eHealth Insomnia Intervention for Adult Survivors of Childhood Cancer: A Randomized Clinical Trial
Phase: NA
Conditions: Childhood Cancer, Insomnia, Neurocognitive Impairment, Survivorship, Late Effect, Sleep
Sponsor: St. Jude Children's Research Hospital

 
 
Official Study Title: eHealth Insomnia Intervention for Adult Survivors of Childhood   Cancer 
CTG Number: NCT04317742 
Document Date: 05/04/2021 

Amendment 5.0 dated: 04/09/2021 
Protocol document date: 04/09/2021 
St. Jude 
SLEEPWELL - NCT04317742
Initial version, dated:  04-17-19, (IRB Approved: 07-30-19) Activation Date: 
Resubmitted, dated 09-13-19 (IRB Approved: 10-24-19) Activation Date: 12-17-19 
Amendment 1.0, dated 12-12-19 (IRB Approved: 01-22-2020) Activation Date: 
Amendment 2.0, dated 09-02-20 (IRB Approved: 10-23-2020) Activation Date: 10-27-20 
Amendment 3.0, dated 10-28-20 (IRB Approved: 11-20-2020) Activation Date: 12-10-2020 
Amendment 4.0, dated 01-14-2021 (IRB Approved: 02-10-2021) Activation Date: 02-19-2021 
Revision 4.1, dated 03-02-2021 (IRB Approved: 03-04-2021) Activation Date: 03-16-2021 
Amendment 5.0, dated 04-09-2021 (IRB Approved: ) Activation Date: 
eHEALTH INSOMNIA INTERVENTION FOR ADULT SURVIVORS OF CHILDHOOD 
CANCER: A RANDOMIZED CLINICAL TRIAL  
Co-Principal Investigators1 
Tara Brinkman, PhD 
Kevin Krull, PhD 
Co-Investigators 
Gregory Armstrong, MD, MSCE1 
Daniel Mulrooney, MD1 
Lee Ritterband, PhD2
Karen Ingersoll, PhD2 
Wendy Leisenring, ScD3 
1St. Jude Children’s Research Hospital, 2University of Virginia, 3Fred Hutchinson, Cancer 
Research Center 
Consultant: 
Kathy Ruble, CRNP, PhD 
Johns Hopkins University 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee 38105-3678 
Telephone: (901) 595-3300 
St. Jude Children's Research Hospital
IRB NUMBER: 19-0121
IRB APPROVAL DATE: 05/04/2021

 
Amendment 5.0 dated: 04/09/2021 
Protocol document date: 04/09/2021 
Contents of this document may not be extracted without permission from the Principal Investigator. 
Protocol MNEMONIC and Title: SLEEPWELL: eHEALTH INSOMNIA 
INTERVENTION FOR ADULT SURVIVORS OF CHILDHOOD CANCER: A 
RANDOMIZEDCLINICAL TRIAL  
Principal Investigators: Tara Brinkman, PhD & Kevin Krull, PhD 
IND Holder: Not Applicable 
Brief Overview: There is evidence that survivors of childhood cancer have a high 
prevalence of poor sleep, including symptoms of insomnia. Insomnia is highly comorbid 
and has been associated with impaired cognitive performance, a range of psychiatric 
disorders, cardiovascular disease, and reduced quality of life. However, we still lack 
knowledge about the direct impact of available internet-based insomnia treatment 
programs for survivors of childhood cancer experiencing insomnia, in addition to how 
improving insomnia symptoms impacts neurocognitive function and late health morbidities 
in this population. Therefore, in this study, we will utilize the resources available in the 
Childhood Cancer Survivor Study (CCSS) to use an accepted, established, efficacious 
internet-delivered CBTi insomnia treatment program and evaluate the efficacy of this 
program in adult survivors of childhood cancer. We are leveraging two electronic health 
platforms to treat insomnia and facilitate data collection. Positive results from this study 
and our use of an internet-based intervention are likely generalizable and be scalable to the 
large and geographically diverse population of childhood cancer survivors with chronic 
health conditions. The CCSS provides a unique opportunity for cost-effective evaluation 
of the efficacy of remote treatment of insomnia in such a large sample of childhood cancer 
survivors. 
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Amendment 5.0 dated: 04/09/2021 
Protocol document date: 04/09/2021 
Protocol MNEMONIC and Title: SLEEPWELL: eHEALTH INSOMNIA 
INTERVENTION FOR ADULT SURVIVORS OF CHILDHOOD CANCER: A 
RANDOMIZEDCLINICAL TRIAL  
Evaluation: Eligible participants will complete a 9-week internet-based insomnia 
treatment program or receive sleep education, depending on group assignment. CCSS 
participants who have been previously identified as having neurocognitive impairment will 
be approached for recruitment. An approach packet consisting of an introduction letter, a 
single page study brochure, and informed consent documents will be mailed to potentially 
eligible participants. Interested participants will be able to return the consent via mail using 
a pre-paid envelope. Alternatively, the packet will include instructions for visiting the study 
webpage, where participants can sign-up and provide informed consent on-line. Those who 
have not responded after two weeks will receive an email alerting them to the study and 
providing a link to the study webpage. Starting three weeks after the initial mailing, a 
trained study interviewer housed within the CCSS Call Center will begin calling non-
responders to provide information, answer questions, and encourage participation. 
Participants will have the opportunity to consent to the study verbally while speaking with 
the CCSS Call Center. Alternatively, survivors who wish to participate will enroll online 
via DatStat Connect (the current online data collection tool for the CCSS). Prospective 
participants will complete an online consent form. After consenting, they will complete a 
series of short online questionnaires to determine study eligibility. We anticipate needing 
to recruit 352 participants to reach the targeted enrollment of 320 at 9 weeks and 280 at 6 
months. Upon enrollment, participants will be asked to complete all the study activities 
completely remotely. For the baseline remote evaluation, participants will complete a 
computerized remote cognitive assessment and will provide a blood sample using the Dried 
Blood Spot (DBS) method. Participants will be asked to complete online questionnaires 
and sleep diaries. Participants will be mailed a WHOOP wrist monitor to wear for 7 to 11 
consecutive days. Two more identical remote evaluations will occur, one immediately after 
the intervention is completed and one 6 months after completion of the intervention.  
Study Design: Randomized Controlled Trial 
Sample Size: Approximately 352 research participants  
Data Management: Collection of eHealth Data Using the RICE Platform: Interaction 
with participants and collection of data will be accomplished using the Research 
Infrastructure Containing E-interventions (RICE) Platform developed at the Center for 
Behavioral Health and Technology at the University of Virginia by Dr. Ritterband (Co-
Investigator). Through a subcontract with Dr. Ritterband and the University of Virginia, a 
study-specific module within the RICE Platform will be used for post-enrollment study 
activities. The platform will be used to: (1) provide access to instructional and 
demonstration videos; (2) collect data, including questionnaires; (3) implement the SHUTi 
program (intervention group) and educational program (control group); and (4) secure 
transmission of data to the study team. The platform allows for input constraints in the 
tools as well as real-time validation of data formats and ranges, providing real-time 
feedback to the user if “out-of-range” values are recorded. Participants will need to be able 
to access the internet on a device of their choosing.  
We anticipate enrollment of 352 participants within a 4-year period. 
Human Subjects: The risk of harm anticipated in the proposed research is not greater than 
that encountered during daily activities or during the performance of routine physical 
St. Jude Children's Research Hospital
IRB NUMBER: 19-0121
IRB APPROVAL DATE: 05/04/2021

 
Amendment 5.0 dated: 04/09/2021 
Protocol document date: 04/09/2021 
Protocol MNEMONIC and Title: SLEEPWELL: eHEALTH INSOMNIA 
INTERVENTION FOR ADULT SURVIVORS OF CHILDHOOD CANCER: A 
RANDOMIZEDCLINICAL TRIAL  
examinations. Monitoring will be performed by the PI, co-investigators, and the IRB 
through annual continuing reviews. All study activities will be done completely remotely, 
and the main requirement is to have internet access, access to a computer or laptop, and 
access to a smart phone or tablet. During the intervention, participants will be instructed 
on how to minimize the risk associated with sleep restriction and to contact study staff if 
they have any significant concerns. As needed, study staff will instruct participants to 
contact their primary care provider. Participants will not be required to complete any of the 
assessments they wish to omit, nor will they be required to answer any questionnaire items 
they do not wish to answer. 
St. Jude Children's Research Hospital
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Amendment 5.0 dated: 04/09/2021 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES ..................................................................................................................... 1 
1.1. 
Primary Objective ........................................................................................................... 1 
1.2. 
Secondary Objectives...................................................................................................... 1 
2.0 
BACKGROUND AND RATIONALE ............................................................................... 2 
2.1. 
Background ..................................................................................................................... 2 
2.2. 
Rationale ......................................................................................................................... 3 
3.0 
RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND STUDY ENROLLMENT
 
7 
3.1. 
Inclusion Criteria ............................................................................................................ 7 
3.2. 
Exclusion Criteria ........................................................................................................... 8 
3.3. 
Research Participant Recruitment and Screening ........................................................... 9 
3.4. 
Enrollment on Study at St. Jude ...................................................................................... 9 
3.5. 
Procedures for Identifying and Randomizing Research Participants ........................... 10 
4.0 
DESIGN AND METHODS .............................................................................................. 10 
4.1. 
Design and Study Overview ......................................................................................... 10 
4.2. 
Study Procedures / Intervention: ................................................................................... 12 
4.3. 
Study Procedures: ......................................................................................................... 13 
4.4. 
Intervention ................................................................................................................... 17 
5.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ................................. 18 
5.1. 
Pre-Study Evaluations ................................................................................................... 18 
5.2. 
Evaluations During Study ............................................................................................. 18 
6.0 
CRITERIA FOR REMOVAL FROM PROTOCOL ........................................................ 20 
6.1. 
Off Study Criteria ......................................................................................................... 20 
7.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ......................... 20 
7.1. 
Reporting Adverse Experiences and Deaths to St. Jude IRB ....................................... 20 
8.0 
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY............ 24 
8.1. 
Data Collection ............................................................................................................. 24 
8.2. 
Study Monitoring .......................................................................................................... 24 
8.3. 
Confidentiality .............................................................................................................. 24 
9.0 
STATISTICAL CONSIDERATIONS.............................................................................. 25 
9.1. 
Summary of Primary and Secondary Objectives .......................................................... 25 
10.0 
OBTAINING INFORMED CONSENT ........................................................................... 27 
10.1. Informed Consent Prior to Research Interventions ....................................................... 27 
11.0 
REFERENCES ................................................................................................................. 28 
 
 
 
 
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1.0 OBJECTIVES 
 
1.1. Primary Objective 
To examine the efficacy of an eHealth intervention for improving symptoms of 
insomnia among adult survivors of childhood cancer. 
 
Hypothesis 1.1.a.: Survivors randomized to an eHealth CBTi intervention will 
report significantly fewer symptoms of insomnia post-intervention compared to 
survivors randomized to online patient education only. 
 
1.2. Secondary Objectives  
 To examine the impact of an eHealth intervention for insomnia on 
the clinical severity of insomnia symptoms in adult survivors of 
childhood cancer. 
 
Hypothesis 1.2.1.: A larger proportion of survivors randomized to the CBTi 
intervention will no longer meet clinical criteria for insomnia post-
intervention compared to survivors randomized to online patient education. 
 
 To determine whether treatment of insomnia symptoms will improve 
neurocognitive function in adult survivors of childhood cancer with 
both insomnia and neurocognitive impairment. 
 
Hypothesis 1.2.2.a: Survivors randomized to an eHealth CBTi intervention 
will report significantly fewer symptoms of neurocognitive impairment post-
intervention compared to survivors randomized to online patient education 
only. 
 
Hypothesis 1.2.2.b.: Improvement in insomnia symptoms will mediate the 
association between intervention status (CBTi vs. online patient education) 
and improved neurocognitive function post-intervention. 
 
Hypothesis 1.2.2.c.: Symptoms of emotional distress and cardiac health will 
be associated with improved insomnia symptoms and neurocognitive 
function. 
 
 To explore the mediating effects of improved neurocognitive 
function, emotional distress, and cardiovascular health on the 
association between insomnia symptoms and quality of life. 
 
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Hypothesis 1.2.3.a.: Survivors with improved insomnia symptoms following 
completion of an eHealth CBTi intervention will report better health-related 
quality of life compared to survivors without improved insomnia symptoms. 
 
Hypothesis 1.2.3.b.: Neurocognitive function, symptoms of emotional 
distress, and biomarkers of cardiovascular health following completion of 
the eHealth CBTi intervention will mediate the association between 
improved insomnia symptoms and quality of life 6-months post-
intervention. 
2.0 BACKGROUND AND RATIONALE 
2.1. Background 
Childhood Cancer Survivors Are a Growing Population with a High 
Burden of Morbidity - More than 80% of children diagnosed with a new cancer 
now survive five years, with most becoming long-term survivors.1 This has 
resulted in a growing population of childhood cancer survivors, estimated to 
approach half a million by 2020.2 Unfortunately, curative treatments also result 
in toxicities that leave many survivors with substantial burden of adverse 
physical and mental health outcomes.3 Morbidities commonly observed after 
cancer treatment include fatigue and sleep disturbance, neurocognitive 
impairment, emotional distress, cardiovascular disease, and diminished quality 
of life (QoL).  
 
Defined as difficulty initiating or maintaining sleep, or nonrestorative sleep 
resulting in decreased daytime function4, insomnia is the most commonly 
reported sleep disturbance among adults. In the general population, rates of 
insomnia range from 10 to 15%, with higher prevalence observed among women 
than men.5 Insomnia also impacts a substantial proportion of childhood cancer 
survivors.  A recent report indicated that 28% of adult survivors of childhood 
cancer (excluding CNS tumor survivors) experience symptoms severe enough 
to warrant active treatment for insomnia.6 Compared to siblings, adult survivors 
of childhood cancer are significantly more likely to report poor sleep efficiency 
(PR=1.3; 95% CI, 1.-1.5), with one-third reporting delayed onset and less than 
7 hours of sleep per night. Notably, sleep disturbances following treatment for 
childhood cancer are often present in adolescence and likely persist for decades 
into adult survivorship. It has been recently reported that approximately two-
thirds of adolescent survivors of acute lymphoblastic leukemia (ALL) 
experience delayed sleep onset and 30-40% had frequent nighttime and 
premature awakenings.7 Insomnia has been associated with many of the late 
health complications observed in survivors of childhood cancer, including 
neurocognitive impairment, emotional distress, and cardiovascular disease. 
Because adult survivors of childhood cancer have been exposed to neurotoxic 
and 
cardiotoxic 
chemotherapies 
and 
radiation, 
their 
compromised 
cardiovascular and neurologic systems may be more sensitive to the effects of 
insomnia on neurocognitive and cardiac functions. Thus, there is not only a need 
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for a widely available therapy to treat insomnia, but there is also a need to 
understand how improved insomnia symptoms impact neurocognitive function 
and late health morbidities in childhood cancer survivors. 
2.2. Rationale 
Insomnia and Neurocognitive Morbidity 
In non-cancer populations, insomnia has been associated with impaired 
cognitive performance, particularly in the domains of attention, memory, and 
executive function.8 A recent meta-analysis revealed moderate effects sizes for 
the impact of insomnia on episodic memory (ES = -0.51), problem solving (-
0.42), and working memory (ES = -0.42).9 Working memory impairment has 
been observed on direct performance-based measures as well as through 
assessment of neural function via integrity of the hippocampus in adults with 
insomnia.(10-11) Insomnia also has been associated with dementia in the general 
population(12-14) and emerging evidence suggests that adult survivors of 
childhood cancer may experience accelerated cognitive aging. Using data from 
the Childhood Cancer Survivor Study (CCSS), we demonstrated that among 
adult survivors (n=1,426), after adjustment for neurotoxic therapies [e.g., cranial 
radiation], poor sleep quality is associated with impaired task efficiency 
(RR=1.23, 1.01-1.49) and memory (RR=1.45, 1.19-1.76); daytime sleepiness is 
associated with emotional regulation problems (RR=1.38, 1.14-1.67), 
diminished organization (RR=1.80, 1.31-2.48), and impaired memory 
(RR=2.05, 1.63-2.58).15 There are no data to suggest that neurocognitive deficits 
precede the onset of insomnia symptoms; however, sleep distribution has been 
shown to exacerbate neurocognitive deficits. 
 
Insomnia and Psychiatric Morbidity 
Insomnia is highly comorbid with a range of psychiatric disorders. Comorbidity 
estimates range between 30% and 50% with depression and anxiety being 
among the most highly comorbid conditions.16-18 Though temporal relations are 
difficult to confirm, insomnia has repeatedly been shown to be a clinical 
predictor of subsequent depression.19 Recent path analyses suggest that sleep 
problems cause significantly more dysphoria than dysphoria causes sleep 
problems.20 Among survivors enrolled in the CCSS, we have shown that 
survivors with elevated depressive symptoms are four times more likely to report 
disrupted sleep, including symptoms of insomnia (OR, 4.4; 95% CI, 3.1 to 6.3).21 
 
Insomnia and Cardiovascular Morbidity and Mortality 
In the general population, insomnia is associated with cardiovascular disease, 
including risk of myocardial infarction, coronary heart disease, and stroke as 
well as increased risk of cardiopulmonary mortality.22, 23 Furthermore, chronic 
insomnia has been shown to be an independent risk factor for new onset 
hypertension, even when controlling for other risk factors including smoking, 
alcohol consumption, depression, race, diabetes, and obesity.24 Elevated resting 
heart rate, lower heart rate variability,25 and poorer cardiorespiratory fitness26 
have been observed among adults with insomnia. Insomnia also has been 
associated with dyslipidemia and hypercholesterolemia.27 In a recent meta-
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analysis, sleep disturbance was significantly associated with increased 
inflammation (i.e. levels of C-reactive protein [CRP] and interleukin-6 [IL-6]).28 
Among survivors of ALL we have demonstrated associations between 
symptoms of insomnia and worse neurocognitive function as well as higher 
levels of IL-6, IL-1β, and high sensitivity CRP and worse performance on 
measures of executive function and processing speed.7 These data suggest a link 
between sleep, systemic inflammation, and neurocognitive function in survivors. 
Moreover, in survivors of childhood cancer, systemic inflammation has been 
implicated as promoting development of cardiovascular disease.29, 30 Because 
symptoms of insomnia are often present many years before the onset of cardiac 
disease in survivors of childhood cancer, we hypothesize that these symptoms 
temporally precede cardiovascular morbidity observed in adult survivors. 
 
Treatment of Insomnia 
Given the significant mental and physical health burden of insomnia, effective 
treatment is critical. Cognitive behavioral therapy for insomnia (CBTi) has 
become the benchmark for treatment and incorporates three key strategies for 
improving sleep: sleep restriction, stimulus control, and cognitive restructuring. 
A recent meta-analysis of CBTi in adults with insomnia found it produced 
moderate to large effect sizes in improved sleep, improvements which lasted up 
to 18 months.31 An additional study in cancer survivors found CBTi performed 
better than a pharmacologic intervention in treating insomnia and improving 
fatigue.32 
 
Although studies are limited, there is emerging evidence that treatment of 
insomnia with CBTi can lead to improved emotional distress and physical health 
outcomes in non-cancer samples with chronic health care needs.33-36 In addition, 
successful treatment of insomnia has been shown to reduce biomarkers of 
inflammation associated with cardiovascular risk.37, 38 However, no study has 
examined the impact of a CBTi intervention on insomnia symptoms in long-term 
adult survivors of childhood cancer, nor has any study examined the impact of 
improved insomnia symptoms on neurocognitive function or late health 
morbidities in childhood cancer survivors. Despite established efficacy, 
traditionally delivered CBT (i.e. face-to-face psychotherapy) is often 
underutilized due to limited access to trained professionals, cost, stigma 
associated with mental health treatment, and time constraints. These barriers are 
even more pronounced in cancer survivors who report limited health care access 
and utilization due to lack of insurance and poor physical health.39 In fact, mental 
health care services are significantly underutilized by survivors of adolescent 
and adult onset cancers.40-43 To reduce access barriers and promote participation 
in CBTi (i.e., treatment uptake), alternative delivery models have been 
developed. One such approach is electronic health delivery or internet-based 
CBTi. A recent systematic review and meta-analysis of 15 internet-based CBTi 
studies reported improvements in sleep efficiency and total sleep time as well as 
reductions in insomnia severity and depressive symptoms. Moreover, no 
differences were observed between internet-delivered versus in-person therapy 
with a trained therapist.44 The internet-delivered insomnia intervention for the 
proposed study, Sleep Healthy Using the Internet (SHUTi), was initially studied 
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in a randomized controlled trial including 44 adults with primary insomnia who 
were randomly assigned to either the internet intervention or wait-list control 
group. Sleep diary data showed significant improvements for SHUTi users in 
sleep efficiency (SE), nighttime awakenings (number and time spent awake), 
and total sleep time; whereas the control group showed no significant changes. 
SHUTi participants also showed clinical improvement in insomnia severity, 
where 73% of SHUTi users fell in the “no insomnia” category after treatment; 
no control participants met this criterion. In addition, although SHUTi was not 
specifically designed to target comorbid symptoms, significant improvements 
were found in mood (e.g., depressive and anxious affect), physical symptoms 
(e.g., fatigue), and QoL.45 More recently, a national trial of SHUTi with 303 
adults with chronic insomnia, including those with psychological comorbidities 
provided further evidence that SHUTi users exhibit greater improvements in 
insomnia severity, sleep onset latency (SOL), and wake after sleep onset 
(WASO) than users of a Patient Education website (Figure 1).46 In sum, internet-
delivered CBTi has been accepted as an established, efficacious treatment for 
insomnia in adults. However, because sleep disturbances in adult survivors of 
childhood cancer may have persisted for many years, if not decades, we aim to 
evaluate the efficacy of an eHealth CBTi program to improve insomnia in this 
population.  
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Theoretical Model 
It has been established that childhood cancer and its treatment may result in 
symptoms of insomnia, neurocognitive impairment, emotional distress, and 
cardiovascular risks (Figure 2), and that these factors contribute to survivor QoL. 
We propose that insomnia may have an overarching impact on neurocognition, 
emotional distress, and cardiovascular health, consistent with observations from 
the general population, but that this impact may be particularly salient in 
survivors with compromised neurologic and cardiovascular systems related to 
prior cancer therapy. Using this model, we propose that insomnia may serve to 
exacerbate or maintain neurocognitive impairment, emotional distress, and 
cardiovascular risks in long-term survivors of childhood cancer, and that 
improved insomnia may serve to improve these late effects, ultimately 
improving survivor QoL. We recognize the potential for bidirectional influences 
among variables; however, based on past literature and the temporal 
developmental of late effects in 
childhood cancer survivors we propose 
to test our a priori hypothesized 
theoretical model. 
 
Barriers to Progress 
Three major factors have limited 
progress in identifying efficacious 
interventions 
for 
neurocognitive 
impairment in adult survivors of 
childhood cancer: (1) limited large 
cohorts of adult survivors of childhood 
cancer; (2) hurdles associated with 
commonly considered interventions; 
and (3) lack of consideration of 
comorbid health conditions. Limited 
research has focused on developing 
interventions for improving late effects 
in cancer survivors. There are few 
childhood cancer centers that follow survivors into their adult years and even 
fewer have the infrastructure to support large intervention trials. The Childhood 
Cancer Survivor Study (CCSS) provides a unique opportunity for such 
interventions, as it consists of >24,000 five-year survivors of childhood cancer 
who were diagnosed between 1970-1999 at one of 31 participating centers in the 
U.S. and Canada. Availability of treatment options for a geographically diverse 
cohort (i.e. survivors relocate with age) have also been a barrier. Cancer 
survivors may be less likely to engage in face-to-face CBTi for several reasons 
including poor physical health, lack of health insurance, stigma, and restricted 
access to the physical environment secondary to chronic disease. Internet 
delivery of CBTi will eliminate many of the physical and emotional barriers 
associated with mental health treatment for survivors. Specifically, survivors 
will be able to independently complete CBTi at home thereby facilitating access 
to and uptake of treatment for insomnia. Finally, prior research examining late-
effects has focused on the direct impact from cancer and cancer therapies. For 
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survivors, these treatment-related risk factors are no longer modifiable. As such, 
interventions have included direct attempts at improving neurocognitive 
function through cognitive stimulation, or adaptive approaches that teach 
survivors to compensate for their deficits. Cognitive training is intended to 
strengthen neural networks through repeated co-activation, with the goal of 
improving efficiency;47 however, our pilot data suggest limited efficacy in 
isolation. Most cognitive interventions are limited by problems of feasibility (i.e. 
high dropout rates, limited disseminability) and resource requirements (i.e. time 
intensive, on-site supervision). Similarly, interventions for depression, anxiety, 
and cardiovascular health have focused on treating specific symptoms (e.g. 
antidepressants for depression, stimulants for fatigue, antihypertensive 
medication for high blood pressure), without consideration of possible comorbid 
conditions that may exacerbate or serve to maintain symptoms. Moreover, these 
pharmacologic approaches place survivors at-risk for adverse drug side effects 
as well as potential drug-drug interactions. This study will address each of these 
barriers by focusing on a large nationally representative cohort of adult survivors 
of childhood cancer, providing an accessible intervention, and considering a 
behaviorally modifiable health condition (insomnia). 
 
3.0 RESEARCH PARTICIPANT ELIGIBILITY CRITERIA AND 
STUDY ENROLLMENT 
 
According to institutional and NIH policy, the study will accession research 
participants regardless of gender and ethnic background.  Institutional 
experience confirms broad representation in this regard. 
 
3.1. Inclusion Criteria  
 Enrollment in CCSS 
 
 Between the ages of 18 and 65 years old 
 
 Meeting at least one of the following three insomnia criteria: 
 
3.1.3.1 Clinically significant insomnia (i.e. score ≥8 on the Insomnia 
Severity Index) 
3.1.3.2 Delayed sleep onset latency (SOL) (i.e. cannot get to sleep 
within 30 minutes, three or more times a week) 
3.1.3.3 Excessive wake after sleep onset (WASO) (i.e. nighttime 
awakenings lasting a total of at least 30 minutes, three or 
more times per week) 
 
 Neurocognitive impairment (i.e. score >84th %ile of sibling 
normative data in at least one domain on the CCSS-NCQ) 
 
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 Regular access to the internet (at least 2-3 days per week) 
 
 Access to a desktop computer or a laptop  
 
 Access to a smart phone (android or iPhone), tablet or iPad with 
Bluetooth Low Energy BLE 4.2 or higher. 
 
 
 Ability to read and speak English 
 
3.2. Exclusion Criteria  
 
 History of a brain tumor 
 
 An irregular schedule that would prevent adoption of intervention 
strategies (i.e. work schedule resulting in usual bedtime earlier than 8 
PM or later than 2 AM or arising time earlier than 4 AM or later than 
10 AM) 
 
 Currently pregnant or breast feeding 
 
 Behavioral treatment for insomnia in the past 12 months 
 
 Diagnosis of a schizophrenia or psychotic disorder 
 
 Alcohol or drug abuse in past year 
 
3.2.6.1. Per exclusion criteria 3.2.6., The Alcohol Use Disorders 
Identification Test (AUDIT) will be used to screen for 
individuals who have active alcohol use disorders and the Drug 
Abuse Screen Test (DAST-10) will be used to screen for 
individuals with drug abuse. Both questionnaires include 10 
items and are well-validated. 
 
 Other 
concurrent 
sleep 
disorders, 
including 
narcolepsy, 
obstructive/central sleep apnea, or restless leg syndrome 
 
 Current treatment or intervention for cognitive impairment (i.e. 
stimulant medication, transcranial direct current stimulation) 
 
 
 
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3.3.  Research Participant Recruitment and Screening 
Recruitment will be conducted by 
the CCSS Coordinating Center at 
St. Jude. As illustrated in Figure 3 
to the right, survivors 
participating in CCSS who have 
been previously identified as 
having neurocognitive 
impairment in at least one of 
three domains in the NCQ48 will 
be approached for recruitment. 
An approach packet consisting of 
an introduction letter, a single 
page study brochure, and 
informed consent documents will 
be mailed to these potentially 
eligible participants. Interested 
participants will be instructed to 
visit the study webpage, where 
participants can sign-up and 
provide informed consent on-line. 
Those who have not responded 
after two weeks will receive an 
email alerting them to the study 
and providing a link to the study webpage. Starting three weeks after the initial 
mailing, a trained study interviewer housed within the CCSS Call Center will 
begin calling non-responders to provide information, answer questions, and 
encourage participation. Eligible participants will have the opportunity to 
consent to the study verbally while speaking with a trained study interviewer 
from the CCSS Call Center. Alternatively, survivors who wish to participate 
will complete an online consent form and then a series of short questionnaires 
to determine study eligibility. This data collection will take place in DatStat 
Connect, which is the online consenting and data collection tool utilized for the 
CCSS.  To date, there are 11,579 non-CNS tumor survivors who were 
previously administered the CCSS-NCQ. Based on those surveys, 4,465 were 
impaired and, conservatively we estimate that 30% of these will have 
comorbid symptoms of insomnia (n=1,339). We anticipate enrolling 52 
participants in year 1 and 100 participants per year in years 2-4, each year 
divided equally by sex.  
 
3.4. Enrollment on Study at St. Jude 
A member of the CCSS study team will create an initial list of potentially eligible 
participants and will send letters/emails containing the information for the study 
website through which consent will be obtained followed by additional 
eligibility questions that cannot be obtained prior to consent by the study team.  
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This will confirm participant eligibility as defined in Section 3.1-3.2 (similar to 
eligibility criteria being confirmed after consent on traditional St. Jude studies).  
Once eligibility is confirmed, the post eligibility questionnaires and assessments 
will be administered and scheduled. The website will provide safeguards to 
ensure that additional assessments and questionnaires cannot be obtained until 
eligibility is confirmed. CCSS team members will monitor this process 
 
3.5. Procedures for Identifying and Randomizing Research Participants  
Prior to initiating the study, team members will be trained on the protocol and 
study procedures. The background to the study, study procedures, consent 
processes for the online or the verbal consent, data transfer, and plans to monitor 
intervention integrity and data quality will be part of the training.  
 
Following the study preparation, initial screening for eligibility, consent and 
additional eligibility verification for the research participants will begin. Once 
consented and eligibility is confirmed, participants will be randomized using a 
permuted-block method with random block sizes, stratified on sex, age (<40 vs. 
>40), and cranial radiation therapy (Y/N). Following randomization, 
participants will complete the remote cognitive assessment, will provide a blood 
sample using the Dried Blood Spot (DBS) method and wear a WHOOP wrist 
monitor for 7 to 11consecutive days. Following the remote evaluation, they will 
receive a direct link to access the SHUTi program or online patient education 
(per randomization). 
4.0 DESIGN AND METHODS 
 
4.1. Design and Study Overview 
This is a randomized controlled trial looking to evaluate the efficacy of an 
internet-based cognitive behavioral therapy intervention (SHUTi) on insomnia 
and other highly prevalent late effects of childhood cancer: neurocognitive 
impairment, emotional distress, cardiovascular risk factors, and quality of life 
(compared to an online patient education control group). Once consented, 
participants will be asked to complete the baseline remote evaluation portion of 
the study. Participants will complete a remote cognitive assessment (CNS Vital 
Signs) wear a WHOOP wrist monitor and will provide a blood sample using 
Dried Blood Spot (DBS) method. Questionnaires and the SHUTi program will 
be completed via the RICE platform hosted by the University of Virginia. The 
post-intervention remote evaluation will occur approximately 10 weeks after 
baseline. The final remote evaluation will occur approximately 6 months post 
intervention. The study schema is illustrated in Figure 4.  
 
 
 
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Figure 4. Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCSS Participants age 18-65 
previously identified as having 
neurocognitive impairment 
Screening/Consent via DatStat Connect, 
or Consent verbally while speaking with 
a trained survey interviewer 
RANDOMIZE 
Sleep Healthy Using the Internet 
(SHUTi) Intervention Group 
Online Patient Education (PE) Control 
Group 
9 Week Intervention Period 
Post-Intervention Remote Evaluation 
Baseline Remote Evaluation  
6 Month Post Intervention Remote 
Evaluation  
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4.2. Study Procedures / Intervention:  
 
 The eHealth Data Using the RICE Platform: 
 
 
Participants will complete the post enrollment questionnaires and the assigned 
intervention arm (SHUTi or patient education) using the RICE (Research 
Infrastructure Containing E-interventions) framework developed by the 
University of Virginia (Dr. Lee Ritterband, Co-Investigator).   
 
RICE includes two core elements: Electronic Study Manager (ESM) and 
Content Management System (CMS), which plays a central role in intervention 
development. The first core element, the ESM, provides a range of research 
study management tools. ESM controls the delivery, access and timing of the 
study data capture for all research participants, including interested and 
consenting candidates as well as experimental, control, and wait-list 
participants. Typically, the research study includes an interest website 
(providing information about the study), online interest and consent forms (to be 
completed online by those interested in being considered for participation), 
online study assessment forms, and dynamically generated email notifications 
and reminders. It contains a field-tested toolset that includes integrated 
components used to define and manage the unique study workflow, online 
interest and consent forms, assessment criteria for purposes of eligibility, and 
participant progress. 
 
The optional second core element, the CMS, uses the ESM toolset and the 
optional Module Builder to deliver a web-based intervention program. 
Intervention content may include text, images, video files, audio files, quizzes 
and custom responses, interactive elements, tailored feedback, and other custom 
programming. CMS is fully integrated with ESM, providing the System 
Administrator with the flexibility to also control the presentation, delivery, 
access, and timing of the intervention content. 
 
