Optimizing Efficiency and Impact of Digital Health Interventions for Caregivers: A Mixed Methods Approach
Phase: NA
Conditions: Family Caregivers, Insomnia, Sleep Initiation and Maintenance Disorders
Sponsor: University of Virginia

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Optimizing efficiency and impact of digital 
health interventions for caregivers: A mixed 
methods approach  
National Clinical Trial (NCT) Identified Number:  NCT04986904 
Principal Investigator: Kelly Shaffer, PhD 
Funded by: National Institutes of Health: National Center for 
Advancing Translational Sciences 
Version Date:  16 August 2022 
 
 
 
 
Confidentiality Statement 
The information contained in this document is the property of the University of Virginia.  Distributing, 
copying, or disclosing information contained in this document requires prior authorization from the 
Principal Investigator, except that this document may be disclosed to the appropriate institutional 
review boards and representatives of the U.S. Food and Drug Administration or other regulatory 
agencies as required by law.   

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Key Roles and Study Governance 
 
Principal 
Investigator 
 
Kelly M. Shaffer, PhD 
PO Box 801075 
Charlottesville, VA 22908 
Ph: 434-982-1022 
Email: kshaffer@virginia.edu 
Fax: 434-244-7516 
 
Sub-
Investigators 
Lee Ritterband, 
PhD 
Email: 
leer@virginia.edu 
PO Box 801075 
Charlottesville, 
VA 22908 
 
Meghan Mattos, PhD 
Email: 
MS2BV@virginia.edu 
PO Box 800782 
Charlottesville, VA 
22908 
Karen Ingersoll, PhD 
Email: 
KES7A@hscmail.mcc.virginia.edu 
PO Box 801075 
Charlottesville, VA 22908 
 
Study Sites 
University of 
Virginia 
PI: Kelly M. 
Shaffer, PhD 
University of Pittsburgh 
PI: Heidi Donovan, PhD 
 
 
 

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STATEMENT OF COMPLIANCE ................................................................................... 5 
ABBREVIATIONS .......................................................................................................... 6 
1 
PROTOCOL SUMMARY ......................................................................................... 8 
1.1 
SYNOPSIS .......................................................................................................... 8 
1.2 
SCHEMA ............................................................................................................ 1 
2 
INTRODUCTION ..................................................................................................... 1 
2.1 
STUDY RATIONALE ............................................................................................. 1 
2.2 
BACKGROUND .................................................................................................... 1 
2.3 
RISK/BENEFIT ASSESSMENT ............................................................................... 4 
3 
OBJECTIVES AND ENDPOINTS ........................................................................... 5 
4 
STUDY DESIGN ..................................................................................................... 5 
4.1 
OVERALL DESIGN ............................................................................................... 5 
4.2 
JUSTIFICATION FOR DOSE ..................................ERROR! BOOKMARK NOT DEFINED. 
4.3 
END OF STUDY DEFINITION ................................................................................. 6 
5 
STUDY POPULATION ............................................................................................ 6 
5.1 
INCLUSION CRITERIA .......................................................................................... 6 
5.2 
EXCLUSION CRITERIA ......................................................................................... 7 
5.3 
JUSTIFICATION FOR STUDY POPULATION ............................................................. 7 
5.4 
LIFESTYLE CONSIDERATIONS .............................ERROR! BOOKMARK NOT DEFINED. 
5.5 
SCREEN FAILURES ............................................................................................. 8 
5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION ................................................ 8 
6 
STUDY INTERVENTION ......................................................................................... 8 
6.1 
DESCRIPTION OF STUDY INTERVENTION(S) .......................................................... 9 
6.2 
DOSING AND ADMINISTRATION ...........................ERROR! BOOKMARK NOT DEFINED. 
6.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...... ERROR! BOOKMARK NOT 
DEFINED. 
6.4 
STUDY INTERVENTION COMPLIANCE ...................ERROR! BOOKMARK NOT DEFINED. 
6.5 
REGISTRATION, RANDOMIZATION AND BLINDING................................................... 9 
6.6 
CONCOMITANT THERAPY ...................................ERROR! BOOKMARK NOT DEFINED. 
7 
STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL ............................................10 
7.1 
STUDY DISCONTINUATION AND CLOSURE ...........................................................10 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ...................................................10 
7.3 
DOSE-LIMITING TOXICITY ...................................ERROR! BOOKMARK NOT DEFINED. 
7.4 
PROCEDURES FOR DISCONTINUATION OF STUDY INTERVENTION ................. ERROR! 
BOOKMARK NOT DEFINED. 
7.5 
LOST TO FOLLOW-UP ........................................ERROR! BOOKMARK NOT DEFINED. 
8 
STUDY ASSESSMENTS AND PROCEDURES .....................................................11 
8.1 
CLINICAL ASSESSMENTS ...................................ERROR! BOOKMARK NOT DEFINED. 
8.2 
RESEARCH SPECIMEN COLLECTION ...................ERROR! BOOKMARK NOT DEFINED. 
8.3 
CORRELATIVE STUDIES .....................................ERROR! BOOKMARK NOT DEFINED. 
8.4 
PARTICIPANT REPORTED OUTCOMES .................ERROR! BOOKMARK NOT DEFINED. 
9 
DATA AND SAFETY MONITORING PLAN ...........................................................13 

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9.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .......... ERROR! BOOKMARK NOT 
DEFINED. 
9.2 
UNANTICIPATED ADVERSE DEVICE EFFECTS .......ERROR! BOOKMARK NOT DEFINED. 
9.3 
REPORTING EVENTS TO PARTICIPANTS ..............ERROR! BOOKMARK NOT DEFINED. 
9.4 
EVENTS OF SPECIAL INTEREST ..........................ERROR! BOOKMARK NOT DEFINED. 
9.5 
REPORTING OF PREGNANCY ..............................ERROR! BOOKMARK NOT DEFINED. 
9.6 
UNANTICIPATED PROBLEMS ...............................ERROR! BOOKMARK NOT DEFINED. 
9.7 
DATA BREACH ..................................................ERROR! BOOKMARK NOT DEFINED. 
9.8 
PROTOCOL DEVIATION ......................................................................................16 
9.9 
PARTICIPANT WITHDRAWALS/DROPOUTS PRIOR TO STUDY COMPLETION .............16 
10 
STATISTICAL CONSIDERATIONS ...................................................................17 
10.1 
STATISTICAL HYPOTHESES ................................................................................17 
10.2 
SAMPLE SIZE DETERMINATION ...........................................................................17 
10.3 
POPULATIONS FOR ANALYSES ...........................ERROR! BOOKMARK NOT DEFINED. 
10.4 
STATISTICAL ANALYSES .....................................................................................17 
11 
REGULATORY AND OPERATIONAL CONSIDERATIONS .................... ERROR! 
BOOKMARK NOT DEFINED. 
11.1 
REGULATORY AND ETHICAL CONSIDERATIONS ....ERROR! BOOKMARK NOT DEFINED. 
11.2 
DATA HANDLING AND RECORD KEEPING .............ERROR! BOOKMARK NOT DEFINED. 
11.3 
PUBLICATION AND DATA SHARING POLICY ..........ERROR! BOOKMARK NOT DEFINED. 
11.4 
CONFLICT OF INTEREST POLICY .........................ERROR! BOOKMARK NOT DEFINED. 
11.5 
ADDITIONAL CONSIDERATIONS ...........................ERROR! BOOKMARK NOT DEFINED. 
12 
REFERENCES ...................................................................................................24 
13 
APPENDICES ....................................................................................................31 
13.1 
SCHEDULE OF ACTIVITIES (SOA) ........................................................................31 
13.2 
REPORTING TABLE ............................................ERROR! BOOKMARK NOT DEFINED. 
13.3 
PROTOCOL AMENDMENT HISTORY .....................................................................36 
 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), applicable United States (US) Code of 
Federal Regulations (CFR), and the National Center for Advancing Clinical Translational 
Sciences Terms and Conditions of Award. The Principal Investigator will assure that no 
deviation from, or changes to the protocol will take place without prior agreement from 
and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection and 
GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  All 
changes to the consent form will be IRB approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided 
consent, using a previously approved consent form. 
 
