Computerized Cognitive Training in Breast Cancer Survivors
Phase: NA
Conditions: Breast Cancer, Cognitive Change, Cognitive Impairment, Quality of Life
Sponsor: Ohio State University

Official Title: 
Computerized Cognitive Training 
 in Breast Cancer Survivors 
NCT Number: 
NCT05570604 
Document Name: 
Study Protocol and Statistical Analysis Plan 
Document Date: 
January 27, 2020 
 
 
 

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Study Title 
Computerized Cognitive Training in Breast Cancer Survivors 
 
Protocol Number: 
IUSCC-0625 
 
Principal Investigator: 
Diane Von Ah, PhD, RN, FAAN 
Professor & Associate Dean 
Indiana University, School of Nursing 
600 Barnhill Drive, Indianapolis, IN 46202 
 
Co- Investigators: 
Robert Considine, PhD 
Bryan Schneider, MD 
Fredrick Unverzagt, PhD 
 
Study Statistician: 
Patrick Monahan, PhD 
 
Support Provided By: 
Center for Enhancing Quality of Life 
 
Protocol Version Date: 
 
 
 
 
 
 
   1/27/2020 
 
 

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Table of Contents 
 
PROJECT ABSTRACT .............................................................................................................................. 4 
1. 
SPECIFIC AIMS ............................................................................................................................ 5 
2. 
SIGNIFICANCE ............................................................................................................................. 6 
3. 
INNOVATION ............................................................................................................................... 7 
4. 
APPROACH ................................................................................................................................... 8 
5. 
STUDY DESIGN............................................................................................................................ 9 
6. 
ELIGIBILITY CRITERIA.............................................................................................................. 9 
7. 
PATIENT REGISTRATION .......................................................................................................... 9 
8. 
STUDY PROCEDURES .............................................................................................................. 10 
9. 
MEASURES ................................................................................................................................. 14 
10. 
DATA ANALYSIS ....................................................................................................................... 15 
11. 
DATA INTEGRITY AND SECURITY ....................................................................................... 16 
12. 
STUDY TIMELINE ..................................................................................................................... 17 
13. 
RISKS TO SUBJECTS ................................................................................................................. 17 
14. 
POTENTIAL BENEFITS ............................................................................................................. 18 
15. 
PATIENT CONSENT AND PEER JUDGMENT ....................................................................... 18 
16. 
DATA AND SAFETY MONITORING PLAN ........................................................................... 19 
17. 
ADVERSE EVENTS .................................................................................................................... 20 
18. 
AE AND SAE REPORTING........................................................................................................ 21 
REFERENCES ......................................................................................................................................... 22 
 
 
 
 

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PROJECT ABSTRACT 
 
For millions of cancer survivors, cognitive impairment is a prevalent, severe, and persistent 
problem that is associated with other symptoms (depressive symptoms, anxiety and fatigue), 
poorer work ability, and poorer quality of life. Available evidence, including work by our own 
group, suggests that cognitive training may be a viable treatment option. However, to date, 
these studies are limited as none have been conducted in the home and therefore fail to 
address the transferability of these empirically based cognitive training programs to general 
practice.  
 
The purpose of this translational research is to conduct a home based single-blind, randomized 
controlled trial to test the feasibility, satisfaction, and preliminary efficacy of cognitive training 
compared to attention control in breast cancer survivors (BCS) as well as to explore potential 
biomarkers of intervention effects.  
 
Specific aims are to: (1) examine the feasibility (facilitators and barriers) and satisfaction of the 
computer-based cognitive training program; (2) test the preliminary efficacy of cognitive training 
on improving cognitive performance (memory, processing speed, attention, working memory, 
executive function)  over time compared to attention control; (3) evaluate cognitive training 
effects on associated outcomes compared to attention control; and (4) explore the effect of 
computerized cognitive training on serum brain derived neurotrophic factor (BDNF) over time 
compared to attention control.  BDNF is widely distributed in the brain, plays a crucial role in 
neuroplasticity and has been observed to correlate with cognitive function in cancer patients. A 
total of 68 eligible BCS will be randomized to computerized cognitive training or attention 
control. A blinded and trained tester will perform data collection and neuropsychological testing 
at two time points: baseline prior to intervention (T1) and immediately after the 10-week 
cognitive training -program (within 90 days) (T2). Feasibility and satisfaction will be assessed 
through objective indicators (study adherence, completion rate) and self-report (facilitators, 
barriers, and perceived satisfaction) and cognitive performance will be assessed through 
objective neuropsychological tests of memory, processing speed, attention, working memory, 
executive function assessed over the phone. In addition, we will measure the effects of cognitive 
training on self-report measures of perceived cognitive function, associated symptoms 
(depressive symptoms, anxiety and fatigue), perceived work ability, and quality of life. Data will 
be analyzed using descriptive statistics and a general linear mixed model (GLMM). Simple main 
effects analyses will be used to follow up statistically significant interactions.  
 
This research innovatively builds on our previous research by: 1) translating findings from the 
laboratory to the home setting and importantly seeks to identify facilitators and barriers of 
intervention use; 2) addresses limitations of previous trials (uses an attention control rather than 
a no-contact or wait-list control), (3) examines cognitive training effects on real-life outcomes 
such as associated symptoms, perceived work ability and quality of life; and (4) will be the first 
study in cancer survivors to explore levels of BDNF as a potentially sensitive outcome measure 
of intervention effects over time compared to attention control. Findings from this study will 
provide necessary information about the feasibility, satisfaction and preliminary efficacy of the 
home-based cognitive training on memory performance and processing speed as well as its 
effects on associated outcomes in BCS. Positive results will lead to a larger, full-scale study to 
determine efficacy and build evidence-based treatment for clinicians to use in treating BCS with 
cognitive impairment. 
 
 
 
 
 

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1. SPECIFIC AIMS 
 
 
 
The goal of this translational research study is to determine the feasibility, satisfaction and 
preliminary efficacy of cognitive training delivered in the home for cancer survivors suffering 
from cancer- and cancer-treatment-related cognitive impairment. In addition, this will be the first 
study in cancer to explore levels of brain derived neurotrophic factor (BDNF), which we now 
know is associated with neural plasticity, as a potentially sensitive outcome measure of 
intervention effects over time compared to attention control. 
 
