Impact of Web-Based Cognitive Behavioral Therapy for Insomnia on Stress, Health, Mood, Cognitive, Inflammatory, and Neurodegenerative Outcomes in Rural Dementia Caregivers: Protocol for the NiteCAPP CARES and NiteCAPP SHARES Randomized Controlled Trial

Background Chronic insomnia affects up to 63% of family dementia caregivers. Research suggests that chronic insomnia prompts changes in central stress processing that have downstream negative effects on health and mood, as well as on cognitive, inflammatory, and neurodegenerative functioning. We hypothesize that cognitive behavioral therapy for insomnia (CBT-I) will reverse those downstream effects by improving insomnia and restoring healthy central stress processing. Rural caregivers are particularly vulnerable, but they have limited access to CBT-I; therefore, we developed an accessible digital version using community input (NiteCAPP CARES). Objective This trial will evaluate the acceptability, feasibility, and short-term and long-term effects of NiteCAPP CARES on the sleep and stress mechanisms underlying poor caregiver health and functioning. Methods Dyads (n=100) consisting of caregivers with chronic insomnia and their coresiding persons with dementia will be recruited from Columbia and surrounding areas in Missouri, United States. Participant dyads will be randomized to 4 weeks (plus 4 bimonthly booster sessions) of NiteCAPP CARES or a web-based sleep hygiene control (NiteCAPP SHARES). Participants will be assessed at baseline, after treatment, and 6- and 12-month follow-ups. The following assessments will be completed by caregivers: 1 week of actigraphy and daily diaries measuring sleep, Insomnia Severity Index, arousal (heart rate variability), inflammation (blood-derived biomarkers: interleukin-6 and C-reactive protein), neurodegeneration (blood-derived biomarkers: plasma amyloid beta [Aβ40 and Aβ42], total tau, and phosphorylated tau [p-tau181 and p-tau217]), cognition (Joggle battery, NIH Toolbox for Assessment of Neurological and Behavioral Function, and Cognitive Failures Questionnaire), stress and burden, health, and mood (depression and anxiety). Persons with dementia will complete 1 week of actigraphy at each time point. Results Recruitment procedures started in February 2022. All data are expected to be collected by 2026. Full trial results are planned to be published by 2027. Secondary analyses of baseline data will be subsequently published. Conclusions This randomized controlled trial tests NiteCAPP CARES, a web-based CBT-I for rural caregivers. The knowledge obtained will address not only what outcomes improve but also how and why they improve and for how long, which will help us to modify NiteCAPP CARES to optimize treatment potency and support future pragmatic testing and dissemination. Trial Registration ClinicalTrials.gov NCT04896775; https://clinicaltrials.gov/ct2/show/NCT04896775 International Registered Report Identifier (IRRID) PRR1-10.2196/37874

ZRG1 BBBP-S (02) MCCRAE, C post-treatment and two follow-ups (6 and 12 months) and include CG sleep, arousal, inflammation, health, mood, burden and cognition, and PWD sleep. The proposed study has four specific aims. Aim 1 focuses on the feasibility and acceptability of NiteCAPP and WebSHE (sleep hygiene educationactive web comparator). Aims 2 and 3 examine NiteCAPP's effects (versus WebSHE) on CG primary/mechanistic (sleep, arousal, inflammation) and secondary outcomes (health, mood, burden, cognition), respectively. Because the PWD's sleep impacts CG sleep, Aim 4 examines NiteCAPP's secondary effects on PWD sleep (objectively assessed). An Exploratory Aim examines the relationships between changes in CG primary and secondary outcomes, and their potential mediators/ moderators. Public Health Implications: Demonstration that rural CGs can use NiteCAPP to target sleep, arousal/stress, inflammation and related health concerns has important implications for multiple stakeholders, including rural CGs, rural PWDs, their families, clinicians and policymakers.

PUBLIC HEALTH RELEVANCE:
This trial uses internet technology and community methods to test the acceptability, feasibility and efficacy of NiteCAPP, a brief web CBT-I for rural dementia caregivers (CGs). It offers new understanding of how NiteCAPP improves CG sleep, arousal and inflammation and prompts downstream effects on other outcomes (health, mood, burden, cognition). Demonstration that rural CGs can use NiteCAPP to target sleep, arousal, inflammation and related concerns has important implications for rural CGs/PWDs, their families, clinicians and policymakers.