 
 
 
 
UVA Lead Principal Investigator 
 
______________________  
_______________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 
 
Pitt Investigator 
 
_______________________  
_________________________  
_________ 
Name (print)  
 
 
Signature 
 
 
 
Date 
 

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ABBREVIATIONS 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
Pitt 
University of Pittsburgh (study site) 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 

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SHUTi 
Sleep Healthy Using the Internet 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
UVA 
University of Virginia (study site) 
 
 
 

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1 
 
PROTOCOL SUMMARY 
1.1 
Synopsis  
Title: 
Optimizing efficiency and impact of digital health interventions 
for caregivers: A mixed methods approach 
Study Description:  
 
 
 
 
  
One hundred high-intensity caregivers with insomnia will be 
enrolled in this open-label pilot trial of SHUTi with pre and 
post-assessments. The relation of caregivers' engagement 
with SHUTi - and among users, the effect of SHUTi on known 
mechanisms of change - with caregiving-related user and 
environment characteristics will be tested. This single-arm 
design focused on intervention mechanisms (e.g., as opposed 
to an underpowered randomized controlled trial measuring 
symptom change) was chosen as it is recommended for 
establishing plausibility to support subsequent larger-scale 
efficacy testing. 
Objectives & 
Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
To test the association of 
SHUTi engagement with 
caregiving context.  
Level of engagement: non-
users (i.e., completed no 
Cores), incomplete users (i.e., 
completed 1 to 3 Cores), and 
complete users (i.e., completed 
4 to 6 Cores) 
Secondary 
 
To describe caregivers’ barriers 
and motivations for SHUTi 
engagement 
• 
Open-ended feedback 
about SHUTi 
• 
SHUTi utility and 
barriers: Internet 
Intervention Utility, 
Evaluation, and 
Adherence 
questionnaires 
To test the association of 
SHUTi efficacy on known 
cognitive mechanisms with 
caregiving context. 
Cognitive mechanisms of 
change targeted by SHUTi  
 
• 
Sleep beliefs: 
Dysfunctional Beliefs 
and Attitudes about 
Sleep scale 
• 
Sleep control: Sleep 
Locus of Control Scale 
Study Population: 
 
Up to about 130 participants who self-report to be a caregiver 
with insomnia. 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
This is a multi-site study enrolling participants from the 
University of Virginia (UVA) and the University of Pittsburgh 
(Pitt). 
 
Description of 
Study Intervention: 
Sleep Healthy Using the Internet (SHUTi) developed by Sub-I 
Ritterband is an NCI-designated research-tested intervention 
that delivers cognitive behavioral therapy for insomnia. 
Study Duration: 
The study will last two years. 

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Participant 
Duration: 
Each participant will be enrolled in the study for 12 weeks. 
 

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1.2 
Schema 
Diaries only 
completed by those 
completing 1 or 
more Core of SHUTi 

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2 INTRODUCTION 
2.1 
Study Rationale  
One in six American adults provide care for a loved one with disabling illness, and these 
family caregivers are more likely to experience insomnia and other psychological 
concerns than the general population. Multiple existing, evidence-based digital health 
interventions may effectively address caregivers’ psychosocial needs and increase 
caregivers’ access to supportive care. For example, Sleep Healthy Using the Internet 
(SHUTi) developed by Dr. Ritterband is an NCI-designated research-tested intervention 
that delivers cognitive behavioral therapy for insomnia. A key translational research 
question remains about existing evidence-based digital health interventions like SHUTi, 
namely, what level of tailoring would be necessary and sufficient achieve optimal 
engagement with and efficacy of these interventions for caregivers? To address this 
research question, up to about 130 high-intensity caregivers with insomnia will be 
recruited to complete a baseline assessment of insomnia and caregiving context. 
Caregivers will then receive access to SHUTi in an open-label trial, then complete post 
assessments. Participants will be categorized according to their level of engagement 
with the 6 intervention “Cores”: nonusers (i.e., completed no Cores), incomplete users 
(i.e., 1 to 3 Cores), and complete users (i.e., 4 to 6 Cores). SHUTi engagement will be 
measured with caregiving context. First, we will test whether caregivers’ engagement 
with SHUTi (i.e., being a non-user vs. incomplete user vs. complete user) is associated 
with their user characteristics (i.e., caregiving strain, self-efficacy, and guilt) and 
environment characteristics (i.e., proximity to care recipient; care recipient functional, 
cognitive, and behavioral status; caregiving tasks). Second, we will describe caregivers’ 
barriers to and motivations for SHUTi engagement from their responses to open-ended 
surveys, and how caregiver-specific tailoring may improve uptake and usage. Thematic 
coding will also examine how caregivers’ recommendations generalize to other 
evidence-based digital health interventions, and findings will be validated using 
synthesized member checking.  
The effects of SHUTi will be evaluated on known cognitive mechanisms of change 
targeted by SHUTi (i.e., more adaptive sleep beliefs, internalized sleep locus of control) 
are associated with differences in caregiving-related user and environment 
characteristics. These findings are not only necessary to direct next research on tailoring 
and testing SHUTi for caregivers specifically, but also to advance the science towards 
our long-term goal, namely, to improve the quality and impact of digital health 
interventions for caregivers, while reducing intervention development inefficiency – a 
goal identified as a high priority for current caregiving research. As such, findings will be 
translatable across research-tested intervention programs and hold significant promise 
to reduce inefficiencies in developing digital health interventions for caregivers, while 
also increasing intervention impact and reach for this underserved population. 
2.2 
Background  
An estimated 47.9 million Americans provide informal, unpaid care to one or more adult 
family members with serious health conditions. 2 About 40% of these caregivers are in 
high-intensity caregiving situations, meaning they spend a significant amount of time 
caregiving (49 hours/week on average) and assist with multiple care tasks (3 activities of 
daily living [ADL] and 5 instrumental ADL [IADL] on average). Compared to lower-
intensity caregivers, high-intensity caregivers have more difficulty accessing affordable 
support services, although they are also more interested in support to manage their own 

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emotional and physical well-being.2,3 Support from family members to seriously ill 
individuals is critical to the sustainability of the U.S. healthcare system, 14 but it places a 
significant strain on these caregivers. Insomnia is among the most common, distressing, 
and impairing psycho-physiological issue for caregivers, who report this problem more 
commonly than non-caregivers.15,16 Compared to about 33-50% in the general 
population,17 up to 90% of caregivers report sleep impairment,18 although rates have 
varied by contexts – for example, 27% in Parkinson’s caregivers,19 50-75% in cancer,20–
22 and 63-68% in dementia.18,23,24 Sleep impairment contributes to caregivers’ anxiety, 
depression, and physical morbidity,21,25–29 which affect caregivers more severely than 
those in the general population.30–33 Moreover, caregivers’ poor sleep also ultimately 
affects their care recipients. Because it increases their distress, sleep-deprived 
caregivers are more likely to exhibit harmful caregiving behavior34 and less able to meet 
the practical and social-emotional needs of the care recipient. 35,36 Additionally, care 
recipients’ sleep disturbance is interrelated with their caregivers’.37,38 Accessible and 
effective insomnia interventions for caregivers are therefore important to the well-being 
of both caregivers and care recipients. Although such interventions are effective, they 
suffer from low enrollment, high dropout, and limited reach to caregivers who already 
have inadequate healthcare access, like caregivers from lower SES or those in rural 
areas. 39–43 Digital health interventions can lower barriers to entry to supportive care for 
caregivers as they are conveniently accessible anywhere and anytime from an Internet-
enabled device. Indeed, caregivers express strong interest in Internet interventions 
because of their convenience.44–46 Multiple existing, efficacious digital health 
interventions may effectively address caregivers’ psychosocial needs. For example, 
Sleep Healthy Using the Internet (SHUTi), developed by Dr. Ritterband, is an NCI 
designated research-tested intervention that delivers cognitive-behavioral therapy for 
insomnia (CBT-I).47,48 Most digital health interventions tested among caregivers, 
however, have been developed de novo for specific caregiving contexts.49–54 Tailoring 
interventions in this way is rooted in behavior change theory: tailoring to a user’s 
characteristics increases information salience, which increases a user’s attention to 
information, which ultimately increases the likelihood that the information will motivate 
behavior change.8 When tested empirically, tailoring typically adds only small gains in 
outcomes relative to generic materials, although gains are typically maintained over 
time.10,55,56 The decision to tailor, and how to tailor, must balance expected benefits of 
increased specificity against reduced reach and increased costs (time and financial). 
The implicit assumption underlying existing research – where de novo interventions are 
developed for caregivers – is that caregivers have different deficits, risk factors, and 
needs from non-caregivers. There is reason to believe this is true and that caregiving 
has unique psychological and environmental factors that would affect use and impact of 
insomnia interventions specifically, and digital health interventions broadly. Specific to 
insomnia interventions, caregivers’ insomnia can be perpetuated by worry about the 
negative impact of sleep loss on their ability to meet the demands of caregiving and a 
feeling of helplessness to improve their sleep due to their caregiving 
responsibilities.22,28,57 Indeed, caregivers do frequently need to organize their sleep 
around the needs of the care recipient38 and often need to support the care recipient at 
night with symptom management or nighttime behavioral issues.22,28 When considering 
digital health interventions more broadly, research repeatedly highlights primary barriers 
to caregivers’ help-seeking being their self-sacrifice – the de-prioritization of caregivers’ 
own needs behind the needs of the care recipient, particularly prominent among high-
intensity caregivers – and caregivers’ guilt when they do prioritize their needs. 58–61 
Caregivers’ often busy and chaotic schedules – also particularly true of high-intensity 
caregivers – likewise commonly get in the way of their ability to commit to consistently 

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participating in interventions. 59,61 Although these factors lend plausibility to the 
assumption that tailoring insomnia and digital health interventions for caregivers is 
needed, this assumption has not often been tested, and therefore the extent to which 
caregivers want and need tailoring for interventions is not known. This assumption may 
be comprehensively examined through the Model for Internet Interventions, 1 published 
by our team as the first testable theoretical model that guides digital health intervention 
development and evaluation by conceptualizing the processes that determine symptom 
improvement through the use of such interventions. 
 Relevant Clinical Experience 
The SHUTi intervention was developed and refined through the Model for Internet 
Interventions.1 The website (6 Cores of CBT-I content tailored to users) and support 
(automated email reminders to complete diaries and Cores) are established. A relatively 
consistent pattern in SHUTi use, or engagement, has emerged across completed trials: 
About 90% of participants complete at least Core 1 and 65% of participants complete at 
least Core 4 or more of the program.5,7,75,76 Those completing through at least Core 4 are 
considered “completers” as they have completed content related to primary change 
mechanisms; also, almost all (>90%) continue on to complete all 6 Cores. One trial of 
SHUTi among people with comorbid insomnia and depression found that only 40% 
completed all 6 Cores;6 this lower rate is not surprising given engagement is affected by 
depressive symptoms.77 Engagement is important, given that trials have also established 
that the more participants use SHUTi, the more they benefit.5,7 SHUTi treatment gains 
have been demonstrated to be mediated through changes to cognitive mechanisms (i.e., 
more adaptive sleep beliefs and internalized sleep locus of control).78 Across trials, 
which have included medically and psychiatrically diverse participants, SHUTi shows 
statistically and clinically significant reductions in participants’ insomnia symptom 
severity (ds = 1.17-2.34).4–7,75,76,79,80 Therefore, because the support and website 
variables will be held constant (i.e., SHUTi), we can isolate the effects of user 
characteristics and environment related to the caregiving context. Our most recent trial 
of SHUTi (NCT03213132, targeting older adults with insomnia, completed September 
2020) assessed whether individuals were caregivers. Of 207 participants randomized to 
SHUTi, 18 self-reported as a caregiver (9%, of whom n = 7 [39%] lived with the care 
recipient). Compared to non-caregivers, caregivers reported less improvement in their 
insomnia after using SHUTi (ISI score difference = 2.37 [95% CI = 0.17, 4.57], p = .03). 
Caregivers also reported less impact of SHUTi on their sleep quality compared to 
noncaregivers (χ2 [1, N = 190] = 4.78, p = .03). There were no significant differences (ps 
> .10) between caregivers’ and non-caregivers’ change in cognitive mechanisms, 
although CIs suggested less benefit for caregivers. The amount that caregivers logged 
into SHUTi (M = 80.56 logins) also did not differ significantly from non-caregivers (M = 
92.92 logins; t[22.83] = 1.10, p = .28 [diff 95% CI = -10.91, 35.64]; Shaffer, Camacho, 
Mattos, Buysse, Donovan, Ingersoll, & Ritterband, under review). These preliminary data 
support the capability of caregivers to engage with SHUTi, yet suggest caregivers 
experience less benefit from the intervention relative to noncaregivers. These data are 
limited, however, given the small sample and minimal information known about this 
caregiver sample, as caregiving was not a focus of this trial. Our proposed study is 
therefore necessary to better understand how caregiving context impacts SHUTi use 
and mechanisms, which ultimately drive symptom improvement, in order to understand 
how SHUTi may need to be optimized for caregivers. Summary of preliminary research: 
Taken together, data demonstrate: (1) caregivers are interested in CBT-I and digital 
health interventions, yet tailoring may be needed to optimize their outcomes, (2) SHUTi 

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is a vetted Internet-based treatment for insomnia, and (3) our combined experience to 
support our successful completion of this study, which builds logically from our past 
research to address our central question of: What tailoring is necessary and sufficient to 
achieve optimal engagement with and efficacy of SHUTi for caregivers? 
2.3 
Risk/Benefit Assessment   
 
 Known Potential Risks  
There always exists the potential for loss of private information. Participating caregivers 
risk potential loss of confidentiality of their self-reported demographics, 
measures of caregiving context and insomnia symptoms and mechanisms, and contact 
information. Participants will need to give study personnel their email address to which 
electronic questionnaires and reimbursement can be sent. 
 
Participants will be asked questions of a sensitive or personal nature (e.g., care 
recipient’s condition, psychological functioning), which potentially could cause 
some discomfort or embarrassment in answering these types of questions. 
 
Although some adults may feel more comfortable providing information over 
the Internet, others may feel less comfortable with this process and have concerns about 
the confidentiality of their digital data. 
 
Among those who choose to use SHUTi, in following some intervention 
recommendations, participants may be asked to restrict sleep at certain times, which 
could lead them to initially feel more tired. This increase in tiredness could potentially 
exacerbate cancer-related fatigue that some participants may be experiencing. 
 
All participants will be able to access support for technical difficulties. However, no 
human therapy support will be provided.  Removing human therapy support from 
provision of care can vastly increase the ability to widely disseminate treatment, but it 
may be associated with several risks. Internet-delivered programs are more restricted 
with respect to the tailoring of intervention recommendations. For example, the Internet 
intervention tailors which cognitive strategies are recommended based on users’ 
endorsement of distorted cognitions, but will not be able to make the recommendation to 
skip the Cognitive Core altogether. With a clinician, treatment can potentially be more 
tailored (e.g., make the decision that a particular patient does not need to focus on the 
cognitive strategies at all). 
 
There may be a risk that participants who have suicidal ideation will not be appropriately 
managed given the geographic limitations of conducting a study remotely. 
 
 Known Potential Benefits  
Participants may learn information about the diagnosis of insomnia, its etiology, general 
treatment strategies, methods of regular monitoring, and prognosis. 
 
Participants could potentially benefit from having improved sleep, improved health, 
reduced psychological distress, and improved quality of life. The potential benefits to the 
caregiving community are that this intervention, and possible future digital health 
interventions like it, would allow for a greater number of caregivers to have access to a 
low-cost and empirically-validated treatment for insomnia. It could potentially reduce 
health disparity by providing treatment that has not previously been available to 

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caregivers in more remote areas where access to a behavioral medicine sleep specialist 
is limited. 
 
 Assessment of Potential Risks and Benefits  
The risk of discomfort in answering personal questions, potential for loss 
of privacy, and risk of increased sleepiness during sleep restriction in the SHUTi 
program is balanced against the potential to achieve optimal engagement with and 
efficacy of an evidence-based treatment for insomnia among caregivers, which would be 
the first treatment of its kind tested among this population. The risk/benefit ratio 
seems reasonable given that there is a chance of long-term benefit to delivering more 
accessible, effective interventions to caregivers with minimal chance of harm to study 
participants. 
 
3 OBJECTIVES AND ENDPOINTS 
  
Objectives 
Endpoints 
Primary 
 
To test the association of 
SHUTi engagement with 
caregiving context.  
Level of engagement: non-
users (i.e., completed no 
Cores), incomplete users (i.e., 
completed 1 to 3 Cores), and 
complete users (i.e., completed 
4 to 6 Cores) 
Secondary 
 
To describe caregivers’ barriers 
and motivations for SHUTi 
engagement 
• 
Open-ended feedback 
about SHUTi 
• 
SHUTi utility and 
barriers: Internet 
Intervention Utility, 
Evaluation, and 
Adherence 
questionnaires 
To test the association of 
SHUTi efficacy on known 
cognitive mechanisms with 
caregiving context. 
Cognitive mechanisms of 
change targeted by SHUTi  
 
• 
Sleep beliefs: 
Dysfunctional Beliefs 
and Attitudes about 
Sleep scale 
• 
Sleep control: Sleep 
Locus of Control Scale 
 
 
 
4 STUDY DESIGN  
 
4.1 
Overall Design 
This study comprises a single-arm (nonrandomized) clinical trial with quantitative and 
qualitative data collection. 
 

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4.2 
End of Study Definition 
Primary completion date is the date that the final participant was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes defined as the final date for the collection of 
data for the primary endpoint. 
 
Study completion date is the date the final participant was examined or received an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and adverse events (for example, last participant’s last visit), 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. 
 
