 
DSMB and to the University of Arizona Human Subjects Protection Program per the 
guidelines set forth in University of Arizona Cancer Center Data and Safety Monitoring 
Board Charter, Table 5: Adverse Event Reporting.  
 
 
All submitted serious adverse events will be processed by the DSMB Coordinator 
monthly for initial trend analysis and then reviewed by the DSMB Chair. The assigned 
QA/QC Monitor will review the SAE reporting process to confirm reporting requirements 
are met. 
 
6.  
Plan for assuring data accuracy and protocol compliance: 
Routine study activity and safety information will be reported to the DSMB quarterly, or 
more frequently if requested. These reports will include: 
• Study activity, cumulative and for the period under review; 
• Safety (narrative description on non-serious and serious adverse events, protocol 
pre-determined early stopping rules for safety or treatment-emergent adverse 
events); 
• Predetermined protocol early stopping rules for efficacy/futility;  
• Status of study in relationship to stopping rules;   
• Current dose level of study agent;  
• Routine monitoring and protocol compliance (describe the monitoring process and 
identify the status of the monitoring); 
• Comments;  
• Attachments (AE data reviewed by the PI to compile the report, SAE letters and 
reports, results of any review(s), applicable correspondence with the IRB or other 
regulatory agencies 
 
 
Data, safety and study progress will be reported to: 
• Human Subjects Protection Program (IRB) at least annually; 
• Sponsor (if applicable) at least every six months. 

 
7. 
Identification of the sponsor or funding agency, as applicable: 
The PI will immediately notify; in writing, the funding agency, if applicable, any action 
resulting in a temporary or permanent suspension of the study. 
 
A copy of this correspondence will also be forwarded to the DSMB and the SRC.  
 
 
 
Appendix 2: List of contraindicated medications: