Objectives

Our main objective is to assess the feasibility and preliminary effectiveness of SRT for newly diagnosed breast cancer patients with acute insomnia. Primary outcomes relate to issues of recruitment and retention, intervention fidelity, data collection procedures, completion of outcome measures, and intervention acceptability. Table 1 summarises the schedule of assessments. Table 2 summarises the primary outcomes and corresponding success criteria for moving forward to a full trial, which are based on a similar pilot RCT of breast cancer patients with insomnia [16] and a RCT of SRT in primary care [17]. Secondary outcomes relate to the effects of SRT, compared to SHE, on sleep, rest-activity rhythms, and mental health.

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Table 1. Schedule of assessments.

https://doi.org/10.1371/journal.pone.0305304.t001

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Table 2. Overview of primary outcomes and success criteria.

https://doi.org/10.1371/journal.pone.0305304.t002

Trial design

This pilot, two-centre, two-arm, parallel group, block randomised (1:1) controlled trial will compare SRT with a SHE control condition. Both groups will continue to receive standard breast cancer treatment as usual (TAU). Consistent with the requirements of a pragmatic trial, there will be no limitations upon usual care for either group. In this way, the trial represents a comparison of SRT+SHE (+TAU) vs. SHE (+TAU), permitting clear judgements to be made regarding the relative clinical utility of SRT. Due to the nature of the SRT intervention, it is not possible to blind the therapists and patients to treatment allocation. However, the statistician will be blinded to treatment allocation (i.e., SRT or SHE) until after data analysis is complete. The trial is prospectively registered with ClinicalTrials.gov (identifier NCT06294041). Ethical approval has been granted by the West of Scotland 3 committee (reference 23/WS/0113). Assessments will take place at baseline, 6 weeks, and 12 weeks post-randomisation (see Fig 1 for trial flowchart).

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Fig 1. Trial flowchart.

https://doi.org/10.1371/journal.pone.0305304.g001

Recruitment

We will recruit 50 newly diagnosed, non-metastatic, breast cancer patients whose primary cancer treatment is surgery. Patients are eligible for recruitment at any point between cancer diagnosis and the onset of chemotherapy or radiotherapy, but efforts will be made to recruit prior to surgery where possible. Potentially eligible patients will be identified by surgical teams at NHS Greater Glasgow and Clyde and NHS Grampian breast cancer results clinics. If the patient expresses interest in participating, a member of their clinical team (i.e., nurse therapist) will conduct a brief eligibility screening questionnaire to confirm initial eligibility. See Fig 1 for full details of the exclusion criteria at this stage. Upon completion of the brief eligibility screener, contact details for potentially eligible patients will be passed to the researcher, who will share the patient information sheet, undertake consent procedures (written consent will be obtained via Qualtrics), and conduct a full screening interview to confirm eligibility.

Inclusion criteria

1. Patient is willing and able to give informed consent
2. Aged 18 years and above
3. Screen positive for acute insomnia, defined as dissatisfaction with sleep quality or duration, accompanied by other night / daytime symptoms, present for between 2 weeks and 3 months
4. Newly diagnosed with non-metastatic breast cancer
5. Primary cancer treatment is surgery

Exclusion criteria

1. Pregnancy
2. Additional sleep disorder diagnosis (e.g., restless legs syndrome, obstructive sleep apnoea, narcolepsy) or screen “positive” for additional sleep disorder at screening interview
3. Dementia / Mild Cognitive Impairment
4. Epilepsy
5. Psychosis (schizophrenia, bipolar disorder)
6. Current suicidal ideation with intent or attempted suicide within past 2 months
7. Night, evening, early morning, or rotating shiftwork
8. Current / previous psychological treatment for insomnia during the last 12 months
9. Chemotherapy and / or radiotherapy commenced

Screening will include an assessment of current sleep status to confirm the diagnosis of acute insomnia, using the Sleep Condition Indicator [18]. It will also include a review of other relevant medical information (diagnosis of other sleep disorders, other medical and psychiatric disorders) to establish that there are no medical or psychiatric conditions that might preclude participation in the trial. Appropriate onward signposting will take place if any information is disclosed during screening that merits further investigation or follow-up (e.g. active suicidality). This procedure is made clear in the Patient Information Sheet.

Interventions

Sleep Hygiene Education (SHE): SHE has been used as a control condition in many trials evaluating SRT. It does not have any therapeutic benefit for insomnia but is often offered as part of usual care, so is a credible alternative to SRT. SHE will be delivered via a booklet that provides information about lifestyle changes (e.g., having a light snack before bedtime, reducing caffeine) and changes to the bedroom environment (e.g., ensuring a dark room, comfortable mattress, optimal room temperature). Patients in the SHE condition will be asked to implement the SHE advice over a 4-week period. One week after randomisation to SHE, the researcher will telephone patients to check they understand the SHE advice and answer any questions they may have. The SRT nurse therapist will have no input into delivery of SHE and will not review patients randomised to this condition.