 
 
Cancer- and cancer-treatment-related cognitive impairment is a national research priority.1 Up 
to 75% of the 2.6 million breast cancer survivors (BCS) living in the United States2-4 report 
problems with memory or feelings of mental slowness.4,5 Deficits in memory and processing 
speed have also been documented on neuropsychological exam6-13 and functional magnetic 
resonance imaging (fMRI).14-18 Cognitive impairment is a prevalent, severe, and persistent 
problem that is associated with other symptoms (depressive symptoms, anxiety symptoms, 
fatigue), poorer work ability19-28 and poorer quality of life.19,29-34 Cognitive training may be a 
viable treatment option.35 To date, a total of 8 pilot studies, including our own randomized 
controlled trial36 have  noted positive effects of cognitive training in cancer survivors.34,36-42 
These findings, combined with evidence from studies in the well elderly,43,44 suggest that 
cognitive training interventions to promote neuroplasticity are likely to be beneficial; however, 
these studies are limited as most have been conducted in the home and therefore, fail to 
address the transferability of these cognitive training programs to general practice. Therefore, 
the purpose of this translational research is to conduct a home based single-blind, 
randomized controlled trial to test the feasibility, satisfaction, and preliminary efficacy of 
cognitive training delivered in the home setting compared to attention control in breast cancer 
survivors (BCS). In addition, this will be the first study in cancer to explore levels of brain 
derived neurotrophic factor (BDNF).  
 
 
Specific aims are to: (1) examine the feasibility (facilitators and barriers to use) and satisfaction 
of the computerized cognitive training program; (2) test the preliminary efficacy of cognitive 
training on improving objective cognitive performance over time compared to attention control; 
(3) evaluate cognitive training effects on associated outcomes over time compared to attention 
control and (4) explore the effect of computerized cognitive training on serum brain derived 
neurotrophic factor (BDNF) over time compared to attention control. A total of 68 eligible BCS 
will be randomized to cognitive training or attention control. A blinded and trained tester will 
perform data collection and neuropsychological testing at two time points: baseline prior to 
intervention (T1) and immediately after the 10-week cognitive training program (within 90 days) 
(T2). Feasibility and satisfaction will be assessed through objective indicators (study adherence, 
completion rate) and self-report and memory and speed of processing will be assessed through 
objective neuropsychological tests. In addition, we will measure the effects of cognitive training 
on self-report measures of perceived cognitive function, associated symptoms (depressive 
symptoms, anxiety and fatigue), perceived work ability, and quality of life.  
 
 
Innovatively, the proposed study builds on our pilot results and addresses limitations of 
previous trials including: (1) uses home based training; (2) uses an attention control rather 
than a no-contact or wait-list control; (3) uses optimal intervention dose based on evidence, (4) 
explores cognitive training effects on real-life outcomes such as perceived cognitive impairment 
(using new PROMIS measures), associate symptoms, perceived work ability, and quality of life. 
This will also be the first study in the context of cancer to examine BDNF as a biomarker of 
intervention effects.  
 
 
 
1.1 Specific Aims and Hypotheses are: 

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Aim 1: To evaluate the feasibility (including facilitators and barriers to use) and satisfaction of 
computerized cognitive training delivered in the home among BCS. 
 
 
Hypothesis 1: BCS assigned to the cognitive training arm will perceive the intervention as more 
acceptable and useful than BCS assigned to the attention control condition.  
 
 
Aim 2: To test the preliminary efficacy of the cognitive training intervention for improving 
perceived cognitive function over time compared to attention control.  
 
 
Hypothesis 2.1: The intervention group will have greater improvement in subjectively measured 
cognitive function (Perceived cognitive impairment and Perceived cognitive capabilities) over 
time compared to attention control. 
 
Secondary and exploratory aims  
Aim 3: To evaluate computerized cognitive training effects on secondary outcomes over time 
compared to attention control.  
 
Hypothesis 3: The intervention group will demonstrate greater improvement in work ability, 
health perceptions, and quality of life over time compared to attention control.  
 
 
Aim 4: To test the preliminary efficacy of the cognitive training intervention for improving 
objective cognitive performance over time compared to attention control.  
 
 
Hypothesis: 4: The intervention group will have greater improvement in objectively measured 
cognitive function over time compared to attention control.  
           
 
 
Aim 5 (exploratory): Explore the effect of computerized cognitive training on serum BDNF 
levels over time compared to attention control.  
 
 
 
2. SIGNIFICANCE 
 
 
 
Research on cognitive impairment in cancer is a national priority: The President’s Cancer 
Panel,1 the Institute of Medicine Executive Summary, the National Cancer Institute Office of 
Cancer Survivorship45 and the National Institute of Nursing Research Strategic Plan46 have all 
identified management of symptoms including cognitive impairment, as a top research priority. 
Research on breast cancer survivors (BCS) is vitally important: This research focuses on 
BCS, the largest group of female cancer survivors. Breast cancer is the second most common 
cancer among women, with one out of eight women, or approximately 12.4% of American 
women being diagnosed with breast cancer at some time in their life.47 In 2015, more than 
230,000 women were diagnosed with breast cancer in the U.S. alone48 with five-year relative 
survival rates at 98% for local stage tumors.  Because BCS constitute the largest group in the 
cancer survivor community, management of symptoms experienced by these women, such as 
cognitive impairment is vitally important.1 Cognitive impairment is a prevalent, severe, and 
persistent problem for BCS: Up to 75%4,49 of BCS report some level of cognitive 
impairment.4,6-9,50-52 Meta-analyses of studies of cancer survivors, including BCS, have 
documented that cognitive dysfunction can be both severe and a life-changing symptom.6-8,10-13 
The largest meta-analysis with 30 studies showed moderate to large decrements in memory (d 
= -0.61 to -0.91) and speed of processing (d = -0.70) in adult cancer survivors compared to 
controls.10 Similarly, a recent meta-analysis of 27 studies of BCS (over 1,562 subjects) found 
small to moderate decrements not only in memory and processing speed; but, also in attention, 
working memory and executive function in both cross-sectional and longitudinal studies.11 
Although longitudinal studies have identified cognitive dysfunction after surgery and prior to 

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chemotherapy and during the acute phase of treatment (e.g. during chemotherapy),53 BCS 
report that cognitive dysfunction is most disruptive and bothersome after treatment (≥6 months 
post-treatment), when other cancer treatment-related symptoms have subsided, and they face 
returning to work.53-56   
 
 
A growing body of research including our own studies has shown that a substantial number of 
BCS continue to have objectively measured memory deficits for up to 20 years post-
treatment49,57-5960 and that BCS perceive cognitive impairment as disruptive and bothersome.54,61 
Cognitive impairment is associated with other symptoms (depressive symptoms, anxiety 
and fatigue), poor perceived work ability, and poorer quality of life: Perceived cognitive 
impairment consistently correlates with higher levels of depressive symptoms, anxiety, and 
fatigue.54,62 In fact, these symptoms have been shown to be the most common symptoms 
reported post-primary treatment. 45 In addition, multiple studies have also shown that cognitive 
impairment demonstrated on neuropsychological tests is associated with higher levels of 
depressive symptoms, fatigue, and anxiety.29,58,63-66 In our own study of 444 BCS compared to 
355 healthy women, cancer- and cancer-treatment related cognitive impairment on 
neuropsychological tests was significantly related to depressive symptoms and fatigue.67 
Furthermore, surveys and qualitative studies by our team and others indicate that cognitive 
impairment can dramatically affect perceived work ability19-28 and quality of life.29,33,57,68-71  
 