The RICE framework contains five primary core components: (1) Flow Builder: 
Used to define the unique combination of procedural and temporal logic that 
determines the paths by which the assessment and online intervention content 
are presented to the user; (2) Questionnaire Builder: Web-based tool for creating 
questionnaires composed of data capture fields, including integers, text, 
checkbox, dropdown, images, or electronic signatures, as part of the 
participant’s online experience. Questionnaires may be used during the 
assessment process, online interest capture, diary collection, and intervention 
follow-ups; (3) Automated E-mailer: Sends out e-mails based on study flow 
logic, with a web-based authoring system for creating the e-mail prompts that 
are sent given developed triggers in the intervention; (4) Module Builder 
(Optional): Authoring tool that brings together the text, images, animations, 
video, audio, and interactive elements that compose an intervention. Modules 
each contain presentation layouts, decoupling the task of content presentation 
from the task of entering and updating study content, resulting in the rapid 
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prototyping of modules; and (5) Administrative System: Centralized tool that 
allows study administrators, regardless of location, to track study progress, 
manage subject accounts and view complete communications audit trail. More 
specifically, this administrative and semi-automated system allows us to track 
participants, including storing all contact information, interview data, 
participant’s current position in the study and intervention, a calendar of events 
that are automatically established for each subject once recruited, tracking of all 
contacts with participants, a robust reporting system providing details about 
which participants need to be contacted for what, on-the-fly reporting of critical 
study parameters (number of recruited subjects, number of participants in each 
condition, completers, drop-outs, etc.), payments, and notes. 
 
The only patient specific information that will be entered in the RICE platform 
includes participant email addresses (necessary for communication and delivery 
of the intervention) and time zones (necessary for data collection purposes). 
 
4.3. Study Procedures: 
Assessment of Sleep  
 
1) Insomnia Severity Index (ISI) is a 7-item, Likert scale, self-report 
questionnaire assessing perception of sleep and consequences of insomnia. The 
ISI has had extensive validity and reliability testing, including for electronic 
delivery and for use in evaluating treatment response. Cronbach α for internal 
consistency is 0.90, convergent validity with measures of fatigue, quality of life, 
anxiety and depression have been reported.50, 51 The scores range from 0 (no 
insomnia) to 28 (severe insomnia); scores < 7 are considered “no clinically 
significant insomnia”. The ISI will be administered at baseline, post-
intervention, and 6-month follow-up.  
 
2) Sleep Diary will be an online diary and will be included in the SHUTi 
program (including the patient education arm). Each diary entry contains 10 
standard sleep questions including bedtime, sleep onset latency, number of 
awakenings, total length of awakenings, wake time, arising time, daytime naps, 
rating of soundness of previous night’s sleep, rating of refreshed feeling upon 
morning awakening and inquiry about sleep aids (over the counter 
medication/alcohol). In addition to the 10 pre-assessment entries required before 
the intervention begins, participants are encouraged to complete the diary daily, 
but entries that are up to 3 days old will be accepted. Sleep diary data will 
generate data on sleep onset latency (SOL), wake after sleep onset (WASO), 
sleep efficiency (SE) and number of awakenings. Data from the sleep diaries 
will be correlated with actigraphy data. 
 
3) Actigraphy will be collected to measure sleep-patterns of each participant. A 
WHOOP wrist monitor to be worn over 7 to 11 consecutive days at three 
specified intervals [baseline, post-intervention, 6 months]. Actigraphy provides 
objective assessment of wrist movement that infers wakefulness and sleep. 
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Functionally, the WHOOP devices provide sleep-pattern measures including: 
SOL, WASO, SE, and total sleep time (TST). Movement triggering the device 
is relatively high during wakefulness and decreases to near-zero values during 
sleep. Analysis of actigraphic records reveals sleep-wake patterns that correlate 
closely with patterns obtained via polysomnographic recordings and behavioral 
observations.52-59 Furthermore, actigraphy is a reliable method for assessing 
sleep-wake patterns and monitoring of treatment response among insomnia 
patients.59,60 Actigraphy is able to sensitively capture change in sleep-wake 
patterns before and after behavioral or medical interventions, and actigraphic 
data from either wrist is highly similar. The mailing of the WHOOP wrist 
monitors will be coordinated by study personnel at St. Jude in collaboration with 
the CCSS coordinating center. Participants will receive a WHOOP wrist monitor 
along with a pre-paid return package. A WHOOP wrist monitor will be mailed 
at baseline and maintained by the participant until the 6-month follow-up. 
Participants will download the WHOOP app to their device (smart phone or 
tablet/iPad with BLE 4.2 or higher) so they can remotely upload their data to a 
secure cloud-based platform hosted by WHOOP and securely accessible by the 
study team at St. Jude.  
 
4) Questionnaires to measure fatigue and daytime sleepiness will be completed 
via the RICE Platform at baseline, post-intervention, and 6-month follow-up.  
These questionnaires will assess the functional symptoms of insomnia using the 
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) 
and Epworth Sleepiness Scale (ESS). 
 
Neurocognitive Functioning 
 
1) The Childhood Cancer Neurocognitive Questionnaire (CCSS-NCQ)61 is a 32 
item self-report questionnaire evaluating 4 domains (8 questions per domain) of 
neurocognitive function: (1) memory; (2) task efficiency; (3) organization; (4) 
emotional regulation. The CCSSNCQ was developed specifically to address 
neurocognitive concerns of adult survivors of childhood cancer. It has been 
administered to over 12,000 non-brain tumor survivors within the CCSS 
cohort,48 and age- and sex-adjusted normative data are available from over 3,000 
siblings of childhood cancer survivors. Extensive psychometric analysis of the 
CCSS-NCQ has been conducted, with the most recent involving Item Response 
Theory analysis and validation with traditional neuropsychological testing.62 
The CCSS-NCQ will be used to screen participants for eligibility. For this study 
we will not utilize organization as an outcome because in our previous studies 
this domain has been shown to be less sensitive in detecting neurocognitive 
impairment. This questionnaire will be completed at baseline, post-intervention, 
and 6-month follow-up via the RICE Platform. 
 
2) We will obtain a direct measure of cognitive function among participants 
using a remotely administered assessment (CNS Vital Signs). This remote 
assessment is completed using a desktop computer or laptop, and is self-
administered. This assessment presents minimal risk to participants and 
enables them to complete the evaluation from their home. The CNS Vital Signs 
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instrument provides written instructions to the participant before beginning of 
each test. The tests evaluate cognition through evaluation of memory, 
attention, non-verbal reasoning, processing speed and reaction time The 
cognitive assessment will include the following tests: Verbal Memory (VBM), 
Visual Memory (VIM), Finger Tapping (FT), Symbol Digital Coding (SDC), 
Stroop Test (ST), Shifting Attention (SAT) Continuous Performance (CPT). 
The total administration time is approximately 25-30 minutes.   
 
 
Emotional Distress 
 
Symptoms of emotional distress will be assessed using the Patient Health 
Questionnaire – 9 (PHQ-9) for depression and the Generalized Anxiety Disorder 
– 7 (GAD-7). The PHQ-9 is designed for the screening and monitoring of 
depressive symptoms as well as for the presence and duration of suicide ideation. 
The PHQ-9 provides cut-off scores for mild, moderate, moderately severe, and 
severe depression. PHQ-9 scores >10 have sensitivity of 88% and specificity of 
88% for major depression. The GAD-7 is designed for the screening and 
monitoring of anxiety symptoms. Cut-off scores are provided for mild, 
moderate, and severe anxiety. Using the threshold score of 10, the GAD-7 has a 
sensitivity of 89% and a specificity of 82% for generalized anxiety disorder. 
These questionnaires have undergone reliability and validity testing across 
individuals with range of health conditions and demographic characteristics. The 
PHQ-9 and GAD-7 will be administered at baseline, post-intervention, and 6-
month follow-up via the RICE Platform.  
 
Cardiovascular Health Indices 
 
1) Using the Dried Blood Spot (DBS) method, blood will be collected to 
measure: 
a. serum biomarkers of inflammation: interleukin [IL] IL 6, high 
sensitivity C reactive protein [hsCRP] 
b. oxidative stress: myeloperoxidase 
c. lipid profile: triglycerides, total Cholesterol, HDL Cholesterol 
 