5 STUDY POPULATION 
In order to verify the age and identity of participants, individuals’ information provided on 
the online interest/prescreening form may be confirmed through Transunion, an online 
people search vendor. When indicated (e.g., not referred from a research registry), the 
study coordinator will enter and/or review the individual’s name (first and last), year of 
birth, phone number, and email to confirm the individual’s age and identity. Individuals 
who do not match on entered information will be emailed to inform them they do not qualify 
for the study. Individuals whose match remains unclear will be contacted to confirm their 
information in case they made an error in completing the interest form. 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the 
duration of the study  
3. Male or female, aged ≥ 18 years of age. 
4. Able to speak and read English. 
5. Self-report providing high-intensity unpaid care (e.g., practical, medical, and/or 
emotional support) to a family member or "family-like" close individual, 
operationalized as a function of time spent caregiving and care task involvement. 
6. Self-report expecting to continue provide high-intensity care for at least another 3 
months. 
7. Have access to any Internet-enabled device (computer, tablet, smartphone) and 
willing to be emailed about the study.  
8. Insomnia severity index score > 10 
9. Residing in the United States or U.S. territory 
 
 
 
 

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5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in 
this study: 
 
Exclusion Criteria: 
1. Unusual average bed/wake times, including for shift work 
2. Current behavioral/psych treatment for insomnia 
3. Medical contraindication (RLS/PLMD, OSA, narcolepsy, parasomnia, dementia, 
Parkinson's, Huntington's, stroke, TBI, brain infection/tumor, 
pregnancy/breastfeeding, hyperthyroidism, cancer, severe respiratory disease, 
epilepsy) 
4. Psychiatric contraindications (  mania/hypomania, alcohol or substance 
abuse/dependence) 
5. Changes to prescription medications in the past 3 months (sleep, steroid, 
amphetamine, other wake-promoting) 
6. Severe computer literacy challenges 
 
5.3 
Justification for Study Population 
In selecting participants for this project, due notice is taken of the National Institutes of 
Health policy concerning inclusion of women and minorities in clinical research. The 
proposed study will be open to men and women of all ethnic and racial backgrounds. We 
will not exclude participants based on their race, ethnicity, or gender. In 2020, the 
National Alliance for Caregiving (NAC), in collaboration with AARP, published their 
executive summary based on data collected from 1,392 caregivers.2 Weighted by 
population estimates, it is estimated that caregivers are predominantly (61%) female, a 
gender distribution that is in accord with the majority of studies of cancer caregivers. 
Therefore, we expect an equivalent proportion of our participants (61%) will be women. 
This expectation is also supported by the fact that insomnia is approximately twice as 
prevalent among women compared to men.104 
 
Every effort will be made to recruit minoritized populations and ensure no selection bias, 
beyond the need to speak English. To estimate the racial distribution of caregivers who 
might be reached through in-clinic recruitment at UVA, given our catchment area 
spanning counties in both Virginia and West Virginia, there are demographic data from 
13,137 patients receiving a diagnosis with any malignant neoplasm at the UVA Cancer 
Center in 2019. Of the over 13,800 patients with a cancer diagnosis to receive oncologic 
care at UVA in 2019, 75% are non-Hispanic White, 13% are African American, 4% are 
Hispanic, and 1% are Asian (7% unknown).  Of the over 1,100 patients with a dementia-
related diagnosis who received care at UVA Memory and Aging Care Clinic in the past 
year, 78% are non-Hispanic White, 14% are African American, 2% are Hispanic, and 
1% are Asian (5% unknown). We will also recruit participants via the University of 
Pittsburgh Caregiver Research Registry and the Clinical Translational Science Institute 
(CTSI) Pitt+Me Research Participant Registry. The Caregiver Research Registry, part of 
the Pitt Center for Social & Urban Research Survey Research Program, comprises over 
1,000 self-identified caregivers who are representative of the Western Pennsylvania 
population and are willing to participate in research studies. Pitt+Me is an institutional 
research participant registry with the primary objective of identifying and recruiting 
UPMC patients of all ages from every University of Pittsburgh Medical Center point-of-

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service location (5.5 million outpatient visits and 388,000 inpatient admissions and 
observation cases annually), as well as community member volunteers, who may be 
eligible to participate in ongoing Pitt clinical research studies. To date, over 230,000 
participants have enrolled in the Pitt+Me registry. The Pitt CTSI Integrating Special 
Populations Core, which comprises special population liaisons who have unique 
expertise in engaging underrepresented populations in research, in order to support 
recruitment of racial and ethnic minority caregivers to this study. With these resources 
and supported by additional community outreach support from the University of Virginia 
integrated Translational Health Research Institute of Virginia (iTHRIV) and the Pitt CTSI, 
we will aim for a sample racial distribution in proportion to that reported from the 2020 
NAC study, which estimated that caregivers in the U.S. are 61% Non-Hispanic White, 
14% African American / Black, 17% Hispanic / Latinx, and 5% Asian American, and 3% 
other race or multiracial.2 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently randomly assigned to the study intervention or entered in the 
study. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants, to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements (for NIH studies) and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
5.5 
Strategies for Recruitment and Retention 
 
For clinic-based recruitment, caregivers will be introduced to the study in one of two 
primary ways: 1) in person, while attending a clinic appointment with an adult patient or 
2) study flyers posted in the clinic rooms. Trained research assistants at both UVA and 
Pitt will be available to meet potential participants in-clinic or discuss the study by phone, 
and the study team members also have robust connections with clinic staff to support 
participant recruitment as well.  
 
For recruitment via participant registry outreach, caregivers will be introduced to the 
study in one of three primary ways: 1) by telephone outreach, 2) by email and/or letter 
outreach, or 3) by matching with our study via the Pitt+Me research study database. The 
Caregiver Research Registry, part of the Pitt Center for Social & Urban Research Survey 
Research Program, comprises over 1,000 self-identified caregivers who are 
representative of the Western Pennsylvania population and are willing to participate in 
research studies. We will also reach out to care partners who have indicated willingness 
to be contacted in research studies via the Pitt Alzheimer’s Disease Research Center 
(ADRC). We will also recruit individuals enrolled in the Contact Database for UVA 
Cancer Center Catchment Area Survey Participants (UVA IRB-SBS 3993). This contact 
database includes participants who opted into being recontacted about future studies 
when they completed the UVA Cancer Center catchment area survey (as has been 
approved by UVA IRB-HSR previously, see HSR 22747 exempt protocol as example). 
 
 
We will also utilize online advertisement and promotion methods to distribute information 
about our study. This may include posts and/or advertisements through Facebook, 
Instagram, Reddit, Twitter, and other websites pertinent to family caregiving and digital 

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health research. Study information may also be distributed through pertinent listservs 
and newsletters by community and partner organizations. Potentially interested 
individuals will be directed to our study website and provided with contact information for 
study staff. 
 
6 STUDY INTERVENTION 
 
6.1 
Description of Study Intervention(s)  
  
Type 
Name 
Investigational 
or Standard of 
Care (SOC) 
Description 
Behavioral 
(e.g., 
Psychotherapy, 
Lifestyle 
Counseling) 
Sleep 
Healthy 
Using the 
Internet 
(SHUTi) 
Interventional 
SHUTi is a self-guided, interactive, 
and tailored Internet-based 
Program that incorporates the 
primary tenets of face-to-face 
cognitive behavioral therapy (CBT) 
for insomnia. Content is presented 
in six Cores, with a new Core 
available seven days after 
completion of the previous 
Core. SHUTi relies on user-entered 
sleep diaries to track progress and 
Tailor recommendations. Each Core 
parallels the structure of traditional 
Weekly face-to-face CBT-I sessions 
and includes: 1) examination of 
Core objectives, 2) review and 
feedback on homework and sleep 
diary from the prior week, 3) 
teaching new intervention material, 
and 4) assignment of homework. 
Intervention content is enhanced 
through goal-setting, graphical 
feedback based on the participant's 
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. 
 
6.2 
Registration, Randomization and Blinding 
All participants must sign the consent form prior to determination of eligibility for this study.    
This study does not involve any blinding or masking procedures.  Subjects will be told 
which treatment they are receiving. 
 

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7 STUDY CLOSURE, STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL 
7.1 
Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to sponsor.  If the 
study is prematurely terminated or suspended, the Principal Investigator (PI) will 
promptly inform the Institutional Review Board (IRB) and sponsor and will provide the 
reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that would warrant termination or suspension include, but are not limited 
to  
• 
Determination of unexpected, significant, or unacceptable risk to participants  
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
• 
Change in funding status 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB, Data and Safety Monitoring Committee (if 
applicable) and/or Food and Drug Administration (FDA) (if applicable). 
 
Participants receiving study treatment at the time of study discontinuation should complete 
procedures described in section 7.4. 
 
 
7.2 
Participant Discontinuation/Withdrawal  
Participants are free to withdraw from participation in the study at any time upon request. 
A participant’s study treatment would be discontinued for the following reasons: 
 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
not be in the best interest of the participant (see section 7.3 for dose-limiting 
toxicities) 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation 
• 
Participant unable to receive study intervention. 
• 
Participant decision to withdraw from study treatment and/or the study 
• 
Initiation of prohibited intervention or medication 
The reason for participant discontinuation or withdrawal from study treatment will be 
recorded. Participants who sign the informed consent form but do not receive the 

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study intervention may be replaced.  Participants who sign the informed consent 
form, and receive the study intervention, and subsequently withdraw, or are 
withdrawn or discontinued from the study, will be replaced. Participants that withdraw 
from the study (not only from study treatment, but all study follow-up) will not be 
contacted for any further study visits. 
A participant will be considered lost to follow-up if he or she fails to complete pre-
assessment and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to complete assessments: 
• 
The site will attempt to contact the participant and counsel the participant on the 
importance of maintaining the program and ascertain if the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant.  
• 
These contact attempts should be documented in the study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 
8 STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
Study Materials and Methods 
 
Participating caregivers will be instructed on how to complete the pre-assessment 
battery of online questionnaires using either computer or mobile device as the participant 
prefers. Estimated completion times are 30 minutes for questionnaires. Upon completing 
questionnaires, participants will complete 10 daily sleep diaries within 14 days. 
Participants will be compensated $40 upon pre-assessment completion. 
 
