Sleep Treatment Education Program for Young Adult Cancer Survivors (STEP-YA): Protocol for an Efficacy Trial

Background Young adult cancer survivors (YACS) are at elevated risk for chronic insomnia, even years after completing treatment. In addition to potential health consequences, insomnia can interrupt social, educational, and vocational development just as they are trying to “make up” for time lost to cancer. Cognitive behavioral therapy for insomnia (CBTI) is recommended as first-line treatment for insomnia but remains largely unavailable to YACS due to several barriers (ie, shortage of trained providers, geographic limitations, financial limitations). Traditional CBTI has not been adapted to meet YACS’ unique developmental and circadian challenges. To improve availability of effective behavioral insomnia treatment for this population, we developed the Sleep Treatment Education Program for Young Adult Cancer Survivors (STEP-YA), a low-intensity educational intervention delivered virtually online. Objective In this phase 2 “proof of concept” trial, primary aims are to test the efficacy of STEP-YA to improve insomnia symptoms and mood in YACS and assess the utility of individualized coaching to improve treatment effects. A secondary aim will explore participant variables associated with clinically significant response to STEP-YA. Methods This 2-arm randomized prospective trial will enroll 74 off-treatment YACS aged 20 years to 39 years with clinically significant insomnia. Each participant completes the STEP-YA intervention in a 1-on-1 synchronous online session led by a trained interventionist following a structured outline. The 90-minute intervention presents educational information on the development of insomnia after cancer and offers specific suggestions for improving insomnia symptoms. During the session, participants review the suggestions and develop a personalized sleep action plan for implementing them. After the session, participants are randomized to either the coaching condition, in which they receive 2 telephone coaching sessions, or the no-coaching condition, which offers no subsequent coaching. The Insomnia Severity Index (ISI) and the Profile of Mood States: Short Form (POMS-SF) are assessed at baseline and 4 and 8 weeks postintervention. Results Enrollment began in November 2022, with 28 participants currently enrolled. We anticipate recruitment will be completed in 2024. The primary endpoint is a change in ISI score from baseline to 8 weeks postintervention. The secondary endpoint is change in mood symptoms (POMS-SF) from baseline to 8 weeks postintervention. Change scores will be treated as continuous variables. Primary analyses will use ANOVA methods. A within-subjects analysis will examine if the STEP-YA intervention is associated with significant changes in insomnia and mood over time. A 2-way ANOVA will be used to evaluate the utility of coaching sessions to improve treatment effects. Conclusions Chronic insomnia has significant negative effects on YACS’ medical, educational, and psychological functioning. STEP-YA aims to address their needs; study results will determine if the intervention warrants future effectiveness and dissemination studies and if individualized coaching is necessary for adequate treatment response. Trial Registration ClinicalTrials.gov NCT05358951: https://clinicaltrials.gov/study/NCT05358951 International Registered Report Identifier (IRRID) DERR1-10.2196/52315

unavailable.To address this, we propose to test STEP-YA, an online educational intervention delivered by a trained presenter.By reducing the barriers to evidence-based treatment, STEP-YA has the potential to make effective insomnia treatment widely available for young adult cancer survivors, significantly improving their health and quality of life.

CRITIQUE:
The written critiques of individual reviewers are provided in essentially unedited form in this section.Please note that critiques and criteria scores, prepared prior to the review meeting, may not have been revised following discussions at the meeting.The "Resume and Summary of Discussion" section summarizes the final opinions of the review committee.

CRITIQUE 1
Significance: 3 Investigator(s): 1 Innovation: 2 Approach: 4 Environment: 1 Overall Impact This is a randomized trial that proposes to test a brief online cognitive behavioral therapy for insomnia (CBTI) intervention and to examine whether two additional coaching sessions are associated with greater benefits.The remotely-delivered intervention is innovative in that it is delivered in a single synchronous session, which addresses common barriers to CBTI access and adherence and is highly scalable and also encourages a self-management approach that is developmentally appropriate for YACS.The investigators are experts in CBTI for YACS, and this work is a logical next step for their R03 and other preliminary work supporting the benefits of online CBTI and single-session sleep interventions for cancer survivors.The environment is outstanding.The strength of the preliminary data is somewhat limited in that only pre-post change in self-report measures resulting from single-arm trials are presented.The comparison condition, which is the single-session intervention with two additional coaching sessions, is not well-justified scientifically and the lack of a control arm remains a concern.The pre-post outcomes to be evaluated consist of two self-report scales; additional measures of sleep health or behavior would strengthen the rigor of this proposal, as would consideration of whether any benefits are sustained beyond 8 weeks.

Significance Strengths
• 1 in 4 YACS experience insomnia after cancer treatment, but insomnia often remains unaddressed • CBTI is effective at improving insomnia in cancer survivors but not accessible to most survivors • STEP-YA is brief (single session), delivered online, and tailored to meet some developmental needs (such as delayed sleep phase, hot flashes and other symptoms, and autonomy goals) • Intervention materials could be more interactive to support continued self-management • Additional measures of sleep health or behavior would increase the rigor of the proposal

Approach Strengths
• Project evaluates effects of STEP-YA (with and without coaching) on insomnia symptoms and mood in YACS with insomnia • Preliminary R03-funded work supports the efficacy of 3-session CBTI for cancer survivors as well as a single-session educational session, the feasibility of online delivery of CBTI, and benefits of a single session CBTI intervention • The intervention is well-described, uses materials that have been reviewed and positively rated by YACS, and a logical extension of the team's previous work

Study Timeline Strengths
• Reasonable Overall Impact This is a high impact proposal with relatively minor weaknesses.The investigators are expert in delivering insomnia treatment to AYA survivors of cancer and propose to evaluate the efficacy of their pilot work (funded by a R03 award) in a moderately scaled R21 that follows the optimization framework laid out in the ORBIT model.The proposal of a relatively simple, but powerful, intervention within a videoconference medium allows the investigators to address an initial efficacy question within the R21 budget.This is innovative and represents a good return on investment.Some tradeoffs are necessary ZCA1 SRB-T (J1) RECKLITIS, C with this strategy, however.Impact is diminished by lack of attention to the daily sleep data, and choice not to include objective assessment of sleep in even a subsample of participants.

Significance Strengths
• Insomnia is a significant problem in AYA cancer survivors.Moreover, techniques for improving insomnia are well-researched and understood.
• The team has a compelling intervention ready to deploy to AYAs with insomnia and the prior publications point logically toward this application as a next step.• The introduction to the application argues that this approach is different from other currently available techniques in its brevity.• Couching this work in the context of the ORBIT model and using this R21 to optimize the intervention is a strength that adds impact.Weaknesses • None noted.

Investigator(s) Strengths
• The team is excellent and obviously capable of the work based on their prior publications and pilot data.Weaknesses • None noted.

Innovation Strengths
• Tailoring the treatment to the needs of the patient and using that tailoring to decrease the time and effort in intervention is innovative.• The remote delivery of this single session intervention is innovative.Weaknesses • None noted.

Approach Strengths
• The team has translated evidence-based strategies for insomnia into an intervention that is ready for deployment.
• The use of the RCT is a strength as it allows the team to prepare for future efficacy work.
• The strategies in the intervention are appropriate and evidence-based.
• The intervention is brief which will help with uptake and should yield high engagement.
• There is evidence that the target outcomes are modifiable.
• The standard of care is appropriate.
• Inclusion and exclusion is appropriate.

Weaknesses
• It is within the team's capability to objectively assess sleep.However, in this resubmission that suggestion was not taken.Self-reported outcomes have low rigor.Accelerometers combined with a daily sleep log are a good middle ground.
• Sleep is a daily variable and there is a missed opportunity to capture the time-series data.

Environment Strengths
• The environment is excellent.

Study Timeline Strengths
• The timeline is appropriate for the aims and feasible.

Protections for Human Subjects Acceptable Risks and/or Adequate Protections
• The plan is detailed and appropriate.

Data and Safety Monitoring Plan (Applicable for Clinical Trials Only):
Acceptable o Data safety and HIPAA compliance are described, as are encryption protocols.

Inclusion Plans
• Sex/Gender: Distribution justified scientifically • Race/Ethnicity: Distribution justified scientifically • Inclusion/Exclusion Based on Age: Distribution justified scientifically • Justified scientifically.

Vertebrate Animals
Not Applicable (No Vertebrate Animals)

Biohazards
Not Applicable (No Biohazards)

Resubmission
• The introduction to the application is well-detailed and the team has made a number of important changes that increase impact.Some notable weaknesses in the methodology remain, and the team attempts to justify them with argumentation.It seems that even if there are limits to including a technique like accelerometers, the benefits of including them in even a subset of participants should be clear to the team and could significantly enhance their preparedness for the full RCT.

Overall Impact
Insomnia often becomes chronic, affecting ~ 25% of YACS.No evidence-based treatments available for YACS.The investigators propose optimization of a pilot tested brief online educational intervention (based on CBT-I, and self-management principles), targeting insomnia specifically in YACS.The PI proposes to test the hypothesis that STEP-YA improves insomnia symptoms (primary outcome) and mood (secondary outcome) and compare coaching versus non-coaching conditions.A secondary aim will explore participant factors associated with clinically significant response to the intervention.The resubmission was responsive to reviewers' comments.The strength of the proposal is the significance of the problem; the innovative intervention, primary outcome, sample size was based on pilot studies targeting the needs of YACS.Weaknesses that moderate the impact included lack of time control for the coaching control arm; An additional control arm may be needed to eliminate the placebo effect.Lack of objective measures to assess insomnia such as actigraphy may be a limitation.

Significance Strengths
• Insomnia often becomes chronic, affecting as many as 25% of YACS.
• Insomnia increases the risk for not achieving educational, social, and vocational milestones critical to young adult development.

Investigator(s) Strengths
• The PI and co-investigators have prior collaboration between them and have expertise to complete the study.Weaknesses • None noted.

Innovation Strengths
• Optimization of an online educational intervention targeting insomnia in YACS.
• Intervention developed on ORBIT model.
• Brief intervention (single synchronous online session) and self-management approach Weaknesses • None noted.

Weaknesses
• Lack of time control for the coaching control arm.
• An additional control arm may be needed to eliminate the placebo effect.
• Lack of objective measures to assess the effect of intervention on insomnia such as actigraphy may be a limitation.

Environment Strengths
• The environment is conducive to successfully complete the aims outlined in the proposal.

Study Timeline Strengths
• Timeline is appropriate to complete the study.

•
Remote delivery and single session addresses common barriers to CBTI access/adherence Weaknesses • Rationale for behavioral coaching and for focusing on the incremental benefits of this intervention component unclear and not well-supported by preliminary work • No control condition • Preliminary work describes pre-post changes from single-arm trials only • No objective measures of sleep behavior, which would be less subject to pre-post demand characteristics than the ISI • Assessment of outcomes at 4-and 8-weeks post-baseline only, limiting ability to evaluate whether any benefits are sustained 5. Environment Strengths • DFCI has outstanding resources to support the proposed research Weaknesses • None noted.

•
Intervention based on pilot data.•Randomized control trial design.•Eligibility criteria of presence of ISI>/=12.•Primary outcome measure (ISI), and sample size based on preliminary study.•Inclusion of minority participants.
Resubmission• Investigators were moderately responsive to previous reviews • CBT-I is a gold standard for treatment of insomnia in adult cancer patients is often not often available and doesn't target mechanisms that cause insomnia in YACS.
Acceptable Risks and/or Adequate Protections Data and Safety Monitoring Plan (Applicable for Clinical Trials Only): Acceptable 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 • Inclusion/Exclusion Based on Age: Distribution justified scientifically The resubmission was responsive to the reviewers' comments. Resubmission•