 
There is an urgent need to build the evidence base for treatment of cognitive impairment 
in cancer survivors. Computerized cognitive training may be a viable treatment option.35 To 
date, a total of 8 pilot studies, including our own randomized controlled trial,36 have noted 
positive effects of computerized cognitive training in cancer survivors.34,36-42 These findings 
suggest that computerized cognitive training interventions are likely to be beneficial; however, 
these studies are limited as they fail to address feasibility issues for implementing a home 
based intervention 
 
3. INNOVATION  
 
This will be one of the first studies to deliver a computerized cognitive training program 
to cancer survivors in the home. Delivery of the home based computerized cognitive training 
has several advantages, including: (1) mitigates transportation needs and thereby, improves 
participation/access to those who would otherwise been unable to (e.g. rural BCS); (2) alleviates 
scheduling difficulties; (3) reduces expenses especially when compared to nurse-led, 
supervised programs;72 and (4) ultimately, allows BCS a role in self-management of this 
symptom. 73 This will be the first trial to leverage an existing and readily available 
computerized cognitive training program in cancer survivors. Brain HQ (formerly InSight), 
utilized in our university-based, RWJF-pilot has never been fully tested in a representative 
population of BCS in their home. Using the readily available Brain HQ program would leverage 
the significant investment made to originally develop these resources and may expand its 
usefulness in translating to the large population of BCS. Fully testing this program has many 
important advantages for clinical practice and public health including: (1) the program 
addresses deficits in memory, speed of processing, and executive function which have been 
linked to diminished life quality and poor perceived work ability, both of which have functional 
and economic impact for BCSs and their families; (2) the program is readily available and, if 
determined efficacious, its uptake could be immediate and cost-effective; (3) the program 
adjusts for individual performance and thus would support BCS with varying deficit levels; and 
(4) the program is practical and relatively easy to use and therefore would allow BCS a role in 
self-management of this symptom. 73  
 
This will be the first randomized, controlled trial of computerized cognitive training to 
adequately address placebo effects. Previous studies in cancer survivors are limited by the 
use of a no-contact or wait-list control comparison group, a study approach that fails to fully 

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address potential placebo effects.  In this enhanced proposal, we will use an attention control 
comparison group that will reduce the variability of factors and biases that might influence 
outcomes of the trial. According to the Center for Drug Evaluation and Treatment74 and 
others,75,76 a well-designed control condition is an essential component of behavioral 
intervention trials. Employing an attention control comparison group like the one proposed in 
this study that is similar to the intervention, but does not have the active component to modify 
cognitive function, will enhance the study by (1) providing a more suitable alternative and, 
consequently, enhance recruitment and retention of participants; (2) improve the internal validity 
of the study; and (3) ensure that the “true effects of the intervention can be discerned.”75  
 
This will be the first randomized, controlled trial to explore the impact of computerized 
cognitive training on tangible, real-life outcomes, such as perceived work ability in 
cancer survivors and BCS.  Considerable research suggests that cognitive impairment after 
cancer and cancer treatment negatively impacts perceived work ability in cancer survivors.19-28 
Theoretical models suggest a crucial link between cognitive impairment and work-related 
outcomes in cancer survivors.77-79 To understand this link better, our team completed a 
comprehensive review of the literature and found a total of 20 empirical studies (9 qualitative, 10 
quantitative and 1 mixed-methods) that demonstrated the deleterious effects of perceived 
cognitive impairment on work-related outcomes including perceived work ability.19-28,30,31,61,80-85 
Based on our work and that of others, it is imperative that we explore the impact of cognitive 
training programs on the real-world issues of work ability in BCS.  
 
This is the first study in cancer to examine BDNF as a potentially sensitive outcome 
measure that will increase our ability to measure intervention efficacy. Brain derived 
neurotrophic factor (BDNF) is a neurotropin that is widely distributed in the brain and plays a 
crucial role in neurodevelopment, neuronal function, and neuroplasticity.86-88 Pre-clinical studies 
in animals have noted that spatial memory is impaired when BDNF signaling is decreased;89,90 
alternatively, brain BDNF was shown to be increased during a spatial learning task89 and when 
rodents are housed in cognitively stimulating environments.91 In clinical studies, including our 
own pilot, researchers have noted that serum BDNF levels were significantly increased after 
computerized cognitive training in non-cancer populations.92,93 In cancer, one small study 
showed that BDNF levels were associated with correct responses on cognitive tests; suggesting 
that serum BDNF levels may be a sensitive measure of cognitive function.94 However, there 
have been no studies examining serum BDNF levels as an outcome measure of computerized  
cognitive training efficacy in cancer. Identifying a sensitive biomarker of neuroplasticity will aid 
future efficacy and effectiveness trials and ultimately, help guide the development of evidence-
based treatment guidelines. 
 
4. APPROACH 
 
PRELIMINARY STUDIES: The proposed study will leverage the expertise of an 
interdisciplinary team of experts in cancer, neuro-psychological assessment, statistics 
and cognitive training in BCS). Our team has been internally (ACS) and externally funded 
(RWJF and Walther Cancer Institute) and have conducted multiple studies which have (1) 
documented clinically significant memory impairment in 52 BCS compared to age and education 
matched healthy control women;59 (2) examined the impact of perceived cognitive impairment in 
134 BCS and found that those with more cognitive concerns had poorer QOL, including more 
depressive symptoms, lower well-being, poorer physical functioning, and greater fatigue;33 (3) 
interviewed 22 BCS which revealed that BCS incur cognitive concerns including memory and 
processing speed and that those deficits impact their self-esteem, social relationships, and work 
ability;19 and most recently (4) we completed the Advanced Cognitive Training in Breast 
Cancer Survivors (PI: Von Ah). With funding from the Robert Wood Johnson Foundation, we 
conducted a randomized controlled trial comparing two cognitive training interventions (memory 
and computerized cognitive training) to a wait-list control group in 82 female BCS at the IUSON. 

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Computerized cognitive training (InSight) compared to wait-list control, resulted in immediate 
and durable improvements in neuropsychological measures of (1) memory at post-intervention 
and 2-month follow-up (effect sizes=0.75 and 0.82; respectively; p<.01) and (2) processing 
speed at post-intervention and 2-month follow-up (effect sizes=0.55 and 0.67, p<0.05). InSight 
training also had the advantage of demonstrating improved perceived cognitive functioning, 
associated symptoms (less depressive symptoms, anxiety and fatigue), and quality of life.36 
This important work represents one of the largest RCT in computerized cognitive training 
in BCS to date and the only one to include a neuropsychological battery. The next logical 
step is to build on this previous work and translate the findings to general practice.  
 
5. STUDY DESIGN  
 
The proposed design is a two-group, randomized, controlled trial. After providing consent and 
completing a baseline assessment, a total of 68 eligible BCS will be randomized to 
computerized cognitive training or computerized attention control. Training sessions have been 
standardized across the BrainHQ training and attention control groups with each group 
completing up to 40 hours over 10 week period (total of up to 40 hours), with the dose based on 
previous research.36 Outcomes will be assessed at baseline and immediately post-intervention 
(within 90 days).  
 
