Study Design
This is a randomised, two-group, parallel, non-blinded, controlled, single-centre, superiority trial. One group will receive combined CBT plus BLT (CBT+). The other group will receive treatment as usual enhanced with a relaxation audio program serving as an active control (TAU+). All participants will be involved in the trial for the six-week duration. Measures will be taken at baseline, at the mid-point of the intervention (3 weeks), and post-treatment (6 weeks). A follow-up assessment will occur at three-months, to evaluate any sustained effects of the intervention on primary and secondary outcomes. This trial and protocol adhere to SPIRIT (48) and TIDieR (49) recommendations.
Recruitment and Consent
Women diagnosed with BC, who receive intravenous chemotherapy treatment at the Peter MacCallum Cancer Centre (PMCC) in Melbourne Australia, will be recruited after diagnosis and prior to the completion of chemotherapy. We have taken several steps to help ensure we achieve adequate recruitment and enrolment. The PMCC pharmacy department will generate a report of potentially eligible women, identified through their chemotherapy chart. The research team will attend the Chemotherapy Day Unit when each eligible woman has a scheduled appointment and approach women in person, which encourages higher enrolment. Due to the stress associated with BC treatment and the commencement of chemotherapy, women will not be approached during their chemotherapy education session or at their first chemotherapy appointment. Potentially eligible women who show an interest in participating will be provided with information about the study. Should they choose to participate, written informed consent will be obtained. After consenting, women will complete further screening assessments to determine whether they are eligible to participate. We have taken steps to help retention and completion of follow-up. The CBT+ condition was carefully designed to minimize burden (see section below on CBT+ Intervention). In the TAU+ condition, we include a mid-point telephone call and emails to maintain engagement.
Screening
Further eligibility will be assessed via structured interviews designed to detect sleep disorders or severe psychiatric disorders. Sections of the Mini International Neuropsychiatric Interview (M.I.N.I.) (50) will be administered including those relating to major depressive disorder (module A), generalized anxiety disorder (module N), manic and hypomanic episodes (module C), alcohol dependence and abuse (module I), substance dependence and abuse (module J), current post traumatic stress disorder not related to cancer experiences (module H), and psychotic disorders (module K). The Duke Structured Interview for Sleep Disorders (51) will be administered in its entirety. A detailed risk management protocol was used to ensure that if previously unidentified disorders were found, women were referred to psychology, psychiatry, or sleep clinics, as appropriate.
Inclusion criteria: women diagnosed with any stage of primary BC; over 18 years of age; receiving intravenous chemotherapy, with or without radiotherapy during the study period; able to provide informed consent; able to understand and speak English; able to regularly receive and access emails; able and willing to wear light therapy glasses.
Exclusion criteria: male; receiving neo-adjuvant chemotherapy; diagnosed with a severe psychiatric disorder or severe substance use disorder as identified through the MINI; having a history of migraines. Individuals with very advanced sleep timing, defined as a habitual bedtime before 8pm and rise time before 4am or delayed sleep timing defined as habitual bedtime after 3am and rise time after 11am, or irregular or non-24 sleep and wake pattern will be excluded, based on the Duke structured sleep interview.
It is possible that eligible participants will be receiving additional treatment for sleep complaints (e.g., psychological treatment, prescribed sleep medication, herbal remedies etc.). These participants will not be excluded, however this information will be obtained via self-reports and medical record extraction and will be adjusted for in sensitivity analyses. Involvement is voluntary, and participants may withdraw from the study at any time. Involvement will not impact participants’ care and their medical treatment will continue as usual.
Randomization
Eligible participants will be randomized into the CBT+ or TAU+ group using a complete randomization scheme generated in advance. Specifically, block sizes of variable size (4, 6, or 8) will be used. Random seeds will be generated to assure allocation concealment and pre-guessing of the allocation sequence at the end of each block. Randomization will be stratified by baseline Insomnia Severity Index (ISI) scores (≤ 7, ≥ 8) and cancer stage (≤ 2, ≥ 3). The randomization scheme was generated and setup in REDCap (Research Electronic Data Capture), by a member of the research staff (Bei) who is not involved in recruitment or delivery of intervention and is not the principal investigator. All participants will receive a random identification number, which will be used to link data from the different assessments. All direct identifiers (e.g., name, address, and telephone numbers) will be stored separately.
CBT+ Intervention
The CBT+ intervention involves seven time-points when materials are delivered across six weeks. The intervention will be delivered via: one face-to-face session of up to 75 minutes, to be conducted at the PMCC in the Chemotherapy Day Unit; one telephone call lasting approximately 20 minutes; seven emails (one per week, that take approximately 15-20 minutes to read); and one brief telephone call (2-5 minutes) at the end of the intervention to ask about adverse events.
Intervention components delivered via email use the online software Mailchimp, which provides professional email templates and automates the timing of intervention delivery.
Cognitive Behavioural Therapy for Insomnia
The intervention materials for the CBT component were adapted from the Cognitive Behavioural Treatment of Insomnia Session by Session Guide (52). Core components of the intervention content include:
- general information and skills for better sleep (e.g., sleep hygiene, relaxation and mindfulness exercises, dealing with night-time worries);
- fostering healthy attitudes and expectations about sleep following cancer diagnosis and during treatment;
- managing sleep challenges specific to cancer patients (e.g., physical discomfort, pain, daytime consequences of poor sleep); and
- identifying and managing symptoms of insomnia (e.g., self-monitoring, stimulus control, sleep scheduling, bed restriction).
The CBT face to face session will be delivered by Helena Bean, provisional psychologist and doctoral graduate student, who has completed >450 hours of clinical client contact and an additional 40 hours of specific CBT-I training. Ms Bean will be supervised by senior clinical psychologists Ms Justine Diggens and Dr Bei Bei.
Light Therapy Individualised Protocol
The light therapy component will consist of daily use of light glasses for the six-week duration of the intervention. Participants will receive a pair of Luminette® glasses with light intensity locked at 1500 lux and will be instructed to wear them for 20-30 minutes upon awakening each morning. The specific timing of use will be established with each participant during the face-to-face session, and will be based on their individual sleep-wake timing and chronotype, accounting for early awakenings. A written light therapy manual covers the key components to be discussed in the face-to-face session.
Minimising Participant Burden
The intervention was designed to deliver effective results whilst being of minimal burden. Given that women with BC already have an intensive treatment regimen, the design of the intervention was carefully considered, weighing the physical and psychological benefits with the effort and time associated for each intervention component. The face-to-face session will be scheduled around participants’ existing appointments to reduce the burden of travel. All other aspects of the intervention can be completed in the comfort of participants’ own homes. The light glasses are comfortable, easy to wear, can be worn over prescription eyeglasses. Outside of morning showers, vigorous exercise, or driving, the light glasses are not likely to disrupt participants’ usual morning routines. Wearing the light glasses will not impair participants’ ability to move around and undertake any domestic or work-related responsibilities (such as preparing and consuming food, household cleaning, reading, writing or typing). Furthermore, the intervention is economical from the perspective of the healthcare system, as it is relatively simple for clinicians to deliver and entails minimal financial expense and burden of time. These are important considerations when evaluating whether the intervention, if effective, could be implemented into routine care.
TAU+ Intervention
The control group will receive two emails containing web links to relaxation audio tracks. These emails will be received during the first and third weeks of the intervention. The first relaxation audio consists of abdominal breathing strategies that may assist in calming the mind and relaxing the body. The second audio consists of a progressive muscle relaxation. Both audio tracks are approximately 15 minutes long, and participants are instructed to listen to these audio tracks whenever they feel it could be beneficial. These relaxation tracks were developed by the Australian Cancer Council to assist people in coping with a cancer diagnosis. The audio tracks do not contain any sleep-specific information. Instead, they include general relaxation strategies that can be used by participants at any time during the day or night. The control group will also receive a brief phone call (15 minutes) during the fourth week of their study, to check in with participants and respond to any queries or complaints. After the three-month follow-up assessment, women in TAU+ will be offered the 7 CBT+ email packages. Women are informed of this during consent that they will be randomised and if randomised to TAU+ will receive the CBT+ materials after their final follow-up assessment.
Relaxation audio was chosen as a control, so that the efficacy of the intervention can be compared to a general relaxation paradigm that may offer benefits for wellbeing and stress reduction but does not specifically target sleep. Furthermore, an active control will reduce the influence of placebo or expectancy effects and ensure that all women who participate in the study receive some effective support. The number of times TAU+ participants open relaxation emails and click on relaxation audio links will be monitored to evaluate participant engagement with the program. Notably, both groups continue treatment as usual, including any standard management of sleep symptoms from their oncology team or other health care providers.