CRITIQUE 1
Significance: 3 Investigator(s): 1 Innovation: 4 Approach: 2 Environment: 2 Overall Impact: This is a resubmission of an Investigator-initiated R01 that proposes to develop a Web-based Cognitive Behavior Therapy program for Insomnia (CBT-I) for caregivers (CGs) of Persons With Dementia (PWD) living in rural environments. The Principal Investigator is outstanding, the Co-Investigators strong and the Environment is excellent. The Resubmission is extraordinarily responsive to the prior Summary Statement in making numerous changes and modifications to the application, perhaps the most substantive being the development and pilot testing of the Web-based package, as well as the inclusion of both genders as CGs, the inclusion of a conceptual model (Cognitive Activation Theory of Stress), a fully developed data analytic plan including Generalized Estimating Equations, elucidation of a Data Safety Monitoring Board, a rationale to study CGs in rural environments, and inclusion of Co-Investigators to enhance recruitment. An additional asset of the application is its alignment with the NIH Science of Behavioral Change initiative. The usage of actigraph data derived from the PWD constitutes a potentially important aspect of understanding mediational effects. Despite these many strengths, there remain some issues regarding the selection of plasma markers, and the particular Heart Rate Variability measure selected here is not well-justified, though it could still serve adequately in the mediational models. The Web-based implementation of CBT-I with rural CGs of PWD can be construed as nominal repackaging of well-established behavioral approaches for sleep interventions that have already been applied by the Principal Investigator and others to many other patient groups, including some in rural setting, albeit in a different venue. The degree of novelty is thus incremental, rather than fundamental, and this impacts the whole of the application, which is generally well-done but not exceptionally innovative.

Strengths
• In response to issues raised on previous review, intervention (NiteCAPP) has been pilot tested and has been the subject of focus groups; these results now well-presented in the application; appropriate care for development of issues specific to older CGs (readability, ease of use, etc.) has been taken; preliminary data from intervention yields > 10% improvements in subjective sleep efficiency, 7-point reduction in ISI and 5-point reduction in BDI, all meaningful and nontrivial effects • The Principal Investigator is well-connected with the local community of PWD and their CGs and has many letters of interest and support from appropriate administrators documenting this that are included in the application • The study is grounded in conceptual model (Cognitive Activation Theory of Stress) • Study will probe mechanism by examining mediators and moderators as predictors of improved sleep (emphasizing not only the "what" but also the "how" and "why") • The PI has worked with CBT-I in older rural populations previously (RESTORE studies) • Web-based delivery of CBT-I makes sense given widespread internet access throughout Missouri • Appropriate statistical analyses including GEE accounting for missing data, correction for familywise error, and examination of mediation effects at each successive time point are proposed • Training plans for therapist/moderators are detailed and specific; plans for monitoring treatment integrity are very explicit and clear

Weaknesses
• Arguably, rurality per se may not be a major an issue in sleep problems, when compared to other factors impacting potential health care disparities, such as race, ethnicity, education or occupation; however, this may not be the case for other components of behavioral health (e.g., obesity), and the Investigators imply that other issues (e.g., stigma) may be more relevant in rural areas • Rationale for these particular inflammatory markers (IL-6, CRP) is not developed • Some aspects of the rationale for reducing inflammation, although theoretically conceivable, are somewhat conjectural and impossible to test, e.g., the case for reducing inflammatory markers such as CRP and IL-6 in the CGs as reducing risk for later neurodegenerative disease; by way of example, the size of such effects might be expected to be much lower than CG's genetic load • More details regarding how specific actigraphic data collected in PWD are to be incorporated into the mediational analyses could be provided

Strengths
• The application contains letters of support from colleagues listed within the University Missouri system (Biostats, Nursing, Neurology, Psychiatry, Family Medicine, and Informatics), from various Consultants outside of University of Missouri, local Alzheimer's Association representatives. This is an impressive show of support.
• Although this is Web-based research, the reputation and physical location of the University of Missouri in Columbia is well-situated to allow access to a statewide population that has a large rural component

Resubmission
• This is resubmission of an R01 originally reviewed by the MESH IRG in June 2019; the Investigators have been extraordinarily responsive to a large number of comments offered by prior Reviewers; their single-page Introduction to this resubmission is a densely packed read that adequately addresses prior IRG comments regarding the original submission

CRITIQUE 2
Significance: 1 Investigator(s): 2 Innovation: 1 Approach: 3 Environment: 2 Overall Impact: This re-submission has been responsive to reviewers criticisms, is responsive to the NIH special interest announcement and proposes a very innovative yet pragmatic approach to helping caregivers (CG) working with patients with dementia (PWD) to manage the debilitating disruption that the PWD sleep disturbance can cause. CGs themselves are a vulnerable population, and are a target group for support and early intervention, to help them maintain their own cognitive functioning and wellbeing, manage their own insomnia and sleep disturbance, while still caring for the loved one with dementia. This proposal takes a train-the-trainer approach to give CGs tools to use for managing sleep disturbance in the PWD, and to provide self-help. It has the potential to transform dementia care in rural settings, and beyond.