We will mail the participants a Dried Blood Spot (DBS) Kit, including written 
directions and a link to a video that explains the procedure in detail 
[https://bcove.video/2LIxHIr]. Participants will collect about six drops of blood by 
pricking their finger. The 6 blood drops usually required to fill a specimen card 
are equal to a total blood volume of about ¼ teaspoon and the collection of a 
dried blood spot sample usually takes about 10 minutes. The samples will be 
shipped to St. Jude Children’s Hospital, where they will be stored until the end 
of the study. At the end of the study, the Dried Blood Spot (DBS) cards will be 
shipped to the University of Washington for analysis. All samples will be 
assayed in duplicate and the average of the two measures will be used for data 
analyses. All samples from individual participants will be run on the same assay 
plate to reduce intra-assay variation. Serum biomarkers will be measured at 
baseline, post-intervention, and 6-month follow-up. 
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2) Resting Heart Rate (RHR) and Heart Rate Variability (HRV) will be 
measured by having participants wear the WHOOP wrist monitor. We will use 
a time domain measure of heart rate variability (HRV), a non-invasive, albeit 
indirect way to investigate autonomic nervous system function. It is attractive 
in this large cohort study, with participants distributed around North America, 
because today’s sensor technology allows remote collection of data in 
participants usual environments while doing their usual activities.  We will use 
the WHOOP® strap wearable biosensor to obtain standard deviation of NN 
(normal to normal RR) intervals (SDNN) measured over a 24-hour period and 
recorded in milliseconds (ms). SDNN captures total HRV; low values over a 
24-hour period indicate lack of circadian rhythm. We selected this measure as 
our primary outcome because of its documented associations with morbidity 
and mortality in several large studies. Data from the Framingham Heart Study 
(N=2501) indicate that a one standard deviation decrement in the SDNN (log 
transformed), captured remotely over 2 hours, is associated with a nearly 50% 
increased risk (HR 1.47, 95% CI 1.16-1.86) of new onset cardiac conditions, 
even after accounting for other known risk factors for autonomic dysfunction.  
In addition, among persons with congestive heart failure (UK-heart, N=433), 
in adjusted models, a 41.2ms decrement in SDNN, measured over 24-hours, 
was associated with a 1.62 (95% CI 1.16-2.44) increased risk for all-cause 
mortality, and the strongest predictor of death related to progressive heart 
failure.63  The WHOOP device includes a photoplethysmography-based heart 
rate/heart rate variability sensor, an accelerometer, and sensors to detect 
ambient temperature and galvanic skin response. For this study participants 
with 24-hour SDNN <50ms will be classified with unhealthy HRV, those with 
values 50-100ms with compromised HRV, and those with values >100ms with 
normal HRV. The participants will wear the WHOOP wrist monitor for a 
period of 7 to 11 consecutive days at three specified intervals [baseline, post-
intervention, 6 months]. The mailing of WHOOP wrist monitors will be 
coordinated by study personnel at St. Jude in collaboration with the CCSS 
coordinating center. Participants will receive a WHOOP wrist monitor along 
with a pre-paid return package. The WHOOP wrist monitor will be mailed to 
the participant at baseline and maintained by the participant for the duration of 
the study. Heart rate data will be uploaded by participants using their smart 
phone or tablet to a secure cloud-based platform hosted by WHOOP and 
securely accessible by the study team at St. Jude 
  
 
3) Physical Activity will be measured by having participants wear the WHOOP 
wrist monitor This device includes atri-axial accelerometer that detects wrist 
movement, which is used to collect objective information on intensity and 
duration of common locomotion activities such as walking and jogging. Physical 
activity of each participant will be measured with the WHOOP wrist monitor, 
which will be worn by the participant for 7 to 11 consecutive days at three 
specified intervals [baseline, post-intervention, 6 months] corresponding to the 
same period when sleep patterns are measured. 
 
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Quality of Life 
 
Health-related quality of life (HRQoL) will be assessed at baseline, post-
intervention, and 6-month follow-up. HRQoL will be measured with the 
PROMIS Global Health questionnaire. This is a widely used 10-item generic 
health profile that provides physical and mental health summary scores.64 The 
Global Health measure will be completed via the RICE Platform. 
 
Exploratory Outcomes 
 
In addition to quality of life we will evaluate, in an exploratory manner, the 
impact of improved insomnia symptoms on work and social adjustment 6-
months post intervention. The work productivity and activity impairment 
questionnaire (WPAI)65, 66 is a 6-item measure that assesses work-related 
impairment reflected by amount of absenteeism, presenteeism, and daily activity 
measures. This measure has good discriminatory and construct validity, as well 
as the ability to detect significant changes in symptoms. The work and social 
adjustment scale (WSAS)67 measures social and work-related impairment 
resulting from mental health problems. The internal consistency is high, with 
Cronbach’s α ranging from .70 to .94 and test-retest reliability is also good 
(r=0.73). The WPAI and WSAS will be completed by participants via the RICE 
Platform. 
4.4. Intervention 
Participants will receive a direct link to access the SHUTi program or online 
patient education (per randomization) from the study team. This will include 
login and password information. Through the RICE platform, St. Jude study 
staff will track and monitor participants who are randomized to SHUTi or patient 
online education. 
 
SHUTi 
SHUTi is a fully automated, interactive and tailored web-based program that 
incorporates the primary tenets of face-to-face CBT-I, including sleep 
restriction, stimulus control, cognitive restructuring, sleep hygiene, and relapse 
prevention. Intervention content is presented in six “Cores,” metered out over 
time. Each Core 
was developed to parallel traditional weekly sessions conducted when delivering 
CBT-I in a face-to-face format, following a similar general structure: 1) 
examination of Core objectives, 2) review and feedback on homework and sleep 
diary data from the previous week, 3) teaching of new intervention material, 4) 
summary of the main points of the Core, and 5) assignment of homework. The 
participant will have nine weeks to complete the six cores and at week 10 will 
be asked to complete post-intervention questionnaires/sleep diaries as well as to 
complete the post intervention remote evaluation. Data will be available on total 
number of participant logins, sleep diaries completed, and core modules 
completed. All participants will be able to access human support through UVA 
for technical difficulties with SHUTi. Intervention content is enhanced through 
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a variety of interactive features, including personalized goal-setting, graphical 
feedback based on reported symptoms, animations and illustrations to enrich 
comprehension, quizzes to test and enhance user knowledge, vignettes to 
promote identification with material, and video-based expert explanations. 
Weekly automated emails are also sent to increase engagement and encourage 
program adherence. However, no human support will be provided to increase 
treatment adherence. Removing human support from provision of care can 
vastly increase the ability to widely disseminate treatment, however, it may be 
associated with reduced adherence. Despite this, a recent study of SHUTi with 
breast cancer survivors indicated that intervention group participants completed 
4.1 (SD = 2.5) cores, with 82.1%, 75.1%, 67.2%, 64.2%, 62.7%, and 59.7% 
completing cores 1, 2, 3, 4, 5, and 6, respectively. The number of cores 
completed was associated with improvements in insomnia symptoms. 
Therefore, we will complete a sensitivity analysis to examine the impact of 
treatment adherence on insomnia symptoms. 
 
Online Patient Education (PE) Control Group 
The online PE program provides static information about: insomnia symptoms; 
the impact, prevalence, and causes of insomnia; when to see a doctor; and basic 
lifestyle, environmental, and behavioral strategies to improve sleep. The content 
for this program was informed based on a review of insomnia-focused websites 
at the time of development. In some areas, content between the PE and SHUTi 
web programs overlap; however, SHUTi differs from the PE website in 
important ways. In contrast to SHUTi, the PE website (1) does not personalize 
or individually tailor treatment recommendations based on user input; (2) 
presents content in a simple, static form, without interactive assessments; and 
(3) delivers content all at once, meaning the user can access full site content 
immediately, rather than having to wait for content to be metered, or unlocked, 
over time. The participant will have 9 weeks to review the patient education 
website and at week 10 will be asked to complete post-assessment 
questionnaires/sleep diaries and complete the remote evaluation for post 
intervention assessments. 
5.0 REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
5.1. Pre-Study Evaluations 
A recruitment mailing will be sent intermittently by the CCSS team to determine 
interest in the study. Screening questions must be completed online via DatStat 
to determine study eligibility.   
5.2. Evaluations During Study 
There are 3 assessment time points during the study: baseline (pre-intervention), 
post-intervention, and 6-month follow-up. At each time point, participants will 
complete a remote cognitive evaluation, give a blood sample using the dried 
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blood spot (DBS) method, wear a WHOOP wrist monitor for 7 to 11 consecutive 
days. Participants in the study will be asked to complete questionnaires and sleep 
diaries at each of these time points.  All assessments will be completed remotely 
and study materials (DBS kits, WHOOP wrist monitors, instruction guide, 
charging cables) will be mailed to the participant. Prior to mailing the equipment 
to the study participant, all equipment will be sanitized with a product from the 
list of Approved Disinfectants & Cleaners available on the COVID-19 
Disinfectant Guide.  The appropriate contact time specific to the disinfectant will 
be used.  We plan to use PDI Sani-Cloth® with a contact time of 2 minute but if 
unavailable only approved disinfectants and cleaners from the list provided by 
St. Jude will be used.  The sanitized equipment will be packed by a study team 
member wearing a mask and gloves. Packages will be sent via non-contact drop-
off. These measures will minimize exposure to other team members and ensure 
social-distancing guidelines are met for study staff. Upon return, the package 
with the equipment will sit for 24 hours before being opened.  The study team 
member will wear gloves and a mask when unpacking the box.  All equipment 
will be sanitized upon return using a product from the list of Approved 
Disinfectants & Cleaners available on the COVID-19 Disinfectant Guide. The 
appropriate contact time specific to the disinfectant will be used. 
 