Sleep Restriction Therapy (SRT): SRT is a manualised, adaptive, behavioural insomnia intervention that is a key active ingredient within multi-component CBT-I. Our SRT protocol [17] involves regularising and (where required) limiting a patient’s time in bed with the aim of increasing homeostatic sleep pressure, over-riding cognitive and physiological arousal, and strengthening circadian control of sleep [11]. Those randomised to SRT will receive 4 weekly sessions totaling approximately 75 minutes of patient-therapist contact time (a detailed description of intervention content is provided in the TIDieR checklist that can be found in S2 Table). SRT will be administered by nurse therapists, trained by LF during a half-day training workshop. LF will also provide supervision to the nurse therapists throughout the intervention implementation phase as required. The nurse therapists will work collaboratively with the patients over a 4-week intervention phase to develop a tailored sleep/wake schedule, by restricting and adjusting time in bed where required. Patients randomised to SRT will also receive a SHE booklet (as above).

The four-week SRT intervention will be structured as follows:

• Session 1 (30 minutes)—The first session will be delivered face to face (either in person or online). The nurse therapist will introduce the rationale for SRT to the patient, review baseline sleep diary data, focus on core SRT principles (not extending time in bed, avoiding napping, keeping regular bed/rise times, maximising daytime natural light exposure, minimising nighttime artificial light exposure), and prescribe new bed and rise times if required. Advice on the management of daytime sleepiness and discussion of barriers/facilitators to implementation will also be offered. Patients will be given a workbook supporting home implementation of SRT and SHE guidance.
• Session 2 (15 minutes)—The nurse therapist will telephone the patient to check progress, provide an opportunity for questions, and advise on titration of the patient’s sleep schedule for the following week based on a structured algorithm.
• Session 3 (20 minutes)—The third session will follow the same structure as session two but will be a face-to-face session. The nurse therapist will review patient progress, explore (and attempt to overcome) barriers to implementation, and further titrate the sleep schedule (where required).
• Session 4 (10 minutes)—The nurse therapist will telephone the patient to check progress, provide an opportunity for questions, and advise on further titration of the patient’s sleep schedule if required. Suggestions for ongoing implementation and the management of residual or recurrent insomnia symptoms will also be provided during this final session.

Assessments

Following completion of screening and consent procedures, eligible patients will be sent an email inviting them to complete a baseline (pre-intervention) assessment. Questionnaires can be completed online, over the telephone, or on paper, depending on patient preference. Insomnia severity will be assessed by the Insomnia Severity Index (ISI) [19], which is valid and sensitive to change in insomnia severity in cancer patients. We will also assess depressive symptoms [Patient Health Questionnaire (PHQ-9)] [20], anxiety symptoms [Generalised Anxiety Disorder Assessment (GAD-7)] [21], fatigue [Functional Assessment of Cancer Therapy (FACT-F)] [22], rest-activity rhythms [Actigraphy, CamNtech Ltd. MotionWatch 8], estimates of subjective sleep [Consensus Sleep Diary] [23], and health-related quality of life [EQ-5D-5L] [24] (from which, quality adjusted life years [QALYs] can be calculated). Within-treatment session outcomes for SRT will also be explored, so patients will be required to complete sleep diaries throughout the 4-week intervention phase providing information on sleep-wake cycles, such as bedtime, sleep onset latency, wake time after sleep onset, morning rise time, total sleep time, ratings of sleep quality and napping behaviour. After completion of baseline assessments, patients will be randomised and either referred to the nurse therapist for commencement of the SRT protocol or provided with the SHE resource. Following completion of the final assessment (12 weeks post-randomisation), those randomised to the SHE condition will be offered the opportunity to complete the SRT protocol without the requirement to complete any further assessments.

Randomisation and blinding

Following completion of baseline assessments, patients will be block randomised (1:1) to either SRT or SHE. The block size will vary from 2 to 4. The randomisation procedure will be administered by the statistician (DY). Due to the nature of the SRT intervention, it is not possible to blind the researcher, nurse therapist, or patients to treatment allocation. However, the statistician will be blinded to treatment allocation until data analyses are complete.

Sample size

As our focus is on feasibility, this trial is not formally powered to test clinical effects. However, based on a mean difference in ISI scores of 4.2 between groups [11] and an estimated standard deviation of 4.5 [17], a sample size of 40 patients (20 in each arm) would be required to achieve a power of 80% with a 5% significance level. We plan to randomise 50 patients (25 to each trial arm) based on an assumed dropout rate of 20% post randomisation. The results from this feasibility trial will help to refine the sample size calculation for a future definitive RCT.