6. ELIGIBILITY CRITERIA 
 
6.1 Inclusion criteria 
 
1. Female gender 
2. ≥ 21 years old at the time of informed consent 
3. Ability to provide written informed consent and HIPAA authorization 
4. First diagnosis of non-metastatic breast cancer.  
5. Self-reported cognitive impairment  
6. Subjects seeking treatment though not currently being treated or with prior treatment 
history for cognitive impairment. 
7. ≥ 1 year post-treatment including surgery, radiation, and/or chemotherapy 
8. Ability to understand, speak, read, and write English 
 
6.2 Exclusion criteria  
 
1. Comorbidities that would sufficiently impair performance or inhibit cognitive training 
such as: history of stroke, encephalitis, traumatic brain injury, brain surgery, 
dementia, or Alzheimers disease.  
2. Cranial radiation or intrathecal therapy. 
3. Current active major depression or substance abuse or history of bipolar disorder 
psychosis, schizophrenia, or learning disability. 
4. History of current or other cancer except for basal cell skin cancer.  
 
 
No potential participant will be excluded due to not having a computer. The study will provide a 
computer tablet with data capability to ensure access to participate. This need is not estimated 
to be high as the most recent Census data identified that 84% of U.S. households own a 
computer and 73% have a computer with a broadband connection to the internet. 
 
 
7. PATIENT REGISTRATION 
 
 
All patients will be registered with the Indiana University School of Nursing. Regulatory files will 
be maintained by the Indiana University School of Nursing Research Department for Breast 
Cancer Survivorship. Applicable regulatory documents must be completed and on file prior to 
registration of any patients. Potential patients will be identified in the Oncology outpatient clinics 

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or by referrals from outside physicians. Patients who appear to be eligible for this trial will 
undergo the Informed Consent Process and be screened for eligibility utilizing the Eligibility 
Criteria. The original signed IRB approved Informed Consent Document and completed 
eligibility checklist will be forwarded to the School of Nursing designee for registration in the 
OnCore® database.  
 
 
Study data will be collected and stored in OnCore®, developed by Forte Research Systems, Inc. 
(www.forteresearch.com). OnCore® Enterprise Research is a comprehensive, web-based, 
Clinical Trial Management System (CTMS) which utilizes an Oracle database.  It has been 
licensed by Indiana University (IU) to support the operations and data capture of clinical 
research trials. 
 
 
The system has been installed and configured within a HIPAA-aligned, Information Technology 
(IT), operations center supported by IU’s IT organization, University Information Technology 
Services (UITS). 
 
 
 
OnCore® provides users secure access with unique IDs/passwords and restricts access by 
assigned roles, from any location, to record, manage, and report on data associated with the 
operation and conduct of clinical trials. 
 
 
The system is comprised of three specific applications—Clinical Research Management (CRM), 
Biospecimen Management (BSM), and Unified Registries Management (URM). Indiana 
University leverages OnCore® to support clinical research operations specifically as it relates to 
the following functions/processes:  electronic Scientific Review Committee (SRC), regulatory 
management, protocol and subject life cycle management, coverage analysis, study financials 
management, subject registration and visit management, subject safety monitoring, protocol 
deviation monitoring, study auditing and monitoring, electronic data management, correlative 
study sample management, specimen banking and management, registries management, effort 
tracking, and reporting. 
 
 
 
8. STUDY PROCEDURES 
 
 
8.1  Recruitment and Consent 
 
 
 
Subjects will be recruited using targeted mailings and direct contact. Similar to our pilot study, 
we will recruit in-person consecutive BCS who are being seen for care at the Indiana University 
Health Systems clinics including the IU clinics on campus (IUSCC) (including Eskenazi Hospital) 
and the associated Northside clinic in Carmel, IN.  
 
 
 
We will also recruit through mailings. Similar to our pilot, we will use: (1) the IU Cancer Center 
tumor registry’s 4,111 potentially eligible BCS, who fit our revised eligibility criteria and the (2) 
the Indiana Clinical and Translational Sciences Institute patient registry which has over 1,975 
potentially eligible BCS. We will review lists to ensure that no duplicate inquires will be sent to 
 
potentially eligible BCS.  
 
 
 
For in clinic recruitment, Dr. Schneider (co-I) or designee will get permission from patients to 
allow project staff to enter the patient’s room during a clinic visit to introduce the study.  
 
 
 
Introduce study and screen for eligibility/interest 
 
For in clinic recruitment, the project recruiter then sequentially approaches each woman at the 
end of her clinic visit with the physician and describes the purpose and nature of the study.  
 

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For those that contact our office in response to a mailing, study staff will discuss the study 
requirements and screen for eligibility (phone or in person. Those determined to be ineligible 
due to depressive symptoms will be referred to their attending physician for follow-up.  
 
 
Distribute study information: Following screening, study staff will send or hand out a study 
packet. Packets will contain a cover letter with contact information; a study brochure; copies of 
the informed consent statement and HIPAA-mandated authorization to allow use of protected 
health information; and a stamped, addressed envelope for returning the signed consent and 
authorization forms.  
 
 
 
Obtain informed consent: Women who are eligible and interested will be consented in person 
in the clinic. Those women who do not return a signed consent will receive a phone call one 
week following their screening date to verify interest in participating and provide additional 
information if needed. Interested women will be instructed on the consent process. Informed 
consent will follow the requirements of the university’s institutional review board 
 
 
Eligibility/Baseline Assessment: After the signed written consent and HIPAA authorization 
forms are received, research staff will telephone the participant and arrange a mutually 
convenient appointment. Assessments will be completed in a private room at the university. 
First, eligibility will be confirmed via self-report by the participant.  
 
 
If ineligible, the subject will be thanked for her time and interest in participating.  
 
 
If eligibility is confirmed, the appointment will continue, and the other baseline assessment 
measures will be administered. Once the neuropsychological assessment and questionnaires 
are completed, the tester will review them and obtain data from the participant on any missing 
items 
 
Randomization: Building on our pilot studies, BCS will be randomly assigned to one of two 
groups: BrainHQ cognitive training or attention control. Assignments will be in a random order 
generated by a computer using blocks of 8, to ensure filling of treatment groups. Randomization 
will occur as close to the start of the training sessions as possible to minimize study drop-out. 
 
Neuropsychological testing, completion of questionnaires and collection of a blood sample for 
BDNF will be collected at two time points during the study. Baseline (T1) data will be collected 
prior to the initiation of the intervention or attention control computerized training. Follow up 
assessments and BDNF blood sample will be collected post-intervention within 90 days of 
completing the intervention or attention control computerized training (T2)  
 
Serum for BDNF analysis and all biomarkers that are part of this study will be prepared by 
laboratory services at IU and will be securely and confidentially (blood sample code) stored in 
the Analyte Laboratory within the Translation Core of the Center for Diabetes and Metabolic 
Disease under management of Dr. Considine (Co-I). The BDNF serum levels will be batch 
analyzed following collection of all samples following the manufacturers’ ELISA protocol. The 
ELISA assay has standards ranging from 7.8 to 500 pg/ml BDNF (this is the possible range for 
all samples). 
 