REQUIRED EVALUATIONS & OBSERVATIONS 
 
Study Procedure 
Time Point 
Baseline 
Post-
Intervention 
6 Month 
Follow-Up 
Dried Blood Spot collection 
(DBS) 
X 
X 
X 
CNS Vital Signs remote 
cognitive assessment 
X 
X 
X 
Insomnia Severity Index (ISI) 
X 
X 
X 
Drug Abuse Screen Test (DAST-
10) 
X 
 
 
Alcohol Use Disorders 
Identification Test (AUDIT) 
X 
 
 
FACIT-Fatigue Questionnaire 
X 
X 
X 
Epworth Sleepiness Scale (ESS) 
X 
X 
X 
Childhood Cancer 
Neurocognitive Questionnaire 
(CCSS-NCQ) 
X 
X 
X 
Patient Health Questionnaire 
(PHQ-9) 
X 
X 
X 
Generalized Anxiety Disorder 
(GAD-7) 
X 
X 
X 
WHOOP wrist monitor  
X 
X 
X 
Health-related Quality of Life 
Questionnaire 
X 
X 
X 
PROMIS Global Health  
X 
X 
X 
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Sleep Diary 
X 
X 
X 
Work Productivity and Activity 
Impairment Questionnaire 
(WPAI) 
X 
X 
X 
Work and Social Adjustment 
Scale (WSAS) 
X 
X 
X 
6.0 CRITERIA FOR REMOVAL FROM PROTOCOL 
6.1. Off Study Criteria 
 
 All protocol interventions are complete 
 Death 
 Lost to follow-up 
 Request of the Patient/Parent 
 Discretion of the Study PI, such as the following  
• The researcher decides that continuing in the study would be 
harmful  
• The participant misses so many appointments that the data 
cannot be used in the study 
• The participant’s condition gets worse 
• New information is learned that the study is not in the 
participant’s best interest 
7.0 SAFETY AND ADVERSE EVENT REPORTING 
REQUIREMENTS 
7.1. Reporting Adverse Experiences and Deaths to St. Jude IRB 
 Only “unanticipated problems involving risks to participants or 
others” referred to hereafter as “unanticipated problems” are required 
to be reported to the St. Jude IRB promptly, but in no event later than 
10 working days after the investigator first learns of the unanticipated 
problem. Regardless of whether the event is internal or external (for 
example, an IND safety report by the sponsor pursuant to 21 CFR 
312.32), only adverse events that constitute unanticipated problems are 
reportable to the St. Jude IRB.  As further described in the definition 
of unanticipated problem, this includes any event that in the PI’s 
opinion was: 
 
• Unexpected (in terms of nature, severity, or frequency) given (1) the 
research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document, as well as other relevant information 
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available about the research; (2) the observed rate of occurrence 
(compared to a credible baseline for comparison); and (3) the 
characteristics of the subject population being studied; and 
 
• Related or possibly related to participation in the research; and 
 
• Serious; or if not serious suggests that the research places subjects or 
others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.  
 
Unrelated, expected deaths do not require reporting to the IRB.  Though death 
is “serious”, the event must meet the other two requirements of “related or 
possibly related” and “unexpected/unanticipated” to be considered reportable. 
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of 
the death.  
 The following definitions apply with respect to reporting adverse 
experiences:  
 
7.1.2.1. Serious Adverse Event: Any adverse event temporally 
associated with the subject’s participation in research that meets 
any of the following criteria: 
• results in death; 
• is life-threatening (places the subject at immediate risk of 
death from the event as it occurred); 
• requires inpatient hospitalization or prolongation of existing 
hospitalization; 
• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or 
• any other adverse event that, based upon appropriate medical 
judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other 
outcomes listed in this definition (examples of such events 
include:  any substantial disruption of the ability to conduct 
normal life functions, allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse), a congenital anomaly/birth defect, secondary or 
concurrent cancer, medication overdose, or is any medical 
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event which requires treatment to prevent any of the medical 
outcomes previously listed.   
7.1.2.2. Unexpected Adverse Event:  
• Any adverse event for which the specificity or severity is not 
consistent with the protocol-related documents, including the 
applicable investigator brochure, IRB approved consent form, 
Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) application, or other relevant sources of 
information, such as product labeling and package inserts; or 
if it does appear in such documents, an event in which the 
specificity, severity or duration is not consistent with the risk 
information included therein; or  
• The observed rate of occurrence is a clinically significant 
increase in the expected rate (based on a credible baseline rate 
for comparison); or  
• The occurrence is not consistent with the expected natural 
progression of any underlying disease, disorder, or condition 
of the subject(s) experiencing the adverse event and the 
subject’s predisposing risk factor profile for the adverse event.  
 
7.1.2.3. Internal Events: Events experienced by a research participant 
enrolled at a site under the jurisdiction of St. Jude IRB for either 
multicenter or single-center research projects. 
 
7.1.2.4. External Events: Events experienced by participants enrolled at 
a site external to the jurisdiction of the St. Jude Institutional 
Review Board (IRB) or in a study for which St. Jude is not the 
coordinating center or the IRB of record. 
 
7.1.2.5. Unanticipated Problem Involving Risks to Subjects or 
Others: An unanticipated problem involving risks to subjects or 
others is an event which was not expected to occur and which 
increases the degree of risk posed to research participants.  Such 
events, in general, meet all of the following criteria:  
• unexpected;  
• related or possibly related to participation in the research; and  
• suggests that the research places subjects or others at a greater 
risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. An 
unanticipated problem involving risk to subjects or others may 
exist even when actual harm does not occur to any participant.  
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 Consistent with FDA and OHRP guidance on reporting unanticipated 
problems and adverse events to IRBs, the St. Jude IRB does not require 
the submission of external events, for example IND safety reports, nor 
is a summary of such events/reports required; however, if an event 
giving rise to an IND safety or other external event report constitutes 
an “unanticipated problem involving risks to subjects or others” it must 
be reported in accordance with this policy.  In general, to be reportable 
external events need to have implications for the conduct of the study 
(for example, requiring a significant and usually safety-related change 
in the protocol and/or informed consent form). 
 
 Although some adverse events will qualify as unanticipated 
problems involving risks to subjects or others, some will not; and there 
may be other unanticipated problems that go beyond the definitions of 
serious and/or unexpected adverse events.  Examples of unanticipated 
problems involving risks to subjects or others include: 
 
• Improperly staging a participant’s tumor resulting in the participant 
being assigned to an incorrect arm of the research study; 
• The theft of a research computer containing confidential subject 
information (breach of confidentiality); and  
• The contamination of a study drug.  Unanticipated problems generally 
will warrant consideration of substantive changes in the research 
protocol or informed consent process/document or other corrective 
actions in order to protect the safety, welfare, or rights of subjects or 
others.  
 
 
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8.0 DATA COLLECTION, STUDY MONITORING, AND 
CONFIDENTIALITY 
8.1. Data Collection  
 
Data collection will be accomplished using online data collection tools DatStat 
Connect, WHOOP Platform, CNS Vital Signs and RICE.  DatStat Connect has 
been utilized by the CCSS for consenting and online data collection.  The 
RICE Platform includes capabilities for contacting participants, providing 
access to instructional and demonstration videos, collecting data and secure 
transmission of data to the study team. The RICE Platform allows for input 
constraints in the tools as well as real-time validation of data formats and 
ranges, providing real-time feedback to the user if “out-of-range” values are 
recorded. WHOOP Platform is a secure cloud-based platform hosted by 
WHOOP that will be used by participants to transmit heart rate data and 
activity/sleep data using an app on their smart phone or tablet, to the WHOOP 
cloud. CNS Vital Signs platform will be used to collect data for the remote 
cognitive assessments. Data will be downloaded and saved in a secure 
database. To protect the confidentiality of the participants, only participant ID 
and year of birth will be used and no PHI will be sent to the CNS Vital Signs 
for the remote cognitive assessment. 
8.2. Study Monitoring 
Lowest Risk:  
This study is considered lowest risk for monitoring purposes. The Principal 
Investigator (PI) and study team are responsible for ensuring protocol and 
regulatory compliance. The St. Jude monitoring group will not monitor this 
study.  The study team is responsible for data quality and will meet as needed to 
review case histories or quality summaries on participants and will generate 
minutes which are signed by the PI. 
 
Protocol continuing reviews by the Institutional Review Board (IRB) and 
Scientific Review Committee (CT-SRC) will occur at least annually.  In 
addition, Unanticipated Problems and/or Serious Adverse Event reports are 
reviewed by the IRB. 
8.3. Confidentiality 
Study numbers will be used in place of an identifier such as a medical record 
number. No research participant names will be included in the final data set. The 
list containing the study number and participant name will be included in a 
secure database only accessible to the St. Jude study team.    
 