After participants complete pre-assessment, they will receive access to SHUTi. 
Participants will be emailed a unique username and password in order to log on and 
securely access SHUTi for 9 weeks. The intervention can be accessed via an Internet 
enabled device, including a computer, tablet, or smartphone. At the start of week ten, 
regardless of intervention progress, participants will be instructed to complete their 
online post assessment. 
 
Non-users’ (i.e., those who completed 0 SHUTi Cores) post-assessment will include an 
open-ended survey regarding barriers to SHUTi adoption, the extent to which barriers 
were related to caregiving, and what modifications may have increased their motivation 
to try SHUTi. Users’ (i.e., those who completed 1 or more SHUTi Cores) post-
assessment will include an open-ended survey assessing SHUTi usage barriers and 
motivations, the extent to which these were related to caregiving, and how tailoring may 
improve usage by increasing salience to caregivers. SHUTi users will also complete 10 
daily sleep diaries in 14 days as part of post-assesement. Participants will be 
compensated $40 upon post-assessment completion. 
 

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Caregivers who agree to be contacted for follow-up will be returned a concise report of 
results from the analyses as part of synthesized member checking procedures, where 
caregivers will be asked to review the report and comment on how results 
compare/contrast with their experiences and needs. 
 
Sources of research materials:  
The sources of research material will include: 
 (1) self-report questionnaires completed over the Internet (including caregiving-related 
user- and environment characteristics; as well as demographics, sleep, self-efficacy and 
other health/psychosocial constructs);  
(2) telephone interview to inquire about sleep problems, insomnia treatment history, and 
computer/Internet usage;  
(3) daily symptom diaries collected over the Internet to track sleep symptoms (e.g., 
minutes to fall asleep) in order to automatically tailor treatment recommendations; and 
(4) open-ended survey items related to either barriers to SHUTi adoption, the extent to 
which barriers were related to caregiving, and what modifications may have increased 
their motivation to try SHUTi (non-users) or SHUTi usage barriers and motivations, the 
extent to which these were related to caregiving, and how tailoring may improve usage 
by increasing salience to caregivers (users).  
 
All data will be collected explicitly and exclusively for this study and will be maintained 
following HIPAA regulations. Data collected through the internet will be obtained through 
secured means and stored on our private servers. Personal Health Information (PHI) will 
be stored separately from study data on a different HIPAA compliant server. Only study 
staff with the requisite IRB-approved Human Subjects Training will have access to 
participant data.  
 
Surveys will be performed according to the Table below: 
 
 
Time Point 
Variable / Measure 
Outcome measured 
Pre 
Post 
Screening 
Caregiving 
High-intensity caregiving (based on National Alliance of Caregiving 
intensity index), future duration 
Screen 
Internet access 
Regular Internet and email access 
Screen 
Contact / verification 
Age/year of birth, name, zip, phone, email 
Screen 
Insomnia 
Insomnia Severity Index 
Screen 
Sleep 
Usual 
bed/wake 
times 
(phase 
shift), 
shift 
work, 
current 
psychological/behavioral treatment for insomnia 
Screen 
Medical 
contraindications 
Dx’ed with: RLS/PLMD, OSA, narcolepsy, parasomnia, dementia, 
Alzheimer’s, Parkinson’s, Huntington’s 
Symptoms of: RLS, OSA 
Ever/recovered: Stroke, TBI, Brain infection, brain tumor 
Current: pregnancy/breastfeeding, hyperthyroidism, cancer, respiratory 
disease 
Current/managed: Epilepsy 
Current/3-mo stable: Steroids, amphetamines, stimulants, prescribed 
sleep medications 
Screen 
Psychological/ 
Psychiatric 
Contraindications 
MINI: 
Mania/hypomania, 
Alcohol 
dependence/abuse, 
Substance 
dependence/abuse 
Dx’ed with psychosis or schizophrenia 
Screen 
Covariates 
Sociodemographics 
Age, household income, health literacy,  
✓ 
 

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Health-related Quality 
of Life 
PROMIS: 2-item Global Physical Health 
✓ 
✓ 
General Distress 
Patient Health Questionnaire-4 
✓ 
✓ 
Predictors: Caregiving-related user characteristics 
Caregiving strain 
Pearlin Stress Scale – Caregiving Overload subscale 
✓ 
✓ 
Caregiving self-efficacy 
Pearlin Stress Scale – Caregiving Competence subscale 
✓ 
 
Caregiving guilt 
Caregiver Guilt Questionnaire – Guilt about doing wrong by the care 
recipient, guilt about not rising to the occasion as a caregiver, guilt about 
self-care subscales 
✓ 
 
Predictors: Caregiving-related environment characteristics 
Proximity to CR 
Whether bedpartner, live together but not bedpartner, other situation 
✓ 
 
CR functional status 
Modified Barthel Activities of Daily Living [ADL] Index 
✓ 
 
CR cognitive status 
Pearlin Stress Scale – Cognitive Status subscale 
✓ 
 
CR problem behavior  
Pearlin Stress Scale – Problematic Behavior subscale (includes night-time 
problems) 
✓ 
 
Caregiving tasks 
Involvement in supporting ADL, Instrumental ADL, and nursing tasks 
✓ 
 
Changes in caregiving  
Single item question (with follow-up open-ended response) if caregiving 
situation has significantly changed during study 
 
✓ 
Aim 1 Outcomes: SHUTi engagement (Core completion recorded through SHUTi online platform) 
Core completion 
Non-user (no Cores completed); Incomplete user (1-3 Cores); Complete 
user (4-6 Cores) 
Through 
SHUTi 
Open-ended feedback 
Free-response survey items – separate surveys for non-users and users 
 
✓ 
SHUTi 
utility 
and 
barriers 
Internet Intervention Utility, Evaluation, and Adherence Questionnaires – 
select items 
 
✓* 
Aim 2 Outcomes: SHUTi efficacy on known cognitive mechanisms 
Sleep beliefs 
Dysfunctional Beliefs and Attitudes About Sleep 
✓ 
✓* 
Sleep control 
Sleep Locus of Control Scale 
✓ 
✓* 
Exploratory: Preliminary Efficacy 
Insomnia severity 
Insomnia severity index 
✓ 
✓ 
Sleep diary metrics 
10 days of sleep diaries in 14 day period 
✓ 
✓* 
*SHUTi users only 
 
 Assessment of Adverse Events 
 
The PI (Dr. Shaffer) is primarily responsible for the reporting of adverse events; all 
members of the research staff are responsible for the assessment of adverse events. All 
spontaneous reports by participants, observations by research staff, reports to research 
staff by family or medical care providers, etc., will be investigated. The investigators will 
assess the relationship of the adverse event as not related, unlikely to be related, 
possibly related, probably related, or definitely related using standard criteria for clinical 
trials.  
 
9 DATA AND SAFETY MONITORING PLAN  
9.1 
Adverse Events and Serious Adverse Events 
 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related. 

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 Definition of Serious Adverse Events (SAE) 
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the 
view of either the investigator or sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or  
• 
a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
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. 
  
 Classification of an Adverse Event 
9.1.3.1 Severity of Event 
For adverse events (AEs) not included in the protocol defined grading system, the 
following guidelines will be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating.  Of note, the term “severe” does not necessarily 
equate to “serious”. 
9.1.3.2 Relationship to Study Intervention 
All adverse events (AEs) must have their relationship to study intervention assessed by 
the clinician who examines and evaluates the participant based on temporal relationship 
and his/her clinical judgment. The degree of certainty about causality will be graded 
using the categories below. In a clinical trial, the study product must always be suspect.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, 
and other possible contributing factors can be ruled out. The clinical event, 
including an abnormal laboratory test result, occurs in a plausible time 
relationship to study intervention administration and cannot be explained by 
concurrent disease, other drugs or chemicals, or other interventions.  

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• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal 
laboratory test result, occurs within a reasonable time after administration of the 
study intervention, is unlikely to be attributed to concurrent disease, other drugs 
or chemicals, or other interventions. 
• 
Possibly Related – There is some evidence to suggest a causal relationship 
(e.g., the event occurred within a reasonable time after administration of the trial  
intervention). However, other factors may have contributed to the event (e.g., the 
participant’s clinical condition, other concomitant events). Although an AE may 
rate only as “possibly related” soon after discovery, it can be flagged as requiring 
more information and later be upgraded to “probably related” or “definitely 
related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test 
result, whose temporal relationship to study intervention makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time 
after of the study intervention) and in which other drugs or chemicals, 
interventions, or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention, and/or 
evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
9.1.3.3 Expectedness 
The Principal Investigator will be responsible for determining whether an adverse event 
(AE) is expected or unexpected by assessing all AEs against cumulative study 
intervention experience.  Expectedness for adverse events and expectedness for the 
purposes of expedited reporting will be determined based on review of the following 
reference documents that describe the nature, severity, and frequency of the events.  
 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to 
the attention of study personnel during study visits and interviews of a study participant 
presenting for medical care, or upon review by a study monitor. 
 