The study will also examine biomarkers that can affect brain functioning including neurotropic 
factor, proinflammatory cytokines, cortisol, and dehydroepiandrosterone (neuro steroid) DHEA. 
 
8.2 Intervention 
 
 
The baseline assessment will be completed and then the participant will be randomized to 
computerized cognitive training or attention control group. An immediate post-test will be 

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completed, which will be 10 weeks after baseline (10 weeks for intervention within 90 days for 
completing the post-intervention assessment). The first visit will last about 1-hour and all other 
visits should last about 50 minutes.  
 
 
 
At baseline, participants will provide demographic, clinical and treatment information, 
questionnaire data, blood sample, and complete a neuropsychological assessment 
administered by a trained and blinded tester.  All other assessments will proceed in the same 
manner; however, demographic and treatment information will not be re-assessed. The medical 
record of BCS’s will be examined for purposes of verifying disease and treatment information, 
including types and dates of treatments received (surgery, radiation, chemotherapy, tamoxifen 
and/or aromatase inhibitors). Data will be linked to participants through the use of a unique 
study-specific identifying number. Only persons on the research team will have access to the 
data. The neuropsychological tester will remain blinded to the randomization of the participants. 
All data are collected for research purposes only. 
 
 
Cognitive Training: As tested in our pilot, the Brain HQ program is designed to enhance 
specific areas of cognitive functioning that will be tested in this study. The goals of the Brain HQ 
program are to improve visual processing speed, learning and memory and attention. The 
exercises include time-order judgment, discrimination, spatial-match, forward-span, instruction-
following, and narrative-memory tasks.97 This program systematically reduces the stimulus 
duration during a series of increasingly difficult information-processing tasks presented via 
computer. The exercises automatically adjust to user performance to maintain an 85% correct 
rate. The program will include 4 hours per week over a 10-week period for a total of up to 40 
hours. We have support from the original developer and Posit Science. For the purposes of this 
trial, any participants who do not complete the total of up to 40 hours will not be counted as 
deviations.  
 
BrainHQ uses five tasks in the form of computer games designed to improve memory, 
processing speed, attention, working memory and executive function including: 
1. Sweep Seeker: The person is asked to clear the rows of blocks presented on the screen, 
either by moving them into horizontal or vertical blocks that have identical color. The goal is 
to refine and increase the response of primary visual cortex neurons and to enable the 
person to increase speed and accuracy of visual processing (executive function) and visual 
memory. 
2. Bird Safari:  The user is first presented with a target bird. Subsequently, a group of birds is 
presented in the peripheral vision and then disappears when the trial begins. The user 
selects the section of the screen where the target bird appeared. The presentation speed 
adapts with user performance (i.e. better performance = faster presentation). The goal is to 
improve speed and accuracy of object identification in peripheral vision and improve visual 
precision important for improving memory.   
3. Jewel Diver:  The person is first presented objects (jewels) on the screen. The objects are 
then covered with occluders (bubbles) and then identical distracters are presented. The 
objects move around in screen and when the movement stops, the user chooses the 
occluders that cover the jewels. The number of jewels adapts to performance (more jewels = 
better performance). The goal is to improve divided visual attention, sustained visual 
attention, visual working memory, and visual precision.  
4.  Master Gardener: The person is presented a series of target stimuli and distracters which 
are presented at one time and then disappear. The locations of the stimuli are marked by 
icons, and the user choses the icons where the target stimuli were once located. The goal is 
to increase speed and accuracy as well as the ability to extract information accurately. 

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5. Road Tour:  The person is presented with a target vehicle briefly in both the center of the 
screen and in one of eight locations in the periphery. Two vehicles are then presented briefly 
in the center of the screen, one of which is the target vehicle. The user must identify the 
location of the target vehicle in the periphery as well as identify which was the target vehicle 
that appeared in the center. The goal of this activity is to improve divided attention and ability 
to extract information and discard irrelevant information from peripheral vision.  
 
 
Attention Control: Control participants will be asked to complete activities on the computer. 
The program offers a choice of activities that will consist of crossword puzzles and word 
jumbles.  Attention Control: Computer-based General Cognitive Stimulation Intervention 
(Computerized Crossword Puzzles): The program offers a pre-determined set of computerized 
crossword puzzles  (www.bestcrosswords.com; http://zone.msn.com/en/crossword; Accessed 
09-15-2015). The site has over 100,000 puzzles and can be accessed easily via the web and 
are free to users. The computerized crossword puzzles do not provide for progressive 
challenges of increasing speed, visual field size, number of distractors or degree of difficulty of 
targeted stimulus differentiation. Training: Participants will be instructed to perform this active 
attention control intervention 4 hours per week over 10 weeks for a total of up to 40 hours, the 
same as BrainHQ. 
 
  
The rationale for this attention control program is (1) it has been routinely and successfully used 
in other NIH-funded cognitive training trials, (2) it has not shown cognitive benefit in previous 
research studies,44,98 and  (3) previous experience by our team and others have shown that it is 
an appropriate computerized attention control alternative.43,44 The delivery format, number of 
sessions, and setting all parallel the intervention of up to 40 hours over 10 week period. Table 1 
describes the difference between the Brain HQ intervention and the attention control cognitive 
training interventions. 
 
Based on the randomization, the project manager will provide verbal and written instruction for 
accessing and using the 
program and the minimum 
amount 
of 
practice 
required. 
BrainHQ 
and 
computerized 
attention 
control 
programs 
will 
capture the date and time 
the participants participate 
in the study.  
 
Post 
Intervention: 
A 
follow up assessment will 
be conducted immediately 
post 
intervention 
(T2). 
Based on our pilot study, 
the 
post-intervention 
assessment 
and 
BDNF 
blood 
draw 
will 
be 
completed within 90 days 
of 
completing 
the 
intervention (T2) training or 
attention control sessions.  
 
Procedures 
for 
Monitoring Treatment Fidelity:  As in our pilot, procedures for monitoring treatment fidelity will 
Table 1 Comparison of BrainHQ to Attention Control  
Element 
Computerized Cognitive 
Training using BrainHQ 
Attention Control 
Computer-Based 
General Cognitive  
 
Visual stimuli 
Intensive & repetitive with 
increasing visual stimuli  None  
Complexity 
of stimuli 
Progressively increased 
speed & processing of 
stimuli with increasing 
distractions  
No Progressive 
Challenge 
Cognitive 
demand 
Tailored; Training 
adjusted by computer to 
85% of individual’s 
threshold 
Not tailored; not 
adjusted or tailored for 
individual threshold 
Visual 
attention & 
memory 
Directed attention with 
each exercise, precision  
No directed attention 
from computerized 
intervention 
Novelty 
Individualized feedback 
and rewards built in to 
respond to the 
participant, game 
features to improve 
satisfaction 
Feedback and rewards 
not provided, may incur 
some satisfaction on 
their own 

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be guided by the Treatment Fidelity Checklist.99 Both groups have been standardized in dose 
(length and content) and delivery method (in-home). Intervention dose will be carefully monitored 
using the computer software built within BrainHQ and Rescue Time software for the active 
attention control (total time on task). These variables will be examined and used in the analysis. 
The PI will be responsible for oversight of treatment fidelity The neuropsychological tester will be 
blinded to group status. The project manager will ensure the participants understand and are 
utilizing the program. Treatment dose and content will be carefully monitored through the InSight 
program . 
 