Assessments and outcomes
Table 1 (below) displays the measurements used in this study and the time points at which they will be administered. Screening interviews will be conducted in person during recruitment prior to randomisation. Baseline (week 0), mid-treatment (week 3), post-treatment (week 6), and three-month follow-up (week 12) questionnaires with self-report measures will be completed online by emailing women a link to a survey on Qualtrics, or via telephone for women who prefer not to complete questionnaires online. Questionnaires completed via Qualtrics will be considered valid if they are completed within ±1 week of the planned time.
During the intervention phase, sleep will be assessed continuously via daily sleep diaries and actigraphy. Sleep diaries will be provided to all women in a paper and pencil format only. The actigraphy watch (ActiGraph wGT3X-BT) is of similar size to a regular wristwatch and will be worn by women continuously during the six-week intervention. For women in the CBT+ group, the sleep diary also will assess daily light therapy adherence. Prior to commencing the intervention, women will be supplied with 6 diaries, one for each week of the intervention, and six pre-paid, addressed envelopes so that at the end of each week, women can post that week’s diary to the research team. Outcome assessment is not blinded as all outcomes (except for sleep based off actigraphy) are patient reported outcomes.
Audio Recording
All face-to-face and telephone contacts will be recorded via Dictaphone for quality control. Audio recordings will be stored securely with password protection. Written informed consent from participants will be sought before obtaining audio recordings.
Primary outcome measures
There are two primary outcomes, these include changes from baseline to post intervention in the Insomnia Severity Index (53), the gold standard for assessing insomnia symptoms and self-reported Sleep Efficiency (SEs). SEs will be obtained from the daily sleep diary based on the consensus sleep diary (54). SEs is calculated using the ratio of self-reported total sleep time divided by the total time spent in bed for sleep. Outcomes will be measured by observing the change in participants’ average SEs between the first week and the last week of the intervention. SEs is commonly used as an indicator of progress in insomnia treatment, as high sleep efficiency scores indicate consolidated sleep (55, 56). (see Table 1 in the Supplementary Files)
.
Secondary outcome measures
Secondary outcomes will include additional dimensions of sleep behaviours assessed via self-reported sleep diaries and actigraphy, and symptoms of fatigue, depression, and anxiety. Sleep onset latency (SOL), wake after sleep onset (WASO) and total sleep time (TST) will be derived from the sleep diaries and the ActiGraph. The ActiGraph wGT3X-BT records continuous activity information using a 3-axis accelerometer along with ambient light. Using the activity data, the wGT3X-BT provides estimates for sleep timing (bed time and rise time), sleep duration (time in bed and TST), and sleep quality (sleep efficiency, SOL, WASO). Actigraphy data scoring will follow standard protocol, integrating estimates from the automated scoring algorithm along with ambient light, and sleep diary reports of bed and rise time. Actigraphy sleep assessments are time and date stamped so that they can be matched with the self-report sleep diary measures. In sleep studies, it is common to evaluate the impact of interventions on multiple behavioural dimensions of sleep as not all dimensions may change. Furthermore, it is helpful to supplement self-reported sleep with an objective measure (actigraphy). Evidence suggests that often, there is only modest agreement between sleep diary and actigraphy, suggesting that these two measures capture unique information and are not redundant (68).
The Patient-Reported Outcomes Measurement System (PROMIS) scales will be used to assess other secondary outcomes including sleep related impairment and sleep disturbance (58), fatigue (59), and mental health measures of depression and anxiety (60).
Treatment moderator and mechanism measures
Potential treatment moderators will be measured as follows. The PROMIS pain intensity short form scale will be used to assess pain (61). The 6-item Credibility Expectancy Questionnaire (62) will be used to assess participants’ perceived credibility and expectancy of treatment. Chronotype will be assessed using 5 self-rated items in the reduced Morningness and Eveningness Questionnaire. Treatment adherence for the CBT and TAU+ control relaxation components will be measured via self-report questions at midpoint and end of treatment assessing the frequency of use and usefulness of strategies. The number of times that participants in CBT+ and TAU+ groups open emails and click on email links will also be monitored. For the CBT+ group, light glasses adherence will be monitored daily – documented as part of participants’ sleep diaries.
The following potential mechanisms of treatment efficacy will also be measured. Beliefs and attitudes about sleep will be measured using the average of 16 self-rated items from the Dysfunctional Beliefs and Attitudes about Sleep Scale and Pre-sleep Arousal Scale (DBAS-16) (64). Vulnerability to insomnia under stress will be assessed using the 9-item Ford Insomnia Response to Stress Test (FIRST) (65). Pre-sleep arousal will be assessed with the Pre-Sleep Arousal Scale (66). Intrusive thoughts will be measured via the 8-item Intrusive Thoughts subscale of the Impact of Events Scale (67).