All AEs related, probably related or possibly related to the study intervention including 
local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study 
intervention (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event.  AEs that are deemed 
related, probably related or possibly related to the study intervention that occur while on 
study must be documented appropriately. AEs will be followed to adequate resolution. 
 
Any medical condition (including a laboratory abnormality) that is present at the time that 
the participant is screened will be considered as baseline and not reported as an AE. 
However, if the study participant’s baseline medical condition worsens at any time during 
the study and the change is deemed related, probably related or possibly related to the 
study intervention, it will be recorded as an AE.  

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Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
The Clinical Coordinator will record all reportable events with start dates occurring any 
time after informed consent is obtained until the last day of study intervention.  At each 
study visit, the investigator will inquire about the occurrence of AE/SAEs since the last 
visit.  Events will be followed for outcome information until resolution or stabilization. 
 Adverse Event Reporting 
 
Add adverse events will be reported to the University of Virginia IRB-HSR according to 
guidelines. Any unanticipated problem or serious and unexpected adverse events will 
require re-evaluation of the risk of the study. Dr. Shaffer will be the person to whom all 
unanticipated problems or serious and unexpected adverse events, whether 
psychological or medical, are initially reported. Dr. Shaffer is a licensed clinical  
psychologist who can evaluate whether the events are SAEs or AEs. Dr. Shaffer will be 
responsible for ensuring that all unanticipated problems or serious and unexpected 
adverse events are reported within 48 hours to the IRB and NCATS. Adverse events will 
be monitored carefully and any necessary steps will be taken to maintain 
participant safety. Any change to the procedures will be forwarded to the IRB for 
approval. The NCATS Project Officer will receive an annual report summarizing all 
adverse events. 
 
9.2 
Protocol Deviation 
 Definition of Protocol Deviation 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 Reporting of a Protocol Deviation 
It is the responsibility of the site investigator to use continuous vigilance to identify and 
report deviations. All deviations must be addressed in study source documents, reported 
to Dr. Shaffer. 
9.3 
Participant Withdrawals/Dropouts Prior to Study Completion 
Participants who withdraw consent and those dropping out of the study secondary to an 
AE will be reported to the IRB of record according to IRB guidelines.  

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10 STATISTICAL CONSIDERATIONS  
 
10.1 Statistical Hypotheses 
 
Primary hypothesis: caregivers’ engagement with SHUTi (i.e., being a non-user vs. 
incomplete user vs. complete user) will be associated with their caregiving-related user 
characteristics (i.e., caregiving strain, self-efficacy, and guilt) and environment 
characteristics (i.e., proximity to care recipient; care recipient functional, cognitive, and 
behavioral status; caregiving tasks). 
 
Secondary hypothesis: the effects of SHUTi on cognitive mechanisms of change 
targeted by SHUTi (i.e., more adaptive sleep beliefs, internalized sleep locus of control) 
will differ by caregiving-related user characteristics (i.e., caregiving strain, self-efficacy, 
and guilt) and environment characteristics (i.e., proximity to care recipient; care recipient 
functional, cognitive, and behavioral status; caregiving tasks). 
 
 
10.2 Sample Size Determination 
 
We will enroll up to about 130 high-intensity caregivers with insomnia into this single-arm 
(nonrandomized) trial. The minimum sample size to achieve is 100. Based on 
completion rates from Dr. Donovan’s (University of Pittsburgh site PI) untailored Internet 
depression management program (non-users = 35%; incomplete = 40%; complete = 
25%) and averages across SHUTi trials (non-users = 10%; incomplete = 25%; complete 
= 65%), we estimate that the sample in the proposed trial will break down as follows: 
22% non-users, 33% incomplete users, 45% complete users. Assuming these response 
rates, the minimally detectable proportional odds (minOR) analyses at power = 80% with 
α = .05 would be a moderate effect size94 (minOR= 2.9) for a sample size of N = 100 
based on rate of dichotomized predictor exposures (computed using the Whitehead 
formula95 in R Hmisc96; see Table below). Controlling for baseline values of cognitive 
mechanisms and covariates, an expected sample size of 78 users (33 incomplete + 45 
complete) would have 80% power with α = .05 to detect a small effect size of a user or 
environment characteristic on cognitive mechanisms at post (R2 = .04 < .10). 
 
 
10.3 Statistical Analyses 
 
10.3.1 Analysis of the Primary Efficacy Endpoint(s) 
 
To test whether SHUTi engagement is associated with caregiving context, ordered 
logistic regressions assuming proportional odds will be fit for each caregiving-related 
user and environmental characteristic on SHUTi core completion, a 3-level ordinal 

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dependent variable (i.e., non-user vs. incomplete user vs. complete user). Models will 
control for a pre-specified set of covariates (i.e., age, household income, health literacy, 
mental and physical health related quality of life) that are not specific to caregivers, but 
affect both caregiving context factors 35,72 and digital health engagement.77,87 Where the 
proportional odds assumption is violated (p < .05), follow-up sensitivity analyses will be 
conducted: two logistic regressions comparing proportional odds between non-users vs. 
users (incomplete and complete) and between non-completers (non-users and 
incomplete users) vs. complete users. Secondarily, we will assess whether caregiving-
related user and environmental characteristics change during the course of the 
intervention period and test whether this change is related to engagement using a 
structural equation mediation modeling approach.88 For users, we will also examine the 
associations between user and environment characteristics with SHUTi evaluations on 
the Internet Intervention Utility, Evaluation, and Adherence Questionnaires. 
 
 
10.3.2 Analysis of the Secondary Endpoint(s) 
 
To describe caregivers’ barriers and motivations for SHUTi engagement, qualitative 
coding of users’ open-ended survey responses from post-assessment will be conducted 
via Dedoose software. Data will be coded using two methods: First, using an a priori 
codebook to tag data according to whether it is: (a) specific to SHUTi; (b) specific to 
CBT-I, but not exclusively SHUTi; or (c) specific to digital health interventions, but not 
exclusively SHUTi. This will facilitate examination of the extent to which caregiver-
specific tailoring recommendations are specific to SHUTi versus generalizable to other 
evidence-based psychosocial digital health interventions. Responses will next be coded 
inductively using thematic text analysis89–91 to identify themes related to caregivers’ 
barriers to and motivations for SHUTi uptake and usage, as well as how caregiver-
specific tailoring may affect each of those constructs. Each response will be coded by 
two independent coders with discrepancies resolved by consensus. The coding team will 
iteratively determine a set of codes; identify, review and name themes; and synthesize 
data into final actionable recommendations for tailoring SHUTi and other digital health 
interventions for caregivers. 
 
Findings and resultant recommendations will be returned to caregivers for synthesized 
member checking92: 
(1) A concise report of results will be sent to caregivers;  
(2) Caregivers will review the report and comment on how results compare/contrast with 
their experiences and needs; and 
(3) Caregivers’ returned responses will be coded to ascertain level of resonance 
between caregivers’ reported experiences and the researchers’ original results. Findings 
and recommendations will be revised according to synthesized member checking 
results. 
 
To test whether the effects of SHUTi on cognitive mechanisms (i.e., more adaptive sleep 
beliefs, internalized sleep locus of control) are associated with caregiving context, a 
continuous regression model will be computed for each user and environment 
characteristic on each cognitive mechanism assessed at post, controlling for 
pre-assessment level of the mechanism.93 Caregivers who are SHUTi users (incomplete 
and complete; not non-users) will be included, and models will control for level of SHUTi 
engagement and pre-specified covariates, with significance set at p< .05. 
 

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11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
 
11.1 Informed Consent Document and Process 
 
Once a potential subject is identified, they will be interviewed either by phone or in-clinic 
in a quiet and private place and may have family or friends with them if they choose.  .  
Once the consent has been read the person obtaining consent will summarize the 
consent form verbally, asking open ended questions to determine if the potential subject 
understands what is being covered in the consent form.   Questions might include:   
• 
Would you summarize for me what you believe what would be asked of 
you if you are in this study?  
• 
Would you benefit from this study? 
• 
What do you feel are the risks of being in this study? 
 
Potential subjects will be given an opportunity to ask questions.  Their level of 
understanding will dictate how much time will be spent covering each item.  Once all of 
their questions have been answered, if they decide to participate, they will be asked to 
sign the consent form, either by paper copy if in-clinic or through HIPAA-compliant 
DocuSign if by phone.  The person obtaining consent will sign the form and subjects will 
be given a copy of the signed consent form (paper if in-clinic; PDF by email if by phone). 
Study procedures will then begin.   
 