The medical records of study participants may be reviewed by the St. Jude IRB, 
FDA, clinical research monitors, etc. 
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9.0 STATISTICAL CONSIDERATIONS 
 
Anticipated Primary Completion Date: January 1, 2022   
Anticipated Study Completion Date: July 1, 2023 
9.1. Summary of Primary and Secondary Objectives  
Statistical Analysis 
A randomized controlled design will be employed for the proposed study. We 
plan to enroll a total of 352 survivors (176 of each sex), and assuming 10% drop 
out by the post-intervention 9-week assessment, we will have a total of 320 
survivors (160 of each sex) remaining for evaluation. Balance of patient 
characteristics between study arms will be evaluated and if necessary, adjusted 
comparisons will be carried out. 
 
The primary endpoint of the study will be the ISI measure of insomnia severity 
represented as described above. The difference in score from baseline to post-
intervention (10 weeks) and baseline to 6 months post-intervention will be 
calculated and the mean of these differences compared between study arms 
using linear regression (adjusted for stratification factors). The primary time 
point of interest will be at 10 weeks, with a secondary endpoint evaluating 
maintenance at 6 months after intervention. Due to potential sex differences in 
insomnia and cognition, a priori we plan to carry out all analyses and report 
results separately by sex. Our study is not powered to detect meaningful 
interaction effects, but if we deem that the effects are reasonably comparable 
between sexes we will consider presenting combined analysis to increase 
precision of the estimate. Because this is a randomized trial we expect analyses 
to be simple and directed towards ascertaining controlled and generalizable 
intervention effects. The primary endpoint will be considered significant at the 
two-sided 0.05 level. Estimates of intervention effects (mean differences) will 
be presented along with associated confidence intervals and two-sided p-values.  
 
Because mean scores do not reflect the number of survivors who have clinically 
significant insomnia symptoms, secondary analyses of sleep will compare the 
proportion of survivors who no longer meet the clinical criteria for insomnia (ISI 
≤ 7) between study arms post-intervention (10 weeks) and at 6 months (noting 
that 100% of eligible participants will meet the criteria at randomization), using 
logistic regression models. Additional measures of sleep will also be 
summarized and compared (sleep diary, actigraphy, fatigue, daytime sleepiness) 
from baseline, post-intervention, and 6 months. Using the same analytic 
framework as above, we will evaluate the effect of study intervention on the 
secondary endpoints of neurocognitive impairment: patient reported (Task 
Efficiency, Memory, Emotional Regulation) and directly assessed (attention, 
memory, and executive function) with continuous outcome measures. 
Additional analyses relevant to secondary objectives focus on better 
understanding the associations and mediating relationships between the CBTi 
intervention, insomnia, neurocognition, emotional distress, cardiovascular risk 
indices and HRQoL (see Figure 2 for theoretical framework). We will evaluate 
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direct relationships between change in ISI (baseline to post-intervention) with 
emotional distress and cardiac health indices at postintervention time points and 
with HRQoL measures. To establish whether a mediation relationship exists, we 
will follow standard methodology68-70 by 1) establishing that there is an 
association between the causal variable (e.g. CBTi intervention) and the 
outcome (e.g. neurocognitive impairment), 2) establishing the association 
between the causal variable and the mediator and 3) showing that the mediator 
is associated with the outcome variable in a model with the causal variable 
included and 4) in the same model as used to evaluate step 3, determine that the 
relationship between the causal variable and the outcome variable is attenuated 
by inclusion of the mediator in the model. We do not expect to observe complete 
mediation in any of our investigations. Specifically, the above methodology will 
be used to test hypothesis 1.2.2.b with the causal variable defined as CBTi 
intervention, mediator as change in insomnia (ISI) and outcomes as 
neurocognitive indices. Hypothesis 1.2.2.c will consider change in insomnia as 
the causal variable, neurocognitive function indices, emotional distress 
symptoms and cardiovascular risk indices as mediators for the outcome HRQoL 
at 6 months. In addition to the stepwise model-based approach outlined above, 
we will also evaluate relationships using Structural Equation Modelling (SEM) 
approaches to evaluating mediation, which would allow simultaneous evaluation 
of the multiple pathways and classes of variables together in a single model, with 
improved power, allowing estimates of direct and indirect effects calculated 
from each.71, 72 All effects size estimates (mean differences and/or odds ratios) 
will be presented along with associated confidence intervals and two-sided p-
values, both unadjusted and adjusted for multiple comparisons. Primary 
therapies for childhood cancer have been associated with insomnia and study 
outcomes (neurocognitive morbidities, emotional distress, cardiovascular risk). 
Because our study inclusion criteria require that survivors have observed 
neurocognitive deficits we do not expect differential responses to SHUTi by 
previous childhood cancer treatment exposures. However, chemotherapy 
exposures and radiation doses are abstracted from medical records and 
cumulative doses of methotrexate (high dose and intrathecal), cytarabine, and 
cranial radiation will be included as covariates in relevant analyses. In addition, 
we will conduct sensitivity analyses to examine their contributions to treatment 
response. 
 
We have planned for 20% attrition over the course of the 6-month study. 
However, if there is a substantial amount of missing data at 9 weeks or 6 months 
we will examine the characteristics of survivors who have complete data with 
those who do not. Depending upon the pattern of missing data, we will conduct 
sensitivity analyses to assess the impact of missing data on the results. We will 
consider factors such as demographic and treatment variables as well as 
premorbid baseline functioning in our sensitivity analyses. 
 
Power and sample size 
We plan to enroll a total of 352 subjects, 176 of each sex), and assuming 10% 
drop out by the post-intervention 9-week assessment, we will have a total of 320 
subjects (160 of each sex) remaining for evaluation. Therefore, within each sex 
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stratum, with 80 survivors per study arm, 80% power and α of 0.05 for the 
primary endpoint comparison of the ISI, we will be able to detect a minimum 
effect size of 0.45. We will continue to enroll participants until we have 320 
evaluable at 9 weeks. Assuming a total dropout of 20% by 6 months post-
intervention, there will be approximately 70 survivors within each sex per study 
arm available for assessment, allowing detection of a 0.48 minimum effect size. 
If sex specific intervention effect estimates are comparable with each other, a 
combined analysis among the 320 survivors evaluable at 10 weeks will be 
sufficient to detect an effect size of 0.31, with 80% power and two-sided α of 
0.05. Secondary endpoints of neurocognition will have ability to detect the same 
effect sizes; secondary endpoint p-values will be presented using both a nominal 
significance level of 0.05 and adjustments for multiple comparisons using a false 
discovery rate methodology.73  
10.0 OBTAINING INFORMED CONSENT 
10.1. 
Informed Consent Prior to Research Interventions  
CCSS participants are recruited via email, telephone, and mail. Recruitment 
materials for this study will be included in the initial mailing and follow-up 
recruitment emails sent. Interested participants will be sent an email that 
contains a link to the study website. Participants will be presented with informed 
consent and will have the opportunity to provide an affirmative indication to 
enroll in the study. In addition to the on-line option to consent to participate in 
this study, participants will also have the opportunity to provide verbal consent 
while speaking with a representative from the CCSS Call Center. 
 
 
 
 
 
 
 
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11.0 REFERENCES 
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Conley S, Redeker NS. Cognitive Behavioral Therapy for Insomnia in the Context of 
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37.  
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Protocol document date: 04/09/2021 
APPENDICES 
 
 
APPENDIX I: Schedule of Evaluations  
 
 
Study Procedure 
Time Point 
Baseline 
Post-
Intervention 
6 Month 
Follow-Up 
Dried Blood Spot (DBS) 
Collection 
X 
X 
X 
Remote cognitive Assessment 
CNS Vital Signs  
X 
X 
X 
Drug Abuse Screen Test (DAST-
10) 
X 
 
 
Alcohol Use Disorders 
Identification Test (AUDIT) 
X 
 
 
Insomnia Severity Index (ISI) 
X 
X 
X 
FACIT-Fatigue Questionnaire 
X 
X 
X 
Epworth Sleepiness Scale (ESS) 
X 
X 
X 
Childhood Cancer 
Neurocognitive Questionnaire 
(CCSS-NCQ) 
X 
X 
X 
Patient Health Questionnaire 
(PHQ-9) 
X 
X 
X 
Sleep Diary 
X 
X 
X 
WHOOP wrist monitor 
X 
X 
X 
Health-related Quality of Life 
Questionnaire 
X 
X 
X 
PROMIS Global Health 
X 
X 
X 
Work Productivity and Activity 
Impairment Questionnaire 
(WPAI) 
X 
X 
X 
Work and Social Adjustment 
Scale (WSAS) 
X 
X 
X 
 
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