Strengths
• Caregivers (CG) of persons with dementia (PWD) are under a great deal of stress as they care for loved ones. They have a rate of risk for dementia that is increased compared with the noncaregiver population. In rural settings, there is little possibility to provide clinician access and even telehealth is challenging to implement. However, internet is readily available in the 1 R01 AG066081-01A1 8 ZRG1 BBBP-S (02) MCCRAE, C community/home. An app supported by a care delivery program that could be used to help support CGs and their PWD partner is highly innovative and pragmatic. It could help transform quality of care in the rural setting where access to medical and dementia support resources is a great challenge. As sleep is one of the most challenging PWD symptoms to manage from a CG perspective, and leads to deterioration of the CG's ability to provide care, the strategies being tested in this proposal have the capacity to make a large social and medical impact, and provide large healthcare savings, as well.

Weaknesses
• No significant weaknesses.

Strengths
• McCrae has a developing leadership track-record in this area.
• The group has done a first rate job pulling together expertise to vet and develop this innovative approach.

Weaknesses
• Biostatistics and modeling effort could be higher in order to maximize data analysis, integration and explore scaling opportunities.

Strengths
• While CBTi apps are no longer novel, this proposal is highly innovative in its approach to the CG-PWD dyad.
• The teaching of the CG to help themselves and the PWD, is highly innovative and may be transformative in this realm.

• Weaknesses
• Plenty of challenges but no significant weaknesses.

Weaknesses
• None noted by reviewer.

Strengths
• This is a carefully thought through and planned train the trainer approach to CG support around sleep.
• The use of the community advisory board is exemplary. They have even provided infrastructure and support for respite care costs for PWDs.
• In-home apnea screen.
• The use of an active control is a strength.
• The 24-hour return contact is an asset and will help to ensure success. • Responsive to the NIH notice of special interest.
• Although not central to the importance of outcome value, the addition of inflammatory mediators (hCRP, IL-6) and autonomic measures (HRV) will potentially demonstrate broader long-term health efficacy.

Weaknesses
• Plans for physiological measures are insufficiently detailed. One might argue that the aim to test the intervention, coupled with evaluation of sleep-wake patterns and self-report indices are significant without the physiological measures, which are underdeveloped with respect to methodologies used.
• Data analysis could be more detailed, but important factors such as handling of missing data are incorporated.
• Access to rural areas and informatics/computer development support are in place

Weaknesses
• No significant weaknesses.

Strengths
• The study timeline is appropriate for the study which plans to include 100 dyads.

Weaknesses
• More time for data analysis would be advantageous, but exploratory analyses undoubtedly will continue past the award.

Acceptable Risks and/or Adequate Protections
• Maybe it's an error and wasn't deleted from a previous version, but the investigators write, "Likewise, participants whose imaging scans reveal abnormalities will be referred to a neurologist or their primary care physician for follow-up". Is a scan even being conducted? • The CG is more often a woman and this is built into the rationale for imbalance in subjects.
Adult CG is appropriate and justified.

Resubmission
• Appropriate response to reviewer concerns.

CRITIQUE 3
Significance: 4 Investigator(s): 2 Innovation: 1 Approach: 4 Environment: 1 Overall Impact: This project is a resubmission of a grant to conduct an initial controlled efficacy trial of NiteCAPP, a web-based CBT for insomnia intervention designed for primary caregivers of individuals with dementia who live in rural settings. Considerable preliminary work has been conducted in support of this adaptation of CBTi for the caregiving population and an initial pilot study provides support for feasibility and acceptability of the approach. The current Stage II trail is designed to provide further support for the feasibility and acceptability of the approach and initial efficacy data. The team plans to recruit 100 CGs and assign them to NiteCAPP or a well-matched, web-based control condition. Both interventions involve 4 x 45 minutes online sessions and 4 booster sessions over a 12-month period. Outcomes will be assessed pre-and post-intervention, and at 6 -and 12-month follow-up. Primary outcomes include sleep parameters, heart rate variability, and blood markers of neurodegeneration and systemic inflammation. Secondary outcomes are CG health, mood, burden, executive function, and the person with dementia's sleep. There are many strengths of this application. It addresses a significant public health disparity, represents a logical next step in Dr. Mccrae's research program, and involves an experienced study team that is geographically well placed to focus on health disparities among rural caregivers. In addition, the development of the intervention was well considered and included community input at all stages of the process, and the preliminary data generally supports the approach. The team were also responsive to many of the issues raised on initial review. Weaknesses of the 1 R01 AG066081-01A1 11 ZRG1 BBBP-S (02) MCCRAE, C application focus on the presented conceptual model, in particularly the consideration of proposed physiological mediators ("arousal" and blood markers of neurodegeneration and inflammation) of health/mood, burden and cognitive outcomes. This model and the rationale for focusing on these physiological parameters as primary outcomes remains unclear.