Qualitative process evaluation

To explore both trial and intervention processes, we will qualitatively explore contextual factors, implementation procedures, and intervention mechanisms of action to fully understand how nurse administered SRT is provided and received in oncology settings. This work complements the quantitative success criteria outlined in Table 2. Specifically, we will evaluate how intervention training is delivered to nurses and its acceptability to them, how the intervention is administered by nurses and whether intervention fidelity is maintained, the patient’s response to the intervention, how they interact with it, what they do as a result and any unexpected consequences. We will also explore any contextual factors within clinics and the wider health service environment that affect intervention implementation during the trial, increasing understanding of barriers and facilitators to intervention implementation, and providing insights for a future trial. To explore these issues, in-depth semi-structured interviews / focus groups (in-person, online, telephone) will be conducted by the researcher across both sites, and we will use theoretical frameworks [25, 26] designed explicitly to understand implementation processes. The sample size for this qualitative process evaluation is 20, comprising 15 patients (10 from SRT, 5 from SHE) and 5 clinical staff (including the nurse therapist and those responsible for patient recruitment).

Adverse events and criteria for discontinuation

Adverse Events (AEs) are defined as any unwanted medical event, reaction or side effect that occurs during the trial. AEs unrelated and related to the interventions will be recorded during treatment. Relatedness will be assessed by the researcher in the first instance, who will complete an adverse event reporting form. This form will then be reviewed and signed off by the CI. An AE will be classified as an unanticipated problem (UP), if the AE is unexpected, if it is related or possibly related to the trial procedures, and if the occurrence indicates that the patients or others are placed at greater risk by completing the trial than previously assumed. Serious Adverse Events (SAEs) such as deaths, suicide attempts, and serious accidents will also be recorded, captured via patient report and/or clinical records. We will also encourage patients to notify the research team of any change to their health and wellbeing that occur during the trial, in order that these can be recorded.

All AEs will be recorded in an adverse event reporting form, where a detailed description of the event and follow-up action will be noted. All SAEs that are deemed to be related to the trial will be reported to the Ethics Committee within 48hrs, and UPs that do not meet criteria for SAEs will be reported to the Chief Investigator within 48hrs, who is responsible to reporting to the Ethics Committee within 30 days. All remaining AEs will be collated for review by the trial steering group (comprised of four independent members, the trial researcher, and the CI).

This trial will be stopped prior to completion if: (a) the intervention is associated with AEs that call into question the safety of the intervention (> 20% of patients develop a SAE related to the intervention); or (b) any new information becomes available during the trial that necessitates stopping the trial; or (c) other situations occur that might warrant stopping the trial. Given previous research on SRT in breast cancer, it is unlikely that these thresholds will be met in this trial. Any decisions regarding discontinuation of the intervention would be made in consultation with the REC and the trial steering group.

Data analysis

As this is a pilot trial, interpretation of the results will be considered with reference to the MRC Framework for Complex Interventions. Details of patient screening, recruitment, retention, withdrawal, adherence, and follow-up will be reported descriptively as outlined in Table 2 above. To assess intervention acceptability, focus group/interview data will be transcribed and analysed using a Framework approach for qualitative data analysis supported by QSR NVivo. Analysis will occur as the interviews are transcribed and we will analyse qualitative process data prior to knowing trial outcomes to avoid biased interpretation. To fulfil our secondary aim, between group comparisons of ISI 6-weeks post-randomisation will be done using t-tests or Mann-Whitney tests. Effect sizes, along with 95% confidence intervals, will be reported for per-protocol and intention to treat analysis.

Public and Patient Involvement (PPI)

In preparation for commencement of this trial, we recruited 5 members of our (previously established) PPI network to help shape the research questions, develop the project design, select suitable outcome measures, advise on the recruitment and data collection strategy, and contribute to proposal writing and editing. This ensures that patient wellbeing and improved patient care are central to our methodology. PPI colleagues will be invited to join each Investigator meeting (every 3 months during the trial), and one is a co-author on this paper. Our PPI network will also help to inform our wider dissemination and communication strategy by identifying key groups who will benefit most from trial outcomes.

Data management

Data will be managed in accordance with GDPR. The data management plan (DMP) is stored at the University of Strathclyde’s DMP repository according to University’s Research Data Management Policy and is subject to regular reviews. Data monitoring will be handled by the independent trial steering committee. After data collection is complete, de-identified data from this trial will be made available as open data through a research data repository [e.g., National Sleep Research Resource, https://sleepdata.org/) and metadata on Pure. None of the recordings from the focus groups/interviews will be shared as open data. Request for data use will be approved by the CI. We will not approve use for commercial purposes.

Trial status

The trial will open for recruitment in June 2024 and will continue recruiting until approximately March 2025, with outcome data expected around April 2026. This trial has received favourable opinion from West of Scotland REC 3 (reference 23/WS/0113).