Sample Size and Power
Based on previous studies of CBT for insomnia and sleep in people with cancer and BLT (69-74), we expect a moderate to large effect size for both primary outcomes. Given our combined CBT+ targets multiple, different mechanisms of change, we expect larger effects than shown in previous studies utilizing only CBT or BLT. Specifically, we expect a standardized mean difference of d = 0.70, corresponding to a medium-to-large between-group effect at the post-treatment assessment.
Power analyses based on an independent samples t-tests showed that a total of 70 women will provide >80% power to detect a standardized mean difference of 0.70 at post-treatment, assuming α = 0.05 and equal variance between groups. Power analyses are not readily available for latent growth models and require complex simulations. Therefore, we chose power analysis based off a t-test as a conservative estimate as due to randomization, no baseline differences between conditions are expected so the difference in the slopes from latent growth models between treatment and control will be based off post-treatment mean differences but should have lower variability due removing variability due to individual differences at baseline. Thus, we anticipate the latent growth models will have more power than a t-test based on post-treatment scores and that our power estimates are conservative, although final power will depend on the difference, variability, and correlations in data over time which are unknown. We will continue recruitment until we reach 70 completers. Progress to date is shown in Figure 1.
Statistical Analyses
Primary analyses will be conducted on an intention-to-treat basis. Thus, results for all randomized women will be analysed in the group to which they were assigned, regardless of protocol violations. The only exception to this will occur if participants withhold or withdraw consent to use their data in the analysis. Statistical analyses will be conducted in R (data management, graphs, preliminary analyses) and MPlus using MplusAutomation (75). As a preliminary step, data will be assessed for outliers and skew and, where appropriate, transformed or winsorized. Prior to primary analyses, we will produce a thorough descriptive profile of the sample, characterizing both the dropout and missing data. There are no interim analyses planned. Statisticians will not be blinded.
Baseline Comparisons
Participant characteristics at baseline will be presented by treatment group, and statistical tests will be conducted to verify that randomization was successful. Discrete variables will be summarized by frequencies and percentages, and baseline group differences tested using chi-square tests. Continuous variables will be summarized using mean (SD) or median (IQR) and baseline group differences, tested using independent t-tests or Wilcoxon signed-rank tests for variables that evidence non-normal distributions. If there are significant differences in any participant characteristics at baseline, the variable(s) will be included as covariates in the final analyses.
Aim 1
To test the efficacy of CBT+ compared to TAU+ for improving symptoms of sleep disturbance. Aim 1 will be tested using latent growth models (LGMs). LGMs will be estimated with an intercept and two, linear slopes, representing a piecewise model. Slope 1 will have loadings constrained to 0, 0.5, 1.0, and 1.0 for weeks 0, 3, 6, and 12, respectively, capturing the linear change from baseline (week 0) to post intervention (week 6). Slope 2 will have loadings constrained to 0, 0, 0, and 1.0 for weeks 0, 3, 6, and 12, respectively, allowing a different slope from post intervention (week 6) to follow-up (week 12) compared to from baseline (week 0) to post (week 6). The means and variances of the intercept and slope factors will be freely estimated (corresponding to random effects in linear mixed models) and the intercept and slope covariances will be estimated. The residual variance will be constrained to equality across time and residuals assumed uncorrelated, corresponding to an independent, homogenous residual structure. Intercepts of indicators will be constrained to 0 to allow estimation of the latent random intercept mean.
There are two stratification factors: screening ISI (≤ 7, ≥ 8) and cancer stage (≤ 2, ≥ 3). These factors will be crossed creating four groups: Early Stage, Low ISI; Advanced Stage, Low ISI; Early Stage, High ISI; and Advanced Stage, High ISI. Dummy codes will be created for each strata, with Early Stage, Low ISI treated as the reference group. These dummy codes will be included as covariates to adjust for their effect on the random intercept, following recommendations that stratification factors be adjusted for in analyses of randomised controlled trials(76, 77).
Treatment effects will be evaluated by creating a dummy code (0 = TAU+, 1 = CBT+). This dummy code will be entered as a predictor of the intercept, Slope 1, and Slope 2. However, treatment factors will be constrained to 0 for the intercept, to implement so-called “constrained longitudinal data analysis”, which studies show provides a more accurate estimate of treatment effects from randomised controlled trials with repeated measures(78, 79).