11.2 Confidentiality and Privacy  
 
Participant confidentiality and privacy is strictly held in trust by the participating 
investigators and their staff. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in 
strict confidence. Consents will be maintained in a confidential manner in accordance 
with the code of federal regulations and HIPAA. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of 
the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, representatives of the Institutional Review Board (IRB), regulatory 
agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, Institutional 
policies, or sponsor requirements. 
 
 

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11.3 Safety Oversight 
 
The study PI will be responsible for the safety oversight for this trial. AEs will be 
monitored throughout the study. 
 
11.4 Site Monitoring 
 
This study does not include a phase III clinical trial and therefore does not require an 
independent data and safety monitoring board. Project investigators will help ensure the 
safety of participants, as well as the validity and integrity of the data, by discussing 
project updates at the ongoing twice-monthly study meetings. At these meetings, we will 
review study progress and address any issues with the research procedures and 
database. Separate consultation will be sought with the study biostatistician regarding 
data issues. Twice-monthly supervision meetings will be held with the trained research 
study assistants at UVA and Pitt (convened via videoconference). Discussion at study 
meeting, separate consultations, and study staff supervision meetings with key 
personnel will cover:  
 
1) recruitment, consent, and enrollment;  
2) unanticipated problems, serious and unexpected adverse events, concluding with 
the safety procedures used to handle and minimize the occurrence of adverse events; 
and  
3) procedures for data collection, data entry, and data storage. Procedures can always 
be modified to enhance the safety of the study if needed. All staff with access to data will 
have completed extensive human subjects protection training through the Collaborative 
Institutional Training Initiative (CITI) training program. 
 
11.5 Data Handling and Record Keeping  
 Data Collection and Management Responsibilities  
 
All possible precautions will be set in place in order to prevent loss of confidentiality 
through rigorous data security measures. All study data collected will be stored 
electronically on a UVA protected network drive and accessible only to the PI and 
essential members of the research team. Survey data will be collected via an online 
survey tool certified for use with HIPAA-regulated personal health information (PHI) and 
protected by the University’s clinical firewalls. A password-protected list matching names 
with code numbers will be kept in a separate computer file and folder from the one 
where the data is stored. If a person agrees to participate in the study, all questionnaires 
will be labeled with the participants’ study ID number, not their name or any other 
identifiable information. All identifiable data (e.g., phone number, email addresses) will 
be kept private on the UVA network drive and a password protected spreadsheet. 
 Study Records Retention  
 
Record retention will be in accord with 21 CFR 312.62 and HIPAA regulations. 
 

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21 
 
 
 
 
 
Type of Event 
To whom will it 
be reported: 
TIME 
FRAME 
FOR REPORTING 
 
HOW REPORTED? 
 
Any internal & external event 
resulting in death that is 
deemed DEFINITELY related 
to (caused by) study 
participation 
An internal event is one that 
occurs in a subject enrolled in 
a UVA protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
Internal & External, Serious, 
Unexpected and related 
adverse event  
 
 
IRB-HSR 
Within 7 calendar 
days from the 
time the study 
team received 
knowledge of the 
event. 
 
Timeline includes 
submission of 
signed hardcopy 
of AE form. 
IRB Online 
 
Unanticipated Problems that 
are not adverse events or 
protocol deviations  
This might include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar 
days from the 
time the study 
team received 
knowledge of the 
event.  
Unanticipated Problem report 
form.  
Unanticipated Problem 
Report Form 
 
 
Protocol 
Deviations/Noncompliance 
The IRB-HSR only requires that 
MAJOR deviations be 
reported, unless otherwise 
required by your sponsor, if 
applicable. 
 
OR 
 
Protocol Exceptions 
See definition- only allowed if 
there is a commercial sponsor 
IRB-HSR 
 
 
Within 7 calendar 
days from the 
time the study 
team received 
knowledge of the 
event.  
 
Protocol Deviation, 
Noncompliance and Protocol 
Exception Reporting Form 
Protocol Deviation 
Protocol Exception 
Reporting Form 
 
 
 

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or a DSMB that has granted 
the protocol exception.  
Data Breach  
The UVA 
Corporate 
Compliance and 
Privacy Office 
 
 
 
ITC:  if breach 
involves  
electronic data  
 
 
 
 
UVA Police if 
breach includes 
such things as 
stolen computers.  
As soon as 
possible and no 
later than 24 
hours from the 
time the incident 
is identified. 
 
As soon as 
possible and no 
later than 24 
hours from the 
time the incident 
is identified. 
 
IMMEDIATELY.  
 
 
UVA Corporate Compliance 
and Privacy Office- Phone 924-
2938 
 
 
 
 
ITC:  Information Security 
Incident Reporting 
procedure,  
https://security.virginia.edu/re
port-information-security-
incident 
 
UVA Police-Phone- (434) 924-
7166 
 
 
 
 
Reporting Requirements for the non-UVA site 
Type of Event 
To whom will it 
be reported: 
TIME 
FRAME 
FOR REPORTING 
HOW REPORTED? 
 
Any internal event resulting 
in death that is deemed 
DEFINITELY related to (caused 
by) study participation 
An internal event is one that 
occurs in a subject enrolled in 
a UVA protocol 
UVA study team/ 
Data Coordinating 
Center (DCC)  
 
UVA lead site or 
DCC will report to 
the IRB-HSR per 
table above  
Within 24 hours 
Written documentation 
Internal, Serious, Unexpected 
and related adverse event  
 
 
UVA study team/ 
Data Coordinating 
Center 
 
Within 7 calendar 
days from the 
time the study 
team received 
Written documentation.   
 

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UVA lead site or 
DCC will report to 
the IRB-HSR  per 
table above 
knowledge of the 
event. 
 
Timeline includes 
submission of 
signed AE form. 
May use the Relying Site 
Serious Adverse Event 
Reporting Form. 
Unanticipated Problems that 
are not adverse events or 
protocol deviations  
This might include a Data 
Breach.   
UVA study team/ 
Data Coordinating 
Center 
 
UVA lead site or 
DCC will report to 
the IRB-HSR  per 
table above 
 
 
Within 7 calendar 
days from the 
time the study 
team received 
knowledge of the 
event.  
Written documentation.   
 
May use the Relying Site 
Unanticipated Problem 
Reporting Form 
Protocol 
Deviations/Noncompliance 
The IRB-HSR only requires that 
MAJOR deviations be 
reported, unless otherwise 
required by your sponsor, if 
applicable. 
 
OR 
 
Protocol Exceptions 
See definition- only allowed if 
there is a commercial sponsor 
or a DSMB that has granted 
the protocol exception.  
UVA study team/ 
Data Coordinating 
Center 
 
UVA lead site or 
DCC will report to 
the IRB-HSR per 
table above 
 
Within 7 calendar 
days from the 
time the study 
team received 
knowledge of the 
event.  
 
 
Written documentation.   
 
May use the Relying Site 
Protocol Deviation/Exception 
Reporting Form 
Data Breach  
Per local relying 
institution 
requirements 
 
The UVA IRB-HSR 
only needs to be 
notified of any 
data breach that 
meets the criteria 
of a UP 
Per local relying 
institution 
requirements 
 
Per local relying institution 
requirements. 
 
 
 
 

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13 APPENDICES 
13.1 Schedule of Activities (SoA) 
  
Procedures 
Eligibility / Enrollment 
Day 0 
Pre-Assessment 
Day 0 + 14 Days 
SHUTi intervention period 
Completion of sleep diaries 
Post-assessment 
9 weeks post-SHUTi initiation +14 days 
Eligibility screening 
X 
 
 
 
Informed consent 
X 
 
 
 
Pre-assessment (online 
questionnaires) 
 
X 
 
 
Baseline sleep diaries 
 
X 
 
 
Access to SHUTi (study 
intervention) 
 
 
X 
 
Post-assessment (online 
questionnaires) 
 
 
 
X 
Follow-up sleep diaries 
 
 
 
X 
 
 

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Data and Safety Monitoring Plan:  IRB-HSR serves as sIRB of Record 
 
13.1.1.1.1.1 
DEFINITIONS: 
1.3 What is the definition of an unanticipated problem?  
Do not change this answer 
An unanticipated problem is any event, experience that meets ALL 3 criteria 
below: 
 Is unexpected in terms of nature, severity or frequency given the 
research procedures that are described in the protocol-related 
documents AND in the characteristics of the subject population being 
studies 
 Related or possibly related to participation in research.  This means 
that there is a reasonable possibility that the incident may have been 
caused by the procedures involved in the research study. 
 The incident suggests that the research placed the subject or others 
at greater risk of harm than was previously known or recognized OR 
results in actual harm to the subject or others 
 
Additional Information: see the IRB-HSR website at  
Protocol Deviations, Non-compliance and Protocol Exceptions 
1.4 What is the definition of a Protocol Exception?   
__X___NA- No outside sponsor 
_____Protocol has a sponsor or a Data & Safety Monitoring Board (DSMB) outside of 
UVA.  Protocol exceptions are circumstances in which the investigator wishes to 
deviate from eligibility criteria or one or more of the specific procedures called for in 
a research plan. Unlike modifications that apply to all subsequent subjects in the 
research, a protocol/research plan exception only applies to a specific subject or 
group of subjects. Exceptions are planned, and the investigator gets approval from 
the sponsor ahead of time. Such a request should be rare and justified in terms of 
serving the best interests of the potential study participant. 
 
