Methods

This chapter uses material from an Open Access article previously published by the research team (see Kyle et al. 2020, BMJ Open1). This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/.

Study design

The HABIT trial was a pragmatic, multicentre, individually randomised, parallel-group, superiority trial. Participants were recruited from general practices across three regions in the UK (Thames Valley, Greater Manchester and Lincolnshire). Assessments took place at baseline and 3, 6 and 12 months post randomisation. The trial was prospectively registered with the ISRCTN (ISRCTN42499563).

Practice and participant recruitment

We identified interested practices in three regions of England (Thames Valley, Greater Manchester and Lincolnshire) through local clinical research networks (LCRNs). In collaboration with the lead CRN, we devised search criteria to identify potentially eligible individuals from practice records. Since insomnia is not commonly coded within practices, records were initially searched for broad sleep-related terms (e.g. cannot sleep, insomnia, non-organic sleep disorders), sleep-related medications (e.g. hypnotics, sedative antidepressants), and key conditions characterised by insomnia (e.g. depressive disorder, fatigue), while applying exclusion criteria (e.g. pregnancy, age, dementia). While this meant that we identified and invited a large number of participants per practice (see Appendix 1), it did increase the possibility of reaching a varied group of people with insomnia. Searches were performed by practice managers, and GPs were given the opportunity to review the list prior to study invitation. Practice managers mailed invitations to identified individuals using Docmail. We also identified potential participants through (1) direct face-to-face GP referral (participants were provided with an information sheet and contact details for the research team), (2) placing posters in practices (containing study contact details) and (3) posting study adverts on practice websites.

Alongside the study invitation letter and participant information sheet, participants were provided with three potential methods to engage with the eligibility process, depending on preference: (1) web-link to complete an online eligibility questionnaire, (2) a brief paper questionnaire with return reply slip (following which the research team contacted participants by phone to complete the remainder of the screening process) and (3) contact details for the research team to arrange completion of the eligibility questionnaire over the phone. Regardless of methods, all interested participants underwent the same eligibility screening questionnaire.

Eligibility criteria

The inclusion criteria were as follows: (1) participant is willing and able to give informed consent for participation, (2) screens positive for insomnia symptoms on the Sleep Condition Indicator34 and meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition35 (DSM-V) criteria for insomnia disorder, (3) self-reported sleep efficiency (SE) < 85% over the past month,36 (4) age ≥ 18 years and (5) able to attend appointments during baseline and 4-week intervention (both face-to-face at the practice and over the phone) and adhere to study procedures.

Exclusions were limited to conditions which may be contraindicated for SRT, or render SRT inappropriate or ineffective: (1) pregnant/pregnancy planning in the next 6 months; (2) additional sleep disorder diagnosis (e.g. restless legs syndrome, obstructive sleep apnoea, narcolepsy) or ‘positive’ screen on screening questionnaire;37 (3) dementia or mild cognitive impairment (MCI); (4) diagnosis of epilepsy, schizophrenia or bipolar disorder; (5) current suicidal ideation with intent or attempted suicide within past 2 months; (6) currently receiving cancer treatment or planned major surgery during treatment phase; (7) night, evening, early morning or rotating shift-work; (8) currently receiving psychological treatment for insomnia from a health professional or taking part in an online treatment programme for insomnia; (9) life expectancy of < 2 years; and (10) another person in the household already participates in this trial.

On completion of screening, eligible participants were invited to a baseline appointment with a member of the research team where they provided written informed consent, completed baseline questionnaires, and were provided with a sleep diary and actigraph watch for the following week. Participants subsequently returned the completed diary and actigraph watch to the research team via postal mail, and were then randomised.

Interventions

Sleep hygiene

While CBT is the guideline treatment, in practice treatment as usual comprises hypnotic or sedative medication, and SH guidance.14 National Institute for Health and Care Excellence (NICE) recommends12 that patients should be provided with SH advice as part of the management pathway, although there is no evidence that SH is effective as a monotherapy.11,38 GPs commonly provide advice on SH but there is little standardisation of such information, in terms of either delivery format or content. Assuming that some participants would have been exposed to such information in the past, and to avoid potential bias, participants in both trial arms were provided with the same SH information. We provided a booklet comprising standard behavioural guidance in relation to lifestyle and environmental factors associated with sleep and sleeplessness.39 Participants randomised to the SH arm were sent their booklet via e-mail or post.