Strengths
• The health of individuals who are caring for loved ones with dementia is a growing public health concern. 63% of caregivers have chronic and enduring insomnia.
• Rural caregivers are at particularly high risk due to difficulty accessing health care.
• A strength of the proposal is the examination of a brief, easily accessible, web-based intervention refined to address the needs of rural caregivers, a group at heightened risk for mental and physical health disparities.
• The use of remote technology to access a rural population.
• Preliminary pilot data supporting feasibility and acceptability of the approach.

Weaknesses
• The Cognitive Activation Theory of Stress model added in the revision is not clear, particularly in regard to the role of physiological pathways. The presented model suggests that "insomnia, arousal and inflammation" prompt CNS changes resulting in adverse health outcomes. Specifically, it is suggested that these factors lead to changes in the sympathetic division of the autonomic nervous system and the HPA axis that contribute to lower health-related QOL, depression, burden and poorer cognitive function. This model lacks clarity. If arousal is defined as activation of the ANS, then it is proposed that arousal leads to arousal? Activation of the sympathetic nervous system and the HPA axis are known to contribute to the control of peripheral inflammation, raising questions about the direction of expected effects. It is proposed that NiteCAPP will decrease peripheral markers of inflammation and thus restore HPA and ANS function. However, an alternate model, supported by existing literature, suggests that sleep disruption dysregulates peripheral pathways (ANS, HPA) and thus results in increased systemic markers of inflammation. In sum, the inclusion of "arousal" and inflammation as primary outcomes is not clearly considered.
• Arousal is assessed by measuring HRV, which provides a better measure of activation of the parasympathetic division of the ANS, than the sympathetic division. If the primary mechanisms of interest are the SNS and HPA axis, then better measures are available.
• Arousal is not clearly defined and references to "improved physiological arousal" and "impaired ANS function" are unclear.
• Preliminary work provides considerable support for the proposed sleep outcomes. However, preliminary evidence in support of the inclusion of markers of inflammation/ neurodegeneration is weak or missing.
• No rationale is provided for the proposed peripheral markers of neurodegeneration.
• The Authors are currently conducting a second pilot trial. It is not clear how this trial will inform the proposed work, particularly if it does not support/replicate evidence for proposed pathways. • The study team is impressive and covers much of the expertise necessary to conduct the proposed trial.

Weaknesses
• The team would benefit from expertise in psychophysiology/neuroendocrinology given the proposed pathways. Although Co-I Curtis is reported to have taken a course in HRV, she does not mention this in her letter and there are concerns about how this measure is understood in the proposal.

Strengths
• The proposal is seen as innovative. Particularly, the development of a user-friendly intervention designed to address insomnia and stress among rural caregivers with limited access to other treatment options.
• The adaptation of traditional CBTi to address other issues confronted by caregivers, e.g., stress.
• Adaptation of the intervention to target sleep in the PWD • Involvement of CG peer advocate.
• Use of booster sessions and plan to follow participants for 12-months.

Weaknesses
• The sections on autonomic arousal and inflammation are not well developed.

Strengths
• The proposed trial is well considered and an appropriate next step for the phase of intervention development.
• Recruitment of an appropriate sample of caregivers with insomnia is carefully considered and appears feasible.
• The intervention has been carefully developed and well adapted to meet the needs of the target population, with engagement of the community at all stages of refinement of the approach.
• Adaptation of traditional CBTi to include challenges affecting rural caregivers, e.g., the addition of problem solving and stress management.
• The inclusion of the PWD in the intervention either directly or through strategies given to the caregiver.
• The study design appears appropriate for the phase of intervention development, including the use of a matched, active control condition.
• Integrity of the intervention is carefully considered.
• The engagement and participation of a community board to help direct the project is a clear strength.
• The data analytic approach appears appropriate and issues relating to power and attrition have been addressed.

Weaknesses
• Issues related to the blood draw that should be considered include the impact of diurnal variation in IL-6, resulting in a need to control time of day of sample collection.
• If examining markers of inflammation, factors that have an acute impact on circulating levels should be considered -e.g., acute illness, vaccination, antibiotics, anti-inflammatory medications. Group differences in other factors should be examined -e.g., inflammatory disease, medications that impact inflammatory mediators, adiposity.
• No methods are provided for the assessment of the proposed biomarkers. Evidence in support of reliability and validity of these methods is also needed.
• It is unclear whether the developed intervention, which appears to be adapted to meet the needs of elderly caregivers, is acceptably to younger caregivers.

Strengths
• Outstanding environment that will contribute to the success of the project.

Strengths
• The study timeline has been carefully considered.

Protections for Human Subjects
Acceptable Risks and/or Adequate Protections • The application has been modified to include a DSMB.

Inclusion Plans
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • For NIH-Defined Phase III trials, Plans for valid design and analysis: Not applicable