 
Qualitative assessment: individual interviews will be conducted over the phone with members 
of the intervention group to understand the perceived facilitators and barriers to use of the 
intervention. All interviews will be conducted after the intervention, voice recorded digitally and 
labeled with a patient identification number.  
 
 
Accrual & Retention: Several steps will be taken to ensure high rates of accrual, retention, and 
representation of minority BCS. These include (1) using culturally appropriate printed study 
information;100-102 (2) contacting potential subjects in person in the clinic, which has been shown 
to be preferred over unsolicited telephone calls 101 and to be more effective in recruiting minority 
subjects;103  and (3) providing participant incentives of $20.00 for every assessment completed 
($40.00 for both) to offset subject burden. 
 
 
9. MEASURES 
 
 
Table 1 displays the quantitative data collection plan and details of measures. The 
neuropsychological battery has been shown to be reliable and valid. 104Based on our pilot, 
estimated completion time for the initial baseline assessment will be 1 hour with each follow-up 
session lasting approximately 50 minutes. Qualitative assessment: individual interviews will be 
conducted over the phone with members of the intervention group to understand the perceived 
facilitators and barriers to use of the intervention. All interviews will be conducted after the 
intervention, recorded digitally and labeled with a patient identification number. This will be done 
only one time and will last up to 30 minutes.  
 
Table 2. Schedule of Quantitative Measures 
 
 
 
No. Items/ 
(Potential 
range) 
 
 
Variable 
Instrument (Measure) 
 T1 
T2 
Instrument 
Range 
Reliability 
S
c
o
r
e 
 
Screening  
 
Perceived 
Cognitive 
Function 
Numeric rating scale 
(0 to 10) 
X 
 
0-10 
n/a 
↓ 
 
 
 
 
 
 
 
Depression  
PHQ-9107,108 
X 
 
 
0.84 
↓ 
 
Aim 1: Satisfaction and Acceptability  
 
 
Satisfaction 
Client Satisfaction 
Questionnaire 
 
X 
8-32 
0.90-0.94† 
 
↑ 
 
Acceptability 
Acceptability Scale 
 
X 
 
NA 
↑ 
 
Aim 2 Subjective 
Cognitive Measures  
 
 
 
Perceived 
Cognitive 
Function  
ƗPROMIS – Applied 
Cognition- Abilities  
X 
 
 
 
X 
 
 
 
33 (33-165) 
 
 
 
0.97† 
 
↑ 
 
↓ 

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ƗPROMIS -  Applied 
Cognition Gen. 
Concerns 16,120 
X 
X 
34 (34-170) 
 
 
Aim 4 Objective 
Cognitive Measures 
 
 
 
Memory  
Rey Auditory-Verbal 
Learning Test 109   
Rivermead Behavioral 
Memory Test110 
X 
 
X 
X 
 
X 
15 words, 5 trials  
(0-75) 
N/A  
Speed of 
Processing 
Symbol Digit 
X 
X 
7-500ms 
0.78* 
 
0.60* 
↑ 
↑ 
 
 
 
 
 
0.71-0.88 
↓ 
Working 
Memory 
Wechsler Adult 
Intelligence Scale IV 
– Digit Span116 
X 
X 
 
 
 
Executive 
Function - 
Language 
Controlled Word 
Association117 
X 
X 
#words/1min 
0.96 
↑ 
 
Aim 3 Other 
Outcomes  
 
 
 
>.70 
↑ 
 
 
 
 
 
 
 
Work Ability  
Work Ability Index 
(WAI) 123-125 
X 
X 
7 (7-49) 
0.98† 
 
0.97† 
 
0.99† 
↓ 
 
↓ 
 
↓ 
Quality of Life 
Quality of Life-Cancer 
Survivors (QOL-
CS)126 
X 
X 
41 (0-10 on 4 
sub-scales)  
0.66* 
↑ 
 
Exploratory Aim 4  
Intervention Effect 
on BDNF 
 
 
 
0.93† 
↑ 
Serum BDNF 
levels  
Serum BDNF –ELISA 
X 
X 
Assa
ys 
range
: 7.8-
500 
pg/ml 
 
Intervention Fidelity 
Assessment & other 
symptoms  
 
 
 
Within assay 
%CV at 
334pg/ml =4.7% 
Within assay 
%CV 825pm/ml 
= 3.4% 
↑ 
Dose 
Time Spent each session – Computer  
 
 
N/A 
Depressive 
Symptoms 
 
Anxiety 
 
Fatigue 
PROMIS-Depression 
Short Form 121 
122 
PROMIS-Anxiety 
Short Form 122 
PROMIS-Fatigue 
Short Form121 
X 
 
X 
 
X 
X 
 
X 
 
X 
8 (0-40) 
 
8 (0-40) 
 
8 (0-40) 
 
 
 
 
 
10. DATA ANALYSIS 
 
 
Descriptive statistics and assessment of internal consistency reliability will be computed for all 
variables. Aim 1 Feasibility and Satisfaction:  Descriptive statistics and frequencies will be 
used to summarize the Client Satisfaction Questionnaire and Acceptability Scale. The two 
groups will be compared on the mean of each item using the t test or Wilxocon rank sum test if 
the parametric assumptions are violated. Qualitative Analysis: A conventional content analysis 
approach, which aims to summarize the informational contents of the data, will be used.126,127 
Common themes across all the participants’ data will be identified and organized into clusters 
and categories. Aims 2-4: A linear mixed-effects models128 to analyze repeated-measures 

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ANCOVA, to compare the effects of cognitive training to attention control will be used. The 
dependent variables, cognitive performance measured post-intervention, will be the primary 
outcomes. The baseline cognitive performance will be adjusted for as a covariate. The other 
independent variables will be the fixed effect for training group (BrainHQ, attention control), the 
Time effect, and the interaction term of Time-by-Training Group. The primary test of interest will 
the Group effect, which compares the two randomized groups on the outcome. The second 
most important test will be the interaction test to determine whether change over time differs for 
the two groups. We will also assess the Time effect, which tests whether scores generally 
changed in one direction for both groups combined. In addition, to ensure equivalence across 
groups potential covariates will be adjusted for in the models on which the various intervention 
and control groups significantly differ after random assignment at a liberal p-value of <.10. Effect 
sizes between the two groups will be computed as differences between adjusted means divided 
by pooled standard deviations. The significance level will be <.05 for all tests of hypotheses. 
Aim 5 provides the estimation of the effect of cognitive training on serum BDNF. Similar to Aims 
1 and 2, a GLMM will be fitted to the data to estimate this effect, while controlling for potential 
known confounding effects including, age, education, smoking status, body mass index, 
medications, physical activity (per DUKE Activity Status Index129) that may influence BDNF 
interpretation130 prior to hypothesis testing; although the RCT design will likely balance these 
factors.  
 