 
 
 

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1.5 What is the definition of a data breach? 
Do not change this answer 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized 
acquisition, access, or use of protected health information (PHI) that 
compromises the security or privacy of such information. 
Additional Information may be found on the IRB-HSR Website:  Data Breach 
13.1.1.1.1.2 
2.  IDENTIFIED RISKS AND PLANS TO MINIMIZE RISK 
_____NA- PI is not the overall person overseeing the safety data for this study.     
___X__All adverse events 
We will monitor the safety of participants and the security and integrity of data through 
several, interrelated strategies. No serious problems are anticipated, but should they occur 
while the subject is in the protocol they will be reported to the IRB according to policies. 
Any unanticipated problem or serious and unexpected adverse events will require re-
evaluation of the risk of the study. As PI, Dr. Shaffer will be the person to whom all 
unanticipated problems or serious and unexpected adverse events, whether psychological 
or medical, are initially reported. Dr. Shaffer is a licensed clinical psychologist who can 
evaluate whether the events are SAEs or AEs. Dr. Shaffer will be responsible for ensuring 
that all unanticipated problems or serious and unexpected adverse events are reported 
within 48 hours to the IRB and NCATS. We will, of course, monitor the profile of adverse 
events carefully and take any necessary steps needed to maintain participant safety. Any 
change to the procedures will be forwarded to the IRB for approval. Additionally, we will 
submit an annual report to the NCATS Project Officer summarizing all adverse events. 
There are a number of procedures in place to protect against possible risks: 
(1) Loss of privacy: All possible precautions will be set in place in order to prevent 
loss of confidentiality. Risks will be minimized by the following considerations: all 
study data collected will be stored electronically on a UVA protected network 
drive and accessible only to the PI and essential members of the research team. 
Qualtrics for Highly Sensitive Data will be used to administer questionnaires: this 
web-based survey tool is frequently used in behavioral health research and is 
HIPAA compliant. The data will be password protected. During data 
summarization and analysis, individual participants will be identified by code 
number only. No data identifying individual participants will be published or 
disclosed to third parties without prior consent of the participant. A password-
protected list matching names with code numbers will be kept in a separate 
computer file and folder from the one where the data is stored. If a person agrees 
to participate in the study, all questionnaires will be labeled with the participants’ 
study ID number, not their name or any other identifiable information. Participants 
will be informed that they can choose to not answer any questions for any 

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reason. All identifiable data (e.g., phone number, email addresses) will be kept 
private on the UVA network drive and a password protected spreadsheet. 
(2) Initial discomfort/embarrassment: For all participants, completing questionnaires 
may cause some distress or discomfort; however, past research has shown that 
such distress is usually minimal and transient. Participants are informed that they 
may withdraw from the study at any time or not answer questions they do not 
wish to address.  
(3) Internet concerns: Although some participants may feel more comfortable 
providing information over the Internet, others may feel less comfortable with this 
process and have concerns about the confidentiality of their data. To address this 
concern, data collected via the Internet will be obtained through secured means 
and stored on private servers. All data on our servers are password protected 
and limited to authorized research personnel. The high-level architecture of the 
system allows us to separate identifying and non-identifying data. We have 
worked out a system given our previous Internet intervention studies in which two 
servers have been set up with one private server configured behind the HIPAA 
compliant firewall where secured data reside, and only individuals who have 
onsite or VPN access are able to connect to this server. A second server 
maintains the front-end Web system so that individuals (the participants) offsite 
can access the program. Data submitted by these users are captured and 
transferred to the secure server. Analyses will be conducted without identifiers. 
(4) Initial tiredness: Participants who follow SHUTi recommendations to restrict sleep 
could initially feel more tired. To minimize the risk associated with sleep 
restriction, the system does not recommend participants restrict sleep to fewer 
than five hours. The initial assigned sleep window is also comparable to how 
much total sleep time the participant is already getting (based on diary data), but 
the sleep time is restricted to a smaller window (i.e., rather than allowing a 
participant to get 6 hours of sleep while spending 8 hours in bed, a participant 
may be asked to spend no more than 6 hours in bed). Participants will be told to 
avoid operating a car or other heavy machinery when they feel tired. To further 
minimize risks associated with sleep restriction, we will instruct participants that 
they may contact us if they have significant concerns. As needed, we will instruct 
participants to contact their primary care provider. 
(5) Limited human element in provision of care: To minimize the risks associated 
with conducting a study online (i.e., more limited in-person assessment or no 
face-to-face treatment), participants will be instructed to contact study staff if they 
have any concerns or questions. This has been done successfully in all of our 
Internet intervention studies, with study staff interacting with participants in the 
participant’s preferred method. Study staff are also well-trained to provide 
technical support. If any participant shows evidence of the need for immediate 
treatment (e.g., active psychosis, suicidal intent) at any time during the consent, 
assessment, and treatment periods, one of the investigators will be notified and 

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the patient will be referred for immediate psychiatric assistance. All participants 
will be able to access support for technical difficulties. All interactions will be 
carefully tracked (number of contacts, type of contact, and number of minutes 
spent on the contact). This information ensures clear communication and prompt 
responses with participants. It also allows us to evaluate whether outcomes are 
affected by interaction with study staff. 
(6) Ethical and legal concerns regarding online intervention provision: We have 
worked extensively with the University of Virginia’s legal counsel to ensure that 
ethical and legal issues are reviewed and addressed in our other Internet-based 
studies and will do so again for the proposed study. Participants will be instructed 
to talk to their Primary Care Physician (PCP) if they have any concerns or 
questions regarding website content. Participants will be required to indicate that 
they have read and accept language that states they should not consider the 
information in the application to be a replacement of medical advice, but should 
contact their PCP if they have questions or concerns. 
 
_____Unanticipated Problems 
__X___Protocol deviations/Issues of noncompliance 
This study does not include a phase III clinical trial and therefore does not require an 
independent data and safety monitoring board. Project investigators will help ensure the 
safety of participants, as well as the validity and integrity of the data, by discussing project 
updates at the ongoing twice-monthly study meetings. At these meetings, we will review 
study progress and address any issues with the research procedures and database. 
Separate consultation will be sought with Mr. Camacho (statistician) regarding data 
issues. Twice-monthly supervision meetings will be held with the trained research study 
assistants at UVA and Pitt (convened via videoconference). Discussion at study meeting, 
separate consultations, and study staff supervision meetings with key personnel will cover: 
1) recruitment, consent, and enrollment; 2) unanticipated problems, serious and 
unexpected adverse events, concluding with the safety procedures used to handle and 
minimize the occurrence of adverse events; and 3) procedures for data collection, data 
entry, and data storage. Procedures can always be modified to enhance the safety of the 
study if needed. All staff with access to data will have completed extensive human subjects 
protection training through the Collaborative Institutional Training Initiative (CITI) training 
program.  
 
_____Audit results 
_____Application of dose finding escalation/de-escalation rules  
These should be outlined under 2.4. 
_____Application of study designed stopping/decision rules 
_____Early withdrawals 

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_____Whether the study accrual pattern warrants continuation/action 
_____Endpoint data 
__X___Other: Specify   Answer/Response: Protecting against loss of confidentiality 
All possible precautions will be set in place in order to prevent loss of 
confidentiality through rigorous data security measures. All study data 
collected will be stored electronically on a UVA protected network drive 
and accessible only to the PI and essential members of the research team. 
Survey data will be collected via the UVA Highly Sensitive Data Qualtrics 
portal, which is certified for use with HIPAA-regulated personal health 
information (PHI) and protected by the University’s clinical firewalls. A 
password-protected list matching names with code numbers will be kept 
in a separate computer file and folder from the one where the data is 
stored. If a person agrees to participate in the study, all questionnaires will 
be labeled with the participants’ study ID number, not their name or any 
other identifiable information. All identifiable data (e.g., phone number, 
email addresses) will be kept private on the UVA network drive and a 
password protected spreadsheet. 
 
13.2 Protocol Amendment History 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
9/2/21 
Removed OnCore registration / 
line about treating physician 
Removing OnCore participant 
registration – this is not 
required as it is expedited 
research. Removing “treating 
physician” as this is not 
applicable to the study. 
 
9/2/21 
Added 
UVA 
Cancer 
Center 
recruitment database 
Added recruitment method 
of 
sending 
letters 
to 
individuals 
previously 
indicating 
interest 
in 
contact for future research 
studies 
 
9/2/21 
Added Karen Ingersoll, PhD 
Added 
Karen 
Ingersoll, 
PhD as subinvestigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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