The primary trial results will be the effect of treatment on Slope 1 (i.e., from week 0 to week 6). This interaction directly tests whether the change in primary outcomes over time is different in the control and intervention arm. Effect sizes of the group difference at each time point also will be calculated.
A similar process will be followed for sleep efficiency, however a continuous time, linear model will be estimated using a mixed effects model in Mplus because up to 42 days of sleep efficiency are collected. A piecewise model is not needed as sleep diary data are not collected at follow-up due to burden. Sleep efficiency may not follow a normal distribution. If the assumption of normality is violated, significance tests and confidence intervals will be based on non-parametric bootstrapping.
Aim 2
To test the efficacy of CBT+ versus TAU+ for psychological outcomes. Aim 2 will be tested identically to Aim 1, but using psychological outcomes in place of the sleep and fatigue outcomes.
Aim 3
To explore potential mechanisms of CBT+ and moderators of the intervention efficacy. Mechanisms (i.e., pre-sleep arousal, beliefs and attitudes about sleep, vulnerability to insomnia under stress and intrusive thoughts before bed) will be tested using mediation conducted in path analyses. Specifically, we will examine the effect of condition on change in mechanisms (e.g., pre-sleep arousal) from baseline to treatment mid-point, and test whether the change in mechanisms from baseline to treatment mid-point accounts for the condition effects on change in outcomes (e.g., insomnia severity index) from baseline to post-treatment and follow-up. Statistical mediation will be determined by evaluating the indirect effects, calculated as the product of the paths from condition to change in mechanisms and from change in mechanisms to change in outcomes. Bootstrapping will be used to estimate the confidence interval for indirect effects and their statistical significance. Given the modest sample size, analyses will be conducted for each mechanism and outcome individually.
Treatment moderators (i.e., pain, chronotype, perceived credibility and expectations of the intervention, and adherence to the intervention protocol) will be evaluated by modifying the primary linear mixed effects analyses from Aims 1 and 2 to include a condition x moderator interaction, along with all lower order effects predicting Slope 1 and Slope 2 of the piecewise model. Individual moderators will be tested in separate models.
Data storage and confidentiality
All participants will receive a random identification number which will be used to link data from the different assessments. Coding all participant data with a unique identification number will minimize the risk of loss of confidentiality. The only dataset with participant identifier information will be the participant tracking system used to follow-up and contact women. All other datasets will label participant records with a unique study number and be stripped of other identifying information; specifically, clinical data will not reside with identifying data. Survey data will be kept in locked files or password-protected data files. All results will be described in aggregate without identification of individual women. Study investigators will have access to the final dataset.
Ethics approval and safety monitoring
The study has received ethics approval from the Peter MacCallum Cancer Centre Human Research ethics committee, protocol number 17/159. Governance and oversight of the trial will be monitored by two committees, the Steering Committee and Data and Safety Monitoring Board (DSMB). The Steering Committee comprises the study investigators and a consumer representative. The DSMB comprises two independent researchers, a consumer representative, and two members of the study investigator team. The DSMB will be responsible for monitoring participant safety, data quality, and implementation of the protocol. If any women report severe symptoms of sleep disturbance, depression, or anxiety, we will inform their clinical team and recommend that they seek a referral to a sleep specialist or clinical psychologist. Any women with previously undiagnosed severe psychiatric conditions identified during screening will also be informed and recommended to seek a referral to psychiatry or clinical psychology. A description of all undesirable and unanticipated events during the intervention phase (adverse events) will be recorded on Qualtrics. As this trial is minimally funded, there is no independent audit. Any protocol modifications will be communicated to the human research ethics committee and participants by the study team. No serious harm is expected as a result of the trial. However, if harm does occur, the primary sponsor and Monash University insurance will cover care for research participants.
Dissemination plan
The results of this study will be disseminated through peer reviewed, scientific publications and presentation at conferences. Three publications are anticipated; one paper reporting primary and secondary outcomes, a second paper focusing on mechanisms of treatment efficacy, and a third on moderators of treatment efficacy. Members of the study team who provide substantive contributions to the design, conduct and reporting of the study will be authors on these and any other unplanned publications based on this study data.
The full protocol and statistical code for data management and all primary analyses will be publicly available through Monash Figshare. A DOI has been reserved and the full study protocol including consent forms will be made available at: http://dx.doi.org/10.26180/5ccba90aae301 once the protocol paper is published. A DOI also has been reserved for statistical code for data management and primary analyses, which will become available once completed: http://dx.doi.org/10.26180/5ccbaafb5262e.