 
Power analysis: We are adequately powered for estimating effect sizes or preliminary efficacy 
(Aim 2). Sample size is based on Aim 2 preliminary tests of post-intervention efficacy of the 
intervention on continuous outcomes. A difference between means equal to 0.80 standard 
deviations represents a large effect size, a medium effect size is 0.50, and a small effect size is 
0.20.96 Using the Nquery software, a sample size of 30 in each group will provide 86% power 
for a two-sided t test to detect a large effect size of 0.80 when alpha is .05, to detect small or 
medium effect sizes. 
 
Methods for Handling Missing Data and Dropouts: The GLMM approach to analysis allows 
use of all available data, including from participants who have incomplete (i.e., partially missing) 
data. We will compare those who dropped out to those who completed the study on various 
demographic and treatment factors and on intervention group membership. To the extent that 
differences exist, we will describe this bias and its potential effects on the results of our analysis. 
Additionally, we will attempt to determine missing data patterns, and, if cell sizes permit, will 
incorporate this information into the analyses by re-running the GLMM with incorporation of the 
missing pattern as a nominal covariate. 
 
Additionally, the influence of treatment dose (i.e.: sessions completed) will be evaluated to 
determine if it should be included as a covariate in the GLMM. Participants will be randomized 
only after completing baseline assessment. There are only two possible missing data patterns: 
baseline and immediate post only. 
 
 
11. DATA INTEGRITY AND SECURITY 
 
All documentation will be stored on a limited-access university server or in locking file cabinets 
in a limited-access, locked project office. All electronic databases housing subject data will be 
password-protected with access limited to study personnel only. Identifying information is 
separated from all data provided by participants through the use of a unique identification code 
assigned by study personnel to each subject.  
 
Analysis of objective neuropsychological data will be monitored for quality assurance. Personnel 
who conduct the neuropsychological assessments (tester) will complete a standardized 

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instruction course and will be certified to deliver the assessment based on criteria developed by 
Dr. Unverzagt (Co-I).  
 
All data entry will be done by trained personnel. Databases will be constructed to include forms 
for data entry that mirror questionnaires and have restricted field ranges and values to prevent 
errors. In addition, quality of data entry will be monitored by the Project Manager, who will 
randomly select patient files to be double-entered and will periodically generate reports for the 
entire dataset to identify outliers, missing data, or other problems. All data will be imported into 
SAS data sets for analysis. Analyses will include only summaries of data; personal identifiers 
will be omitted 
 
12. STUDY TIMELINE 
 
Study Timeline 
May 
June 
July 
Aug 
Sept 
Oct 
Nov 
Dec 
Jan 
Feb 
Mar  Apr 
Study start up (hiring, 
training, finalize all 
study protocols) 
X 
 
 
 
 
 
 
 
 
 
 
 
Enrollment and 
baseline data collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Randomization, 
delivery of 
intervention/control 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Follow-up data 
collection, data entry 
and management 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Analyze preliminary, 
baseline and follow-up 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dissemination: 
literature review, theory 
review, intervention 
description, baseline 
and final study findings 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
13. RISKS TO SUBJECTS 
 
 
Potential risks associated with study participation are minimal. Subjects may experience: (a) 
bruising, bleeding, soreness or rarely, fainting of infection as a result of venipuncture for 
collection of the blood samples (b) psychosocial risks and (c) breach of confidentiality. Risks in 
the psychosocial realm would involve any anxiety or distress that may result from participation in 
the scheduled study assessments and/or phone interview. Based on our prior work with similar 
assessment protocols, we anticipate that any negative psychological reactions will be 
uncommon and generally very mild. There is always some risk that a woman’s responses during 
the study will become known to others outside the research project staff. No unusually sensitive 
information is being collected in our study; for example, we are not collecting information on 
sexual behavior or criminal behaviors, or substance abuse. 
 
 
 
Steps will be taken to minimize any potential risks associated with study participation.  
 
 
 
To minimize bruising, bleeding, soreness or rarely fainting or infection as a result of 
venipuncture. Our experienced research staff is trained and certified in phlebotomy. They will 
apply universal precautions when drawing blood to reduce the risk of infection and will take 
steps to minimize discomfort to subjects including application of pressure on the site following 

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needle withdrawal. Additionally, subjects will be asked to remain in a sitting position for five 
minutes after blood has been withdrawn and will be observed for any untoward effect.  
 
 
To minimize any psychosocial or physical risks, participants will be told that they have the 
option of discontinuing their study participation at any time during the course of an assessment 
session or at any point during the study. Research assistants will be trained to identify unusual 
distress and will notify the PI, who will conduct follow-up assessments and refer participants to 
their healthcare provider if necessary.  
 
 
 
To minimize risks associated with breach of confidentiality we will assign each study 
participant a unique identification number and using this to identify all study data records. A 
single list connecting the study identification number with each participant's name will be kept in 
a password-protected database on a limited-access university server. Furthermore, all study 
data records, or digital recordings will be maintained in locked file cabinets and/or password-
protected databases on limited-access university servers. Access to study data records will be 
furnished only to individuals who are members of the project research team. All personnel who 
are involved in the design or conduct of this research will have successfully completed human 
subjects training.  
 
 
For women who exhibit extreme scores on the PHQ-9 brief depression screen we will adhere to 
the following  PHQ-9 Referral Algorithm:  Score ≥ 15, negative response to self-harm item: 
Refer to physician for follow-up; Score ≥ 15 positive response to self-harm item: Keep patient on 
the telephone, assess emergent needs of patient. If immediate risk is low, refer to suicide hot 
line and inform patient you will be notifying her oncologist for follow-up. If immediate risk is high, 
call 911, refer to suicide hot line, and inform patient you will be notifying her oncologist for 
follow-up. 
 
14. POTENTIAL BENEFITS 
 
 
 
Subjects may benefit from participating in cognitive training with improvement in memory 
performance and/or speed of processing. This research will provide information about the 
efficacy of the BrainHQ cognitive training intervention in BCS. This research could also provide 
a non-pharmacological alternative to address cognitive impairment in a generally younger 
population of cancer survivors who currently have limited or no other treatment options.  Risks 
of participation are minimal.  
 