Consistent with the requirements of a pragmatic trial, there were no restrictions on usual care for both groups. In this way, the trial represents a comparison of SRT + SH plus treatment as usual versus SH plus treatment as usual, permitting clear judgement to be made regarding the relative clinical utility of SRT in routine clinical practice.

Sleep restriction therapy

Participants in the intervention arm were offered nurse-delivered insomnia therapy in the form of SRT, a manualised behavioural intervention (see Table 1 for a detailed description). SRT is hypothesised to treat insomnia symptoms by reducing and standardising a patient’s time in bed with the aim of increasing homeostatic sleep pressure, over-riding cognitive and physiological arousal, and strengthening circadian regulation of sleep.23–25 It involves implementation of a prescribed and restricted sleep schedule, which is reviewed and adjusted each week by a therapist in order to optimise SE (the proportion of time spent in bed asleep). Time in bed is initially restricted to match reported total sleep time (TST) (with 5 hours set as the minimum sleep opportunity). PNs and research nurses from CRN were trained to deliver SRT. Nurses received a 4-hour training session on sleep, insomnia and the delivery of SRT as well as access to supporting resources (e.g. recorded video clips and a list of frequently asked questions and answers in relation to treatment delivery). Trained nurses delivered manualised SRT over four brief, weekly sessions (total contact time = approximately 1 hour 5 minutes). In session 1 the nurse introduced the rationale for SRT alongside a review of sleep diaries, selection of bed and rise times, management of daytime sleepiness (including implications for driving) and discussion of barriers/facilitators to implementation. Participants were provided with a booklet to read in their own time, which included information on theory underlying SRT and a list of SH guidelines (identical to those provided to the control arm). Participants were provided with diaries and SE calculation grids to support implementation of SRT instructions and permit weekly review of progress. Sessions 2, 3 and 4 consisted of brief sessions (10–15 minutes) to review progress, troubleshoot any difficulties and advise on adaptation of the sleep schedule. Sessions 1 and 3 took place in person at the practice while sessions 2 and 4 were conducted over the phone. Therapy materials were reviewed by our patient and public involvement (PPI) advisory group, which included people with lived experience of insomnia and SRT.

Outcomes

A list of outcomes and time points and corresponding objectives can be found in Table 2.

Measures

Insomnia severity. Insomnia severity was measured with the ISI,40 a validated self-report questionnaire, at baseline and 3, 6 and 12 months post randomisation. The ISI is a seven-item self-report measure assessing both night-time and day-time symptoms of insomnia. The possible range on the scale is from 0 to 28, with higher scores indexing more severe insomnia symptoms. The internal consistency of the measure is high (α > 0.90) in both clinical and community samples.41 An ISI score of ≥ 11 is sensitive for insomnia disorder while a ≥ 8-point reduction is associated with moderate improvement in insomnia as assessed by an independent rater.41

Health-related quality of life. HRQoL was assessed with the Short Form questionnaire-36 items (SF-36)42 [mental component summary (MCS) score and physical component summary (PCS) score] at baseline and 3, 6 and 12 months post randomisation.

Sleep-related quality of life. Sleep-related quality of life was measured with the Glasgow Sleep Impact Index3 (GSII, ranks 1–3) at baseline and 3, 6 and 12 months post randomisation. At baseline, the GSII asks participants to generate, in their own words, three areas of sleep-related impairment. These areas are ranked in order of concern (1–3) and then rated on a visual analogue scale with respect to the previous 2 weeks (0–100, with lower scores indicating greater level of impairment). At follow-up, participants are asked to rate the same areas of impairment, enabling group-level analyses on the three patient-generated ranks.

Depressive symptoms. Depressive symptoms were assessed with the Patient Health Questionnaire-943 (PHQ-9) at baseline and 3, 6 and 12 months post randomisation.

Work productivity. Work productivity was assessed with the self-rated productivity and activity impairment questionnaire44 (WPAI) at baseline and 3, 6 and 12 months post randomisation. The WPAI yields three outcomes for those engaged in employment: absenteeism (% work time missed due to insomnia), presenteeism (% impairment while working due to insomnia) and work productivity loss (overall work impairment/absenteeism plus presenteeism due to insomnia). The final outcome relates to non-work activity impairment and can be completed by all participants.

Pre-sleep arousal. Pre-sleep arousal was measured with the pre-sleep arousal scale45 (PSAS) at baseline and 3, 6 and 12 months post randomisation.

Sleep effort. Sleep effort was assessed with the Glasgow Sleep Effort Scale46 (GSES) at baseline and 3, 6 and 12 months post randomisation.

Sleep parameters. Self-reported sleep parameters were derived from sleep diaries. Participants completed the consensus sleep diary47 for 7 days at baseline and 6 and 12 months post randomisation. Objective sleep-parameters were obtained from actigraphy. Participants wore an actigraph watch (MotionWatch 8, CamNtech Ltd., Cambridge, UK) for 7 days at baseline and 6 and 12 months post randomisationand were instructed to press a marker button on the watch when attempting sleep. These event markers were used to define sleep periods by an experienced scorer blinded to treatment allocation. In the absence of event markers, a decision was made based on bed and rise times from the sleep diary following a decision flow-chart developed at the Sleep and Circadian Neuroscience Institute, University of Oxford. Sleep variables of interest were calculated by the validated in-built algorithm of the MotionWare software 1.2.47. The following sleep parameters were derived from sleep diaries and actigraphy recordings: sleep onset latency (SOL), wake-time after sleep onset (WASO), SE, sleep quality (SQ, diary only) and TST.

Sleep-promoting medication. Medication use was quantified from sleep diaries at baseline and 6 and 12 months post randomisation. Use of prescribed hypnotics and other sleep-promoting medications (e.g. sedative antidepressants, antihistamines, antipsychotics, melatonin) was extracted in order to capture (1) proportion of nights of use per participant and (2) proportion of participants in each group at each time point who used sleep promoting medication at least once during the 7-day recording period.

Cost-effectiveness. Intervention records captured the number and duration of nurse-led sessions to quantify cost of delivery per trial participant. The Client Service Receipt Inventory48 (CSRI) captured self-reported service use, the WPAI was used to index productivity losses and utilities were measured with the EuroQol Questionnaire49 [EuroQol-5 Dimensions, three-level version (EQ-5D-3L)] to enable calculation of quality-adjusted life-years (QALYs). In addition to the EQ-5D-3L, participants completed two additional utility measures, the Short-Form-6 Dimensions (SF-6D)50 (derived from the SF-36) and the EQ-5D-3L + Sleep,51 at 3, 6 and 12 months. EQ-5D-3L + Sleep contains the same five dimensions as the original EQ-5D-3L questionnaire plus an extra dimension on sleep. A value set has been developed for EQ-5D-3L + Sleep enabling utility values to be obtained.51 Utility values derived from the SF-6D and EQ-5D-3L + Sleep were used to estimate QALYs over the 12-month trial period so that we could assess, in pre-defined exploratory analyses, whether sensitivity to SRT could be improved with these measures (relative to the standard EQ-5D-3L).

Process evaluation. Semistructured interviews were conducted with trial participants, nurses, GPs or practice managers across the three study sites and throughout the trial. Number of appointments attended/received by participants, fidelity appraisal of recorded consultations, and adherence to the prescribed sleep window were also considered. Fidelity of sessions was assessed by a clinical psychologist for a subsample of recordings using a bespoke rating scale (range 0–26 for treatment session 1 and 0–16 for session 3) and converted to % score. Adherence to the prescribed sleep window (intervention group only) was quantified as the number of nights per week that the participant adhered (within 15 minutes) to the nurse-prescribed bed and rise times. Bed and rise times were derived from sleep diaries completed during the 4-week intervention phase and converted to a % score. Adherence was computed for participants with a minimum of 14 out of 28 diary days. Control group contamination (i.e. the possibility that participants in the SH arm access SRT via the trained PN) was assessed using an item from the CSRI and positive responses were followed up via phone interview to collect further information.

Serious adverse events (SAEs). We defined SAEs as any untoward medical occurrence that (1) results in death, (2) is life-threatening, (3) requires inpatient hospitalisation or prolongation of existing hospitalisation, (4) results in persistent or significant disability/incapacity or (5) consists of a congenital anomaly or birth defect. Nurse therapists and participants were prompted to self-report SAEs. Along with self-reporting of SAEs, we also used responses on the CSRI which includes questions on hospitalisations, to follow up participants who reported being hospitalised. We recorded planned hospital admissions at baseline and, when they occurred, these were not counted as SAEs. SAEs were assessed for severity, seriousness and relatedness to study procedures by a medically qualified member of the team. SAEs are reported after date of randomisation until either the date of trial withdrawal or 6-month follow-up completion, whichever was earlier.

Adverse events (AEs). We recorded incidences of falls, accidents (including road-traffic accidents and work-related injuries), near-miss driving incidents, and falling asleep while driving alongside outcomes at baseline and 3, 6 and 12 months post randomisation.

Sample size

It was estimated that 235 participants would be required in each group to detect a group difference of 1.35 points [standard deviation (SD) = 4.5] on the ISI with a power of 90% at 5% level of significance (two-sided). This equates to a standardised effect size of 0.3. The SD was chosen based on the results from the primary care evaluation of SRT.28 Accounting for 20% attrition we aimed to recruit 588 participants (294 per group). During the trial, overall attrition initially appeared higher than expected, and therefore we made a protocol amendment to increase the sample size depending upon attrition. Research Ethics Committee (REC) approval for the change was obtained in February 2020. We sought a sample size of 628 participants if attrition was 25% or less, and 672 participants if it was between 25% and 30%. Attrition was estimated to be around 25% and therefore our revised target sample size was 628.

For the process evaluation interviews, we aimed to recruit up to 15 participants from each of the 3 stakeholder groups (trial participants, nurses, GPs or practice managers), consistent with our previous experience of framework analysis52 and ensuring a sufficient number of interviews to achieve theoretical data saturation.53

Randomisation

Participants who completed baseline assessments (including having completed at least 4 days of sleep diary) were eligible for randomisation. Participants were randomised (1 : 1) to SRT or SH using a validated web-based randomisation programme (Sortition), with a non-deterministic minimisation algorithm to ensure site, use of prescribed sleep-promoting medication (yes/no), age (18–65 vs. > 65 years), sex, baseline insomnia severity (ISI score < 22 vs. 22–28) and depression symptom severity (PHQ-9 score < 10 vs. 10–27) were balanced across the two groups. Appropriate study members at each site had access to the web-based randomisation software to complete randomisation and subsequently informed participants of their allocation.

Blinding

This was an open-label study and therefore both participants and nurses were aware of allocation. The participant information sheet informed participants that the study compared two different sleep intervention programmes but did not reveal the study hypothesis. Treatment providers (nurses) were not involved in the collection of trial outcomes. Outcomes (questionnaires, diaries and actigraphy) were self-completed, remotely, by participants. Due to impracticalities associated with blinding of the research team, combined with minimal risk of bias due to use of self-report outcome measures, researchers at each site were aware of treatment allocation. Communication from the research team to participants, post randomisation, was limited to collection of outcome assessments and not therapeutic procedures. The statisticians remained blind to allocation. A full detailed statistical analysis plan (SAP) was prepared and finalised before data collection was complete.

Statistical methods

Descriptive statistics of recruitment, dropout and completeness of interventions were calculated. Baseline variables are presented by randomised group using frequencies (with percentages) for binary and categorical variables, and means (and SDs) or medians (with lower and upper quartiles) for continuous variables. There were no tests of statistical significance nor confidence intervals for differences between groups on any baseline variables. There was no planned interim analysis for efficacy or futility.

The primary analysis population included all eligible randomised participants who had at least one outcome measurement. Participants who withdrew from the trial were included in the analysis until the point at which they withdrew. Participants were analysed according to their allocated treatment group irrespective of what treatment they actually received. Every effort was made to follow up all participants.

Primary outcome. A three-level linear mixed-effect model was fitted to the ISI score assessed at 3, 6 and 12 months following randomisation. Practice and participant were included as random effects. The model specified an unstructured variance–covariance structure for the random effects. Fixed effects included randomised group, minimisation factors [baseline ISI score (continuous), site, age (continuous), use of prescribed sleep promoting medication (yes/no), sex and baseline PHQ-9 score (continuous)], time, and a time by randomised group interaction term to allow estimation of treatment effect at each time point. The estimated difference between arms at 6 months was extracted from the model by means of a linear contrast statement.

Secondary outcomes. Continuous secondary outcomes were analysed using the same method. Secondary outcomes that were binary were analysed using generalised linear mixed-effect models with appropriate link function. For continuous outcomes standardised effect sizes (Cohen’s d) were calculated as the adjusted treatment effect divided by the pooled SD at baseline.

The Mann–Whitney test was used for three of the secondary outcomes (WPAI absenteeism, proportion of days usage of prescribed hypnotic medication, and proportion of days usage of prescribed other medication) due to violation of model assumptions. The p-value for a difference is reported at each time point, and no treatment effect has been reported.

The two count outcomes of interest were the number of times falling asleep while driving and the number of falls. The SAP stated that these outcomes would be analysed using a Poisson model and if there were excess zeros and/or over-dispersion in the data, a zero-inflated Poisson model and/or a negative binomial model would be considered instead. Both outcomes had excess zeros; < 10% of participants had one or more times falling asleep while driving or number of falls. Due to the event rates being low, a simpler analysis was undertaken instead. These outcomes were defined as a binary outcome [no (0 events)/yes (1 + events)], and a logistic mixed-effect model was used.

Serious adverse events were analysed based on the number of participants who actually received the intervention and Fisher’s exact test was used to compare SRT and SH.

Missing data and sensitivity analyses. The following sensitivity analyses were pre-specified in the SAP to examine the robustness of the primary outcome results to different assumptions regarding missing data:

1. analysis adjusted for baseline covariates found to be predictive of missingness
2. exclusion of any self-rated insomnia severity scores from the analysis which were deemed to be outliers (none were observed)
3. analysis using pattern mixture model to examine the robustness of the missing at random assumption
4. analysis for missing data on the primary outcome at 6 months assuming plausible arm-specific differences between responders and non-responders.

Full details of the sensitivity analyses were specified in the SAP. Multiple imputation of the primary outcome analysis was also conducted as a post hoc sensitivity analysis.

Moderation analyses. We conducted pre-specified subgroup analysis of the primary outcome by baseline actigraphy-defined sleep duration (< 6 vs. ≥ 6 hours), sleep medication use, depression severity (PHQ-9), age, level of deprivation, and chronotype [assessed with the morningness–eveningness questionnaire, reduced version (MEQr)].54 The subgroup analyses were conducted using the same method above but adding a three-way interaction term between randomised group, assessment time point, and a subgroup indicator variable to allow the treatment effect to be estimated at each time point and in each level of the subgroups.

Mediation analyses. We proposed in the statistical analysis plan to use structural equation modelling for the mediation analyses; however, due to convergence problems, the analysis strategy was revised and conducted using the Baron and Kenny55 approach but adapted to make use of linear mixed-effect models (similar to Freeman et al.56). A mixed effects model was fitted to estimate the mediator-outcome effect and another mixed effects model to estimate the treatment-mediator effect. The indirect effect was then calculated as the product of the effect of the mediator at 3 months on outcome at 6 months and the effect of treatment on mediator at 3 months. Confidence intervals and p-values were calculated using Sobel’s test. This allowed us to determine the extent to which the 3-month arousal and sleep effort outcomes (PSAS, GSES) mediated the 6-month ISI outcome. All models included baseline assessments of the mediator and ISI as covariates.

Compliance and adherence. A complier-average causal effect (CACE) analysis of the primary outcome was carried out to determine the impact of compliance with the allocated intervention on the treatment effect. Compliance was defined as attending at least one treatment session. CACE models were estimated using an instrumental variable approach where the outcome is total ISI score at 6 months adjusted for baseline ISI. Additionally, models were fitted adjusting for baseline characteristics that appeared to be associated with compliance. Sensitivity analyses were carried out which adjusted the definition of compliance to attending at least two, three or four sessions, and multiple imputation was carried out on the primary CACE analysis as a sensitivity analysis to assess the impact of missing data.

We also explored the effect of level of adherence to prescribed bed and rise times (captured by sleep diaries) on the primary outcome in those who received SRT. Percentage treatment adherence was categorised (≥ 0 to ≤ 40/> 40 to ≤ 60/> 60 to ≤ 80/> 80 to ≤ 100) and descriptive estimates for the ISI at 6 months (primary end point), change from baseline to 3 months, and change from baseline to 6 months are presented for each category. Treatment effects on the change scores for different levels of adherence were estimated by fitting a group by categorised adherence interaction in the model, with the reference category being the control group. The models are adjusted for baseline ISI score and a random effect is fitted for practice. Therefore, these estimated treatment effects reflect difference in the change in ISI from baseline for each adherence category as compared to control.

All analyses were conducted using Stata (version 16.1).

Economic evaluation

A within-trial economic evaluation was performed to estimate the incremental cost-effectiveness of SRT over SH. Full details are described in Chapter 4 and a brief summary is presented here for continuity.

The cost–utility analysis was conducted from the recommended NHS and PSS perspective. Individual patient data on the use of health services were collected at 3, 6 and 12 months post randomisation as part of the follow-up data-collection process. We calculated the cost of delivering the SRT intervention, including preparation and training of nurses, and the cost of sending SH information to the control group. HRQoL was captured through the EQ-5D-3L at baseline and 3, 6 and 12 months post randomisation, and was used to calculate QALYs. Cost and QALYs were combined to calculate the incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB) statistics.

Process evaluation

We used a Framework approach to data analysis supported by QSR NVivo (version 10), with the framework based on the main areas of implementation, mechanisms of impact, and contextual factors together with the more detailed issues that arise from these.57 Full details of the methodology and analysis are provided in Chapter 5. Analysis began as soon as the initial interviews were transcribed, and interview schedules were applied flexibly so that qualitative data were collected iteratively, allowing themes that were identified in earlier interviews to be explored in later ones. We analysed qualitative process data prior to knowing trial outcomes to avoid biased interpretation. Analysis of quantitative data allowed us to ascertain the extent to which we sampled participants with differences in insomnia severity at baseline, and the integration of qualitative and quantitative data enabled us to link improvements in sleep (efficiency) to interview findings from patients and staff.

Patient and public involvement

Four people from the Healthier Ageing Public and Patient Involvement group, University of Lincoln, read and provided detailed comments on the original grant proposal, helping to shape key methodological choices. For example, the group recommended adding a patient-centred measure of quality of life and assessing long-term follow-up of sleep and daytime functioning outcomes. Two individuals, one with experience of insomnia and SRT, contributed during the conduct of the trial by reviewing the participant information sheet, consent form, therapy workbooks and questionnaire measures. They recommended amendments to improve the readability and accessibility of all participant-facing documents. They also advised on recruitment procedures and methods to engage prospective participants and retain enrolled participants, and were members of the Trial Steering Committee (TSC) who met every 6 months during the trial. They supported interpretation of findings and will advise on dissemination of findings once published.

Ethical approval

The trial received both Health Research Authority approval (IRAS: 238138) and ethical approval (Yorkshire and the Humber – Bradford Leeds REC, reference: 18/YH/0153).

Summary of changes to the project protocol

Table 3 summarises the key changes made to the protocol during the trial.