 
Importance of the Knowledge to be Gained: 
 
Knowledge will be gained on the efficacy of a commercially available cognitive training 
intervention that may help improve cognitive impairment in cancer survivors. This study will 
provide the necessary evidence regarding the use of cognitive training in breast cancer 
survivors. Such improvement is essential to helping improve BCS quality of life. Risks in this 
study are minimal. Findings will provide empirical evidence for or against the use of the 
cognitive training intervention for improving memory performance and processing speed. 
Importantly, either positive or negative findings will provide guidance for clinicians’ 
recommendations and consumers’ treatment selections relative to the use of this type of 
advanced cognitive training This research study will provide efficacy data about the cognitive 
training intervention and will offer a non-pharmacological alternative to improving cognitive 
performance in breast cancer survivors, who have limited or no other treatment options. In 
addition, if efficacious this cognitive training program could be tested in a broader population of 
cancer survivors incurring similar cognitive deficits 
 
15. PATIENT CONSENT AND PEER JUDGMENT 
 

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The protocol and informed consent form for this study must be approved in writing by the 
appropriate Institutional Review Board (IRB) prior to any patient being registered on this study.   
 
 
Changes to the protocol, as well as a change of principal investigator, must also be approved by 
the Board.  Records of the Institutional Review Board review and approval of all documents 
pertaining to this study must be kept on file by the investigator (housed in the Clinical Trials 
Office) and are subject to inspection at any time during the study.  Periodic status reports must 
be submitted to the Institutional Review Board at least yearly, as well as notification of 
completion of the study and a final report within 90 days of study completion or termination.   
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 
16. DATA AND SAFETY MONITORING PLAN 
 
This study will be conducted in accordance with the IU Simon Cancer Center Institutional 
DSMP for Low Risk Trials. 
 
Investigators will conduct continuous review of data and subject safety. Quarterly review 
meetings for low risk trials are required and will include the principal investigator, clinical 
research specialist and/or research nurse (other members per principal investigator’s 
discretion). Quarterly meeting summaries should include review of data, the number of 
subjects, significant toxicities as described in the protocol, and responses observed. Study 
teams should maintain meeting minutes and attendance for submission to the DSMC upon 
request. 
 
Data and Safety Monitoring Committee 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial.  The DSMC will review this 
study annually to review overall trial progress, toxicity, compliance, data integrity, and accrual 
per the Institutional DSMP. 
 
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), 
deviations, reportable events, and any other outstanding business.  Major issues may require 
further DSMC review or action. 
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the subject warrant early closure of the study, the DSMC Chair and Compliance 
Officer must be notified within 1 business day via email, and the IRB must be notified within 5 
business days. Alternatively, the DSMC may initiate suspension or early closure of the study 
based on its review. 
 
Study Auditing and Monitoring 
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the Institutional 
DSMP. Reports will be reviewed by the full DSMC at the time of study review. 
 
Data Management/ Oncore Reporting Requirements 
The DSMC reviews data and study progress directly from Oncore; therefore, timely data entry 
and status updates are vital.  Study data must be entered within Oncore promptly, no later than 
one week from study visit occurrence.  Subject status in Oncore will be updated in real time, as 
this may affect overall trial enrollment status.  Global SAEs and deviations will be reviewed on a 
monthly basis by the DSMC Chair directly from Oncore. 
 
Study Accrual Oversight 

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Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol  
Progress Committee (PPC) reviews study accrual twice per year, while the PPC coordinator 
reviews accrual quarterly. 
 
Oncore Safety Reporting 
In addition to protocol- and regulatory-required safety reporting, all serious adverse events 
(SAEs) will be captured in the Oncore system within 1 business day of notification.  Initial SAE 
reporting will include as much detail as available, with follow-up to provide complete information. 
Attributions will be assessed to study drugs, procedures, study disease, and other alternate 
etiology. 
 
Protocol Deviation Reporting 
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by the 
DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the time of study 
review.  For serious or repetitive protocol deviations, additional action may be required by the 
DSMC. 
 
17. ADVERSE EVENTS 
 
 
 
Adverse Event (AE): 
 
An adverse event is defined as untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. An adverse event can 
be ANY unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of an intervention, whether or not considered 
related to the intervention (attribution of ‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’, or ‘definite’).  
Adverse events will be graded according to the NCI Common Toxicity Criteria, Version 4.0. 
 
 
For this study, an Adverse Event will be defined as any reaction or undesirable event that 
occurs while a subject is on the research protocol whether or not it is considered relate to the 
study intervention (cognitive training). Such events could include illness, signs, symptoms, or 
abnormal laboratory tests that have appeared or worsened during the course of the trial 
regardless if any causal relationship to the study can be made. 
 
 
Serious Adverse Event (SAE): 
 
A serious adverse event is any untoward medical occurrence resulting in one or more of the 
following: 
 
• 
Results in death or ANY death occurring within 30 days of a biopsy procedure (even if it 
is not felt to be related).  
• 
Is life-threatening (defined as an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
Requires inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
▪ 
NOTE: Hospitalizations that are not considered SAEs are:  
• 
Hospitalization planned prior to biopsy procedure 
• 
Hospitalization of less than 24 hours 
• 
Hospitalization for elective treatment of a pre-existing condition 
unrelated to biopsy procedure. 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the patient or may require 
intervention (e.g., medical, surgical) to prevent one of the other serious outcomes listed 

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in the definition above).  Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions not resulting in hospitalization; or the development of drug 
dependency or drug abuse. 
 
 
Attribution: An assessment of the relationship between the AE and the medical intervention. 
CTCAE does not define an AE as necessarily “caused by a therapeutic intervention”. After 
naming and grading the event, the clinical investigator must assign an attribution to the AE 
using the following attribution categories: 
 
 
Relationship 
Attribution 
Description 
Unrelated to investigational intervention Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
18. SAE REPORTING 
 
 
18.1 SAE Reporting to the IRB:  
 
Unanticipated problems involving risks to subjects or others will be reported within 5 days of 
becoming aware of the event to the IRB if they:  
 
• 
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 than was 
previously known or recognized.   
 
 
If the serious adverse event does not meet all three (3) criteria listed above, the event does not 
have to be promptly reported to the Indiana University IRB.  However, it should be reported at 
the time of continuing review 
 
18.2 SAE Reporting to the IUSCC Data Safety Monitoring Committee:  
 
Regardless of study sponsorship, the study team must enter all initial and follow-up SAE, 
expedited, and noncompliance reports into OnCore® for review by the DSMC chair and/or 
coordinator. Expedited reports may include IRB Prompt Report Forms and additional SAE forms 
as required by the sponsor. When follow-up information is received, a follow-up report should 
also be created in OnCore®. This DSMC reporting requirement is in addition to any other 
regulatory bodies to be notified (i.e., IRB, FDA, pharmaceutical company, etc.). The DSMC chair 
and/or coordinator will review all SAE, expedited, and noncompliance reports monthly.   
 
 
 
 

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Jansen CE, Miaskowski C, Dodd M, Dowling G, Kramer J. A metaanalysis of studies of 
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